Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Mitochondria in skin health, aging, and disease

Abstract

The skin is a high turnover organ, and its constant renewal depends on the rapid proliferation of its progenitor cells. The energy requirement for these metabolically active cells is met by mitochondrial respiration, an ATP generating process driven by a series of protein complexes collectively known as the electron transport chain (ETC) that is located on the inner membrane of the mitochondria. However, reactive oxygen species (ROS) like superoxide, singlet oxygen, peroxides are inevitably produced during respiration and disrupt macromolecular and cellular structures if not quenched by the antioxidant system. The oxidative damage caused by mitochondrial ROS production has been established as the molecular basis of multiple pathophysiological conditions, including aging and cancer. Not surprisingly, the mitochondria are the primary organelle affected during chronological and UV-induced skin aging, the phenotypic manifestations of which are the direct consequence of mitochondrial dysfunction. Also, deletions and other aberrations in the mitochondrial DNA (mtDNA) are frequent in photo-aged skin and skin cancer lesions. Recent studies have revealed a more innate role of the mitochondria in maintaining skin homeostasis and pigmentation, which are affected when the essential mitochondrial functions are impaired. Some common and rare skin disorders have a mitochondrial involvement and include dermal manifestations of primary mitochondrial diseases as well as congenital skin diseases caused by damaged mitochondria. With studies increasingly supporting the close association between mitochondria and skin health, its therapeutic targeting in the skin—either via an ATP production boost or free radical scavenging—has gained attention from clinicians and aestheticians alike. Numerous bioactive compounds have been identified that improve mitochondrial functions and have proved effective against aged and diseased skin. In this review, we discuss the essential role of mitochondria in regulating normal and abnormal skin physiology and the possibility of targeting this organelle in various skin disorders.

Facts

  • Skin is the largest organ with high turnover rate in the human body.

  • Mitochondria play a vital role in the skin.

  • Mitochondrial dysfunction induces skin aging.

  • Skin disorders manifest mitochondrial dysfunction.

  • Targeting mitochondria may help rejuvenate skin.

Open Questions

  • How do mitochondria regulate skin aging?

  • Is mitochondrial dysfunction a primary or a secondary cause of skin aging?

  • Does targeting mitochondria prevent or slow down skin aging?

Introduction

The skin is the outer sheath of the body, which interfaces with the external environment. It is a complex structure made of several tissue layers, each with a distinct cellular composition. It has crucial functions like sensation, heat insulation and prevention of water loss, and acts as a physical barrier to pathogens. The upper layer of the skin is the epidermis, a stratified structure interspersed with hair follicles. The outer epidermal surface is made of cornified keratinocytes or corneocytes that form a dense cytoskeletal network of keratin filaments. At the same time, the basal layer harbors the epidermal stem and progenitor cells, which continuously regenerate the epidermis. The dermis lies underneath the epidermis and consists of dermal fibroblasts that produce collagen and elastin that form the extracellular matrix (ECM), as well as the melanocytes that produce the photo-protective pigment melanin1. With aging, both the epidermis and dermis undergo thinning and lose their regenerative capacity, which manifests as wrinkling, dryness, and mottling. Also, chronic exposure to environmental elements like ultraviolet (UV) radiations cause deleterious effects in the skin cells2. UVA and UVB radiation are not only associated with premature skin photo-aging but also various inflammatory reactions and skin cancer3.

The skin is a high turnover organ, with a continuously regenerating epidermis. The epidermal progenitors are thus highly proliferative and metabolically active and rely on adenosine triphosphate (ATP) for their energy requirements. ATP is mainly produced through oxidative phosphorylation (OXPHOS) in the mitochondrion, which is the bioenergetics center of the eukaryotic cell4. This double membrane-bound organelle is involved in essential functions like energy production, fatty acid oxidation (FAO), heme and steroid biosynthesis, apoptosis, and calcium signaling. Mitochondrial respiration utilizes a series of protein complexes located at the inner membrane, collectively known as the electron transport chain (ETC). These complexes sequentially transport electrons and translocate protons to the intermembrane space creating a proton gradient, which is utilized to generate ATP5 (Fig. 1). The natural by-products of OXPHOS include reactive oxygen species (ROS) such as superoxide anion, singlet oxygen and peroxides, which can disrupt macromolecular and cellular structures. Although ROS production can be triggered by external stimuli such as ionizing radiations and carcinogens, the generation of endogenous ROS is highest in the mitochondria6. The oxidative damage caused by mitochondrial ROS production is an essential molecular basis of various pathophysiological conditions, including aging and cancer7.

Fig. 1: Mitochondria in skin health.
figure1

Mitochondrion is a double-membrane organelle found in the cytoplasm of almost all eukaryotic cells. It is the site of cellular respiration and most ATP production. Mitochondrial respiration utilizes a series of protein complexes: complex I (NADH dehydrogenase), complex II (succinate dehydrogenase), complex III (cytochrome c reductase) and complex IV (cytochrome c oxidase) located in the inner mitochondrial membrane. These complexes sequentially translocate electrons (e) to create a proton gradient (H+). Complex V (ATP synthase) then makes use of this gradient to phosphorylate ADP to ATP.

Mitochondria are unique organelles that possess a maternally inherited autonomous genome. The mitochondrial DNA (mtDNA) encodes for 13 OXPHOS proteins, in addition to 22 tRNAs and two rRNAs8 (Fig. 2). Due to their physical proximity to the ETC and therefore, ROS, mtDNA is highly susceptible to mutations, which invariably disrupt OXPHOS, thus triggering a vicious cycle of increased ROS production and mtDNA damage9. Somatic mutations in mtDNA are often observed in various diseases, including cancer. Besides, mtDNA exists as multiple copies, and studies have associated abnormal copy numbers with different pathophysiological states10. Some mtDNA mutations or single nucleotide polymorphisms (SNPs) can persist in a population, giving rise to haplogroups with distinct geographical distribution; at present, around 27 major mitochondrial haplogroups are known, and many have been correlated with a higher risk of cancers and other diseases, including those of the skin11.

Fig. 2: Mitochondrial OXPHOS subunit composition.
figure2

Schematic representation of mammalian respiratory chain complex. The ETC consists of five complexes, with subunits encoded by both mtDNA (yellow) and nuclear DNA (red). The human mtDNA genome encodes only 13 OXPHOS proteins, while the nuclear DNA encodes the remaining 80% of the OXPHOS proteins.

Recent studies have established an essential role of the mitochondria in skin homeostasis, as well as disorders such as cancer, inflammatory conditions, and rare inherited diseases. The mechanistic basis of mitochondrial dysfunction in the skin and other organs, is primarily ROS production and oxidative stress, although other mitochondrial pathways have also been linked with certain skin disorders (Fig. 3). In this review, the essential role of mitochondria in regulating normal skin physiology, as well as in healthy/premature skin aging and skin cancers, have been discussed. Also, the therapeutic targeting of mitochondria in various skin disorders has been considered.

Fig. 3: Consequences of mitochondrial dysfunction.
figure3

Mitochondrial dysfunction is accompanied by enhanced ROS production, reduced antioxidant defense mechanism, altered cellular respiration, altered metabolism, and enhanced cell death.

Role of mitochondria in skin homeostasis

Mitochondria-dependent epidermal differentiation

The epidermis is a self-renewing layer that depends on the subsequent differentiation and migration of the proliferative basal keratinocytes to the cornified keratinocytes in the outermost squamous layer12. Studies increasingly show that mitochondrial ROS generation plays a regulatory role in the differentiation of various cell lineages via several downstream transcriptional factors like C/EBP, Notch, and β-catenin, and increased ROS levels promote differentiation of murine embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs), as well as tissue-specific multipotent epithelial stem cells13. Hamanaka et al.14 found that conditional mitochondrial transcription factor A (TFAM)-knockout mice had a high neonatal mortality rate due to impaired epidermal barrier function and lacked normal fur. Also, primary keratinocytes isolated from these mice failed to differentiate in vitro. Since TFAM drives mtDNA replication and cells lacking TFAM have defective OXPHOS and low ROS levels, it is reasonable to surmise that mitochondrial respiration and ROS production are essential for keratinocyte differentiation. Indeed, antioxidant treatment of wild-type keratinocytes blocked their differentiation, while exogenous administration of H2O2 restored the same in TFAM−/− keratinocytes. Further mechanistic analysis revealed that mROS promoted epidermal differentiation by activating the Notch and β-catenin signaling cascades. Besides, low levels of H2O2 generated in the skin fibroblasts exposed to physiological doses of UVB rays activated the keratinocyte growth factor receptor and promoted keratinization.

Mitochondrial respiration also requires Ca2+ uptake, and a Ca2+ gradient has been observed in the epidermis in vivo15. Keratinocyte differentiation in vitro is enhanced by increasing Ca2+ levels, whereas the opposite effects are seen upon inhibiting mitochondrial calcium uptake16. In a recent study, Bhadhuri et al.17 used the gene network-based bioinformatics approach to screen for hub proteins involved in epidermal differentiation and identified the mitochondrial proteins MPZL3 and FDXR. Functional analyses further showed that the proteins co-localized proximally in the keratinocyte mitochondria and promoted their differentiation by inducing ROS generation. Interestingly, depletion of the myelin protein zero-like 3 (MPZL3) is associated with dermatitis and alopecia in mice, and the ETC enzyme ferredoxin reductase (FDXR) sensitizes various human epithelial cell lines to ROS-induced apoptosis. Allombert-Blasie et al.18 showed that the terminal differentiation of keratinocytes was accompanied by the activation of the mitochondrial caspase-dependent apoptotic pathway

The melatonin-mitochondria axis in the skin

Melatonin (N1-acetyl-5-methoxytryptamine) is a neuro-hormone secreted by the pineal gland that regulates the circadian rhythm in mammals. It is also synthesized in other organs like the retina, cochlea, lungs, liver, kidney, immune system, and the skin, and its levels are tightly regulated by both hepatic and epidermal metabolism19. It has a pivotal photo-protective role in the cutaneous tissues, in addition to regulating wound healing, pigmentation, inflammation, and immune responses. Melatonin and its metabolites directly act on skin cells expressing the G protein-coupled melatonin type (MT) 1 and 2 receptors following UV or X-ray exposure, and attenuate macromolecule damage by scavenging the radiation-induced free radicals20. Pharmacological doses of melatonin protect keratinocytes and melanocytes from UVB-induced damage in vitro21. Full-thickness human skin histo-cultured ex vivo showed significantly lower levels of the DNA damage marker 8-hydroxy-2′-deoxyguanosine (8-OHdG) following UV exposure when pre-treated with melatonin22. Apart from direct scavenging of ROS like H2O2, singlet oxygen, and NO, melatonin and its derivatives also protect the skin cells from radiation damage by increasing the activity of antioxidant enzymes22,23. Interestingly, high levels of endogenous melatonin have been detected in human and rodent skin cells, including melanocytes, keratinocytes, and epithelial cells, in addition to the enzymes involved in melatonin synthesis and metabolism19.

The potent radio-protective and antioxidant role of melatonin in the skin raises the possibility of mitochondrial involvement. Indeed, studies have increasingly pointed to a “symbiotic” relationship between melatonin and epidermal mitochondria, with the latter serving as the site of cutaneous melatonin biosynthesis and metabolism. In contrast, melatonin has regulatory effects on the mitochondrial ETC and antioxidant machinery. Melatonin is metabolized in the mitochondria via the cytochrome c and H2O2-dependent kynurenic pathway, and the cytochrome P450-dependent indolic pathway19,24. The primary metabolites of melatonin include N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), 6-hydroxylmelatonin, and N-acetylserotonin, which accumulate in the epidermis following UVB exposure in a dose-dependent manner19. A melatonin biosynthetic machinery may also be present in the mitochondria since oocyte mitochondria can synthesize melatonin from serotonin in a cell-free system25. It remains to be elucidated whether cutaneous mitochondria also have a similar function. Melatonin can directly increase the electron flux through the respiratory chain and enhance ATP production by donating electrons. One study showed that 6-hydroxymelatonin promoted electron transfer from complex III to complex IV (cytochrome c oxidase), which may help restore the age-dependent decline in mitochondrial bioenergetics. Besides, melatonin mediates the reduction of cytochrome c and augments H2O2 scavenging26.

The intracellular Ca2+ homeostasis-regulating protein complex calmodulin also binds to melatonin, indicating the role of the latter in mitochondrial functions like autophagy and apoptosis as well27. One study showed that topical application of melatonin improved the barrier function of the epidermis by increasing keratinocyte proliferation28. It can also accelerate wound healing and augment the effects of antimicrobials29. Given that ROS production also plays a role in tissue repair and regeneration30, the melatonin-mitochondrial axis may also be the driver of epidermal wound healing.

Mitochondrial role in skin aging

In addition to the inevitable time-induced changes, the skin is also highly susceptible to photo-aging due to chronic exposure to solar UVA and UVB radiations2. Aging affects the protective role of the skin against physicochemical and biological attacks, as well as its thermoregulatory, sensory, immunological, and hormonal functions. The structural and functional manifestations of cutaneous aging are premature and more severe in the photo-aged compared to the chronologically aged skin. Furthermore, since photoaging is a cumulative process, it is more pronounced among older individuals who have been regularly exposed to the sun for long periods. Both intrinsic and environmental factors affect the epidermal and dermal layers of the skin. Histologically, chronological aging is characterized by significant epidermal thinning, which manifests as dryness and wrinkles1.

In contrast, photo-aged skin has a thick, leathery appearance with deeper wrinkles and uneven pigmentation31. Several studies have directly or indirectly linked mitochondrial dysfunction to both chronological and photo-aging of the skin32. At the molecular levels, aged skin is characterized by damaged mitochondria, mtDNA deletions, high ROS levels, and oxidative stress in both the dermal and epidermal layers (Fig. 4).

Fig. 4: Mitochondria in skin aging.
figure4

a Skin aging categories: Intrinsic (internal) aging and extrinsic (external) aging. b Skin aging is characterized by loss of membrane potential, elevated levels of ROS, DNA damage leading to nuclear and mitochondrial gene mutations, respiratory chain defect due to enzyme alterations, altered cellular regulation, and disease progression.

Chronological skin aging

Mutations and deletions in mtDNA are known to accumulate in post-replicative tissues with aging, which is accompanied by a steady decline in mitochondrial function33, increased ROS production, and loss of mitochondrial membrane potential (MMP), followed by increased mitophagy, and apoptosis. A 4977 base pairs extended region of mtDNA, including the genes encoding complexes I, IV, and V of the respiratory chain, is frequently deleted in the aged human skin34. This “common deletion” is more evident in the skin of individuals older than 70 years and increases with sun exposure34. Kaneko et al.35 compared the neck skin samples of German and Japanese women and found a general increase in the frequency of the common deletion with age, and in sun-exposed versus photo-protected skin. Besides, a strong positive correlation was observed between the density of common deletion and skin wrinkles among the Japanese women, while the higher frequency of common deletion correlated with fewer pigmented lesions among the German women. The latter also showed a slightly higher amount of the common deletion compared to Japanese women, which may be due to intrinsic genetic variations, or different cultural attitudes towards sun exposure. In a recent study, Singh et al.36 established an inducible mtDNA-depletion mouse model with a dominant-negative mutation in the mtDNA polymerase POLG1. The mice had ubiquitous mtDNA depletion and correspondingly reduced OXPHOS. The phenotypic manifestations included extensive skin wrinkling and fur loss, which in turn were associated with epidermal hyperplasia and hyperkeratosis. The transgenic mice had increased levels of matrix metalloproteinases that are often increased during skin aging. Interestingly, turning off the mutant POLG1 expression restored the cutaneous pathologies to the wild-type level. This study is the first to prove that mtDNA depletion is the underlying cause of skin aging and that restoring mitochondrial functions can restore skin youthfulness.

The age-dependent accumulation of ROS in the keratinocytes, and the concomitant loss of MMP, results in a metabolic shift from OXPHOS to the anaerobic glycolysis. Prahl et al.37 isolated keratinocytes from skin biopsies of old and young donors and found a distinctly glycolytic phenotype of the older keratinocytes, and addition of the ETC component coenzyme (Co) Q10 restored mitochondrial metabolism in the aged cells. Consistent with this, an age-related decline in complex II (succinate oxidoreductase) activity has also been observed in aged human skin fibroblasts38. Damaged mitochondria are cleared away by a highly conserved pathway called mitophagy, or the selective autophagy of mitochondria39. Mitophagy levels increase considerably after cellular stress or damage, and homeostasis between mitochondrial biogenesis and mitophagy is vital for a healthy mitochondria pool. Aymard et al.40 demonstrated a critical role of autophagy and mitophagy in keratinocyte differentiation, which also raises the possibility of mitochondrial fragmentation in aged keratinocytes owing to the increase in ROS levels with aging and elevated mitochondrial fission in response to oxidative stress. Recently, Mellem et al.41 studied the mitochondrial network in young and old human skin for the first time in vivo and found significantly fewer mitochondrial clusters in the keratinocytes. A highly connected physical network of mitochondria in the epidermal cells of the younger compared to the older skin. The latter had a significantly fragmented mitochondrial network, indicating poor recycling and excessive mitophagy. The similarities in mitochondrial dynamics in normal differentiation and aging could either be due to common pathways that are dysregulated during aging or simply due to the aging-related reduced epidermal turnover42.

Coenzyme Q (CoQ10) is a lipophilic isoprenylated quinone that acts as an electron shuttle between complex I/II and complex III of the ETC, and as a ROS scavenger that protects against membrane lipid oxidation43. Both the antioxidant and bioenergetic roles of CoQ10 are closely associated with skin aging and other disorders. CoQ10 levels are 10-fold higher in the epidermis compared to the dermis and decrease significantly with age. Reduced CoQ10 content in aged dermal fibroblasts is associated with lower activity of the complexes I/III and II/III, membrane depolarization, and generation of superoxide anions44. Furthermore, several studies have shown that topical application of CoQ10 on photo-aged skin ameliorates the phenotypic signs of aging and restores mitochondrial function45. The age-related glycolytic shift reported by Prahl et al.37 in the human keratinocytes was also associated with impaired CoQ10 function and was reversed by its exogenous application. CoQ10 is synthesized de novo by the mevalonate pathway and can be inhibited by 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors like statins. Marcheggiani et al.46 recently showed that statin mediated CoQ10 inhibition in human dermal fibroblasts triggered oxidative stress and mitochondrial dysfunction, and lead to premature “aging” of the cells in vitro.

Photo-aging

Chronic UV exposure induces nuclear and mitochondrial DNA damage and oxidative stress in the skin cells, which can progress to photo-aging and or skin cancer. UVB mainly acts on the epidermal keratinocytes and melanocytes, while UVA can penetrate more deeply into the dermis47. A cardinal marker of photo-aging, which is relatively less obvious in chronological aging is large-scale mtDNA deletion. Berneberg et al.48 reported a 10-fold higher rate of a 5000 bp deletion in the mtDNA of photo-aged compared to sun-protected skin cells. In a later study, the same group49 found that repeated exposure of the normally unexposed buttock skin to UVA increased the frequency of mtDNA deletions in the dermal cells by 40% compared to the non-irradiated skin.

Interestingly, these UV-induced deletions can persist over many years and can increase by 30–40 folds even in the absence of further irradiation47,48. UVA/B exposure, however, is not homogenous across the entire epidermis, since some parts of the body are more frequently exposed to the sun than others. Krishnan et al.50 observed a significantly higher frequency of a 3895 bp mtDNA deletion block in habitually exposed areas of the skin compared to the less exposed regions. In a recent study by Powers et al.51 an unusually high rate of the common mtDNA deletion (4977 bp) and a 3895-bp deletion was observed in the sun-exposed skin biopsies of elderly individuals that were diagnosed negative for any skin cancer.

Repeated exposure to sub-lethal doses of UVA resulted in mtDNA deletions in primary human keratinocytes52 and dermal fibroblasts, which was accompanied by decreased mitochondrial function, increased activity of collagen-degrading enzymes53 and oxidative stress, which further exacerbated the mitochondrial damage54. Schroeder et al.55 generated mtDNA-depleted human skin fibroblast lines. They found that in addition to aberrantly high oxidative stress, these cells showed the typical molecular features of photo-aged skin, such as increased levels of collagen degrading metalloproteases (MMPs) and downregulation of the genes involved in collagen biosynthesis45, which translates to the extensive wrinkling of photo-aged skin31. This is consistent with the hypothesis of altered collagen metabolism in photo-aging, first proposed by Fisher et al.46. Furthermore, skin fibroblasts isolated from patients with Kearns–Sayre syndrome (KSS), a rare inherited disorder characterized by extensive mtDNA deletions, showed higher ROS levels and increased activity of photo-aging-related genes56. Oyewole et al.57 compared the protective effects of mitochondria-specific antioxidants and cellular antioxidants (resveratrol and curcumin) against UVA-induced mtDNA damage in human dermal fibroblasts. They detected significantly higher photo-protection by the former. These findings collectively indicate that UV-induced photo-aging is directly linked to mtDNA depletion and that the phenotypic features of photo-aged skin are the result of mitochondrial dysfunction and ECM degradation.

In addition to the UV radiation, infrared (IR) rays have also been associated with photo-aging of human skin. Schieke et al.58 showed that exposure to IR dysregulated the expression of metalloproteases in primary human fibroblasts. Similar changes were observed in situ in human skin exposed to IR54, while chronic exposure to IR also resulted in the typical clinical signs of photo-aging in animal models59. Schauen et al.60 detected a significant increase in the intra-mitochondrial levels of ROS in primary human skin fibroblasts exposed to IR, indicating a direct role of the mitochondria in IR-induced photo-aging. Consistent with this, treatment of IR-exposed human fibroblasts with either an antioxidant or an ETC inhibitor reversed the signs of photo-aging61. The underlying mechanism of IR-induced mitochondrial damage was elucidated by Karu et al.62 who showed that the IR rays are absorbed by the copper atoms of ETC complex IV, leading to disturbed electron flow and ‘leakage,’ and increased ROS production.

Mitochondrial perturbations, such as mtDNA mutations/deletions, loss of MMP, and the uncoupling of the OXPHOS machinery induces mito-nuclear retrograde signaling. The effect of retrograde signaling is a global alteration in nuclear gene expression, which leads to metabolic shift, apoptosis, and mitophagy. In recent years, retrograde mitochondrial signaling has been directly linked with various pathological states. In the context of photo-aging, retrograde mitochondrial signaling alters the expression of nuclear genes involved in collagen biosynthesis and degradation, inflammation, and neovascularization, all of which contribute to the appearance of the photo-aged skin61. The presence of oxidized proteins in the upper dermal layers of photo-damaged skin lends support to this hypothesis63.

While chronological aging is associated with a 10–20% decrease in melanin production per decade, chronic UV exposure increases the amount of this photo-protective pigment, resulting in the typical “mottled” appearance of photo-aged skin64. Melanocytes are highly susceptible to oxidative damage since melanogenesis is pro-oxidative and have higher basal levels of ROS compared to other cell types. Melanocytes from UV-exposed skin show an increase in ROS and melanin levels compared to the cells isolated from normal skin. While endogenous melanin is known to protect melanocytes from photo-oxidative damage by absorbing the UV rays, chronic UV exposure can lead to melanin oxidation, which in turn increases ROS levels and further aggravates the oxidative damage. There is evidence indicating that the melatonin-regulated cutaneous circadian clock also controls melanogenesis in the human epidermis and cultured fibroblasts65.

Mitochondrial role in skin cancer

Skin cancer is the most common malignancy affecting humans and accounts for 40% of all cancer cases worldwide. It is classified into the non-melanoma skin cancers (NMSCs) that include basal-cell carcinoma (BCC) and squamous cell carcinoma (SCC), and the melanocyte-derived melanomas. Although the latter comprise only 5% of all skin cancer cases, they are associated with a significant mortality rate of 25% as well as metastasis risk66. Skin cancer risk is linked to UV radiation, and the incidence of all skin cancer types have significantly increased in the last 2–3 decades due to increased exposure to UV rays, both due to the thinning ozone layer and frequent use of tanning beds. The risk of developing skin cancer, especially malignant melanoma, is also higher in the Caucasian population on account of their lower cutaneous melanin content67. Mitochondria have been implicated in almost all human cancers, primarily on account of their role in ROS generation and apoptosis. Congenital and somatic mutations in mtDNA have been detected in most tumors, including those affecting the skin68,69,70, and tumorigenic stimuli such as radiation and carcinogens are known to damage the mtDNA directly71,72,73,74,75. Furthermore, mounting evidence suggests that mitochondria are involved in the interplay between oxidative stress, hypoxia76,77,78,79,80,81, and metabolic reprogramming of tumor cells82,83,84,85,86.

Mitochondrial involvement in other skin conditions

In addition to skin aging and cancer, mitochondrial dysfunction has also been associated with various common and rare skin disorders that can be broadly classified into three types: dermal manifestations of primary mitochondriopathies, skin diseases due to mitochondrial dysfunction, and cutaneous manifestations of genetic diseases that affect mitochondria. Clinically, these disorders can be present as hair abnormalities, inflammation, rashes, hypo- and hyperpigmentation, and acrocyanosis (i.e., blueness of extremities). The underlying molecular mechanisms have been identified for most, and mainly involve dysfunctional OXPHOS and high ROS generation, mutations in mtDNA, an imbalance between mitochondrial biogenesis and mitophagy, and aberrant expression levels of nuclear-encoded mitochondrial proteins. In addition, dysregulation in other mitochondrial metabolic pathways and structural proteins have also been implicated. The entire gamut of skin diseases with direct or indirect mitochondrial involvement has been summarized in a recent review by Feichtlinger et al.87 (Fig. 5 and Table 1).

Fig. 5: Skin disorders caused by mutations in mtDNA encoding mitochondrial proteins.
figure5

Skin disorders are a heterogeneous group of diseases caused by mutations in mitochondrial (this figure) and nuclear DNA (Table 1).

Table 1 Skin disorders caused by mutations in nuclear DNA affecting mitochondrial functions.

Skin manifestations of congenital mitochondriopathies

Although congenital mitochondrial diseases are primarily neuro-musculopathies, various organs are dependent on mitochondrial respiration and therefore affected by organelle dysfunction. Several reports have surfaced over the years regarding the cutaneous involvement of mitochondrial syndromes, although the results are heterogeneous and lack consensus. Bodemer et al.88 observed 14 children with assorted mitochondria-related disorders (e.g., myopathies, Leigh syndrome, deafness, Wolfram syndrome, hypotonia, Pearson syndrome, etc.), and detected specific skin and hair abnormalities like alopecia, brittle hair, rashes, mottled pigmentation, erythematous lesions, acrocyanosis, hypertrichosis, etc. Abnormal OXPHOS was confirmed using cultured skin fibroblasts from all patients, with abnormal ETC protein expression in 3 cases and mtDNA aberrations in one case. The authors surmised that a mitochondriopathy should be considered if sudden and unexplained cutaneous signs manifest along with an unrelated disorder. Sonam et al.89 assessed 25 children with Leigh syndrome, a neuro-metabolic disorder involving both mitochondrial and nuclear mutations, and observed hypertrichosis and hypopigmentation in most patients. Two mtDNA mutations—T3271C and A3243G—in the MELAS syndrome are associated with nail disorders90. Hypomelanosis has also been observed in some cases of Kearns–Sayre syndrome, a multi-organ mitochondrial disorder characterized by large mtDNA deletions91. Alper’s syndrome is a rare, autosomal recessive neurological disorder caused by mutation(s) in the POLG1 gene. Campuzano-García et al.92 reported a case of a 10-month-old boy with Alpers syndrome in Mexico (2015) that showed hyperpigmented macules with hypochromic centers in the skin folds of the armpits, groin, and foot dorsum. The rashes were bilateral and mostly concentrated over the dorsal regions. AlSaman et al.93 reported a case of a hypotonic 12-month old infant in Saudi Arabia with mtDNA depletion syndrome (MDS) who also showed sparse and brittle hair, scaly skin, eczema, and reticular pigmentation.

The Hutchinson–Gilford progeria syndrome (HGPS) is a very rare congenital disease caused by a dominant mutation in the lamin A gene, which encodes for a structural protein that maintains mitochondrial shape. The cutaneous symptoms of HGPS include hair loss (alopecia), extensive skin wrinkling, and loss of subcutaneous fat that further lends an aged appearance. A recent study on a progeroid patient in Bangladesh reported novel maternally inherited mtDNA mutations, especially in the D-loop region94, which correlates with reduced OXPHOS and mitochondrial dysfunction seen in dermal fibroblasts isolated from HGPS patients95.

Skin diseases caused by mitochondrial dysfunction

Several skin diseases are associated with mutations in mitochondrial proteins encoded by mitochondrial or nuclear genes or other aberrations in mtDNA that lead to disrupted OXPHOS, excessive ROS generation, mitochondrial fragmentation, which directly results in the cutaneous symptoms. For instance, non-epidermolytic palmoplantar keratoderma (NEPPK) is associated with the A7445G mutation in mtDNA, which affects the ETC complex IV subunit 1, and decreases cellular respiration96. Dupuytren’s disease, a maternally inherited condition characterized by abnormal thickening of the skin of the hands, is caused by a mutation in mtDNA 16S rRNA97. The molecular basis of several skin diseases is reduced mitochondrial respiration due to mutations in the nuclear genes encoding OXPHOS proteins. For instance, mutations in the complex IV-encoding nuclear gene COX7B is responsible for the rare autosomal dominant aplasia cutis congenita (APLCC), which is typified by the congenital absence of the epidermis98. Besides, a defective complex III due to mutated BC1 (ubiquinol–cytochrome c reductase) synthesis-like protein is the genetic basis of the Bjornstad syndrome, an autosomal recessive disease characterized by twisted hair shaft and brittle hair99. The iron-porphyrin complex heme is essential for cytochrome c function, and the heme synthesis pathway involves both nuclear and mitochondrial proteins. Mutations in genes encoding for heme biosynthesis enzymes often result in photosensitivity and skin inflammatory conditions like dermatitis100. The Krebs cycle provides essential metabolites for heme synthesis, and its disruption has been linked with alopecia and pigmented rashes. Epidermolysis bullosa simplex (EBS), a unique skin condition characterized by recurrent epidermal blistering following minor abrasions or bruises, is caused by mutations in the Plec1 gene that encodes for the outer mitochondrial membrane protein plectin. Plec1 mutations not only result in abnormally shaped mitochondria but also complex I and complex IV inhibition101. Mutations in the mitochondrial pyrroline-5-carboxylate reductase 1 protein result in extensive fragmentation of the mitochondrial network, which is the genetic basis of autosomal recessive cutis laxa type IIB (ARCL2B), a progeroid skin syndrome characterized by wrinkled and sagging skin102.

Skin manifestations of genetic diseases affecting the mitochondria

Mutations in DNA repair genes indirectly lead to mitochondrial dysfunction due to the accumulation of defective mtDNA and form the genetic basis of multiple congenital disorders with skin involvement. For instance, the Rothmund–Thomson syndrome, which presents cutaneous symptoms like sparse eyebrows and eyelashes, is caused by a mutated helicase RecQ protein-like 4 (RECQL4). The absence of RECQL4 is associated with the accumulation of mtDNA damage and a compensatory increase in mtDNA copy number103. Mutations in the RECQL2 ligase are known to increase mitochondrial ROS production and are the cause of Werner syndrome, a rare autosomal recessive adult progeria with considerable skin involvement104. The genetic basis of the neurodegenerative disorder ataxia-telangiectasia (AT) is the loss of the AT mutated (ATM) gene, which is the master regulator of the DNA damage response. There is significant heterogeneity in its symptoms, and some affected individuals show premature graying of hair, vitiligo, blotchy pigmentation, and inflamed granulomatous lesions. Lack of the ATM gene not only causes massive genomic instability but also impairs mtDNA repair, resulting in reduced OXPHOS and increased mitophagy105. There is strong evidence linking aging-associated telomere shortening and impaired mitochondrial metabolism. Dyskeratosis congenita (DKC) is a progressive dermatological condition characterized by premature graying and wrinkling, nail dystrophy, and abnormal pigmentation, and caused by mutations in the telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT) genes106,107. Although there is no direct evidence, the significant increase in oxidative stress in cells harboring the above mutations indicate mitochondrial involvement. In addition to impaired mtDNA repair, autoantibodies against mitochondrial proteins (mtABs) also result in mitochondrial dysfunction. High levels of mtABs against multiple mitochondrial proteins have been detected in autoimmune skin disorders like systemic lupus erythematosus (SLE) and pemphigus vulgaris108,109. Consistent with this, keratinocytes isolated from pemphigus vulgaris patients show increased ROS levels and impaired OXPHOS110.

Mitochondrial targeting for skin regeneration

Therapeutic targeting of mitochondria in the skin involves either boosting ATP production or scavenging the excess amounts of free radicals. For instance, numerous studies have demonstrated the anti-aging effects of CoQ10 on cultured human dermal fibroblasts44. It is a critical ingredient in many anti-aging and regenerative skin creams, and as shown by Knott et al.111 topical application of two different CoQ10-containing formulas significantly replenished the levels of this antioxidant in the dermal and epidermal layers of older skin (>60 years). Photo-stressed skin benefitted from CoQ10 application on account of reduction in in situ free radical levels. Schniertshauer et al.112 further showed that CoQ10 could restore ATP production, prevent mitophagy, and alleviate oxidative stress in aged skin cells. Nicotinamide, also known as Vitamin B3 or niacinamide, is the precursor of NAD+, which is required for mitochondrial ATP production. The deficiency of nicotinamide causes pellagra, which is characterized by photosensitive dermatitis. The topical application of nicotinamide has shown anti‐inflammatory effects against rosacea, acne, autoimmune skin conditions, and hyperpigmentation. It is a popular additive in “high-end” formulations for regenerating aged and sun-damaged skin113. Vitamin C or ascorbic acid is a potent antioxidant that is used in various anti-wrinkle creams to increase collagen synthesis, and topical application of 10% Vitamin C reversed UV-induced oxidative damage by scavenging ROS114. There is evidence that resveratrol directly improves mitochondrial function in various cell types by increasing organelle biogenesis and attenuating ROS production115. In addition to cosmetic problems, the treatment of inflammatory and other serious skin diseases also involves mitochondrial targeting. For instance, the anti-inflammatory glucocorticoids that are used to treat SLE and pemphigus vulgaris increase mitochondrial membrane potential at low doses but reduce mitochondrial function at high doses116. Taken together, bioactive compounds targeting the mitochondria have proved effective against age-related as well as UV-induced skin damage, in addition to different skin diseases with mitochondrial involvement.

References

  1. 1.

    Rittié, L. & Fisher, G. J. Natural and sun-induced aging of human skin. Cold Spring Harb. Perspect. Med. 5, 1 (2015).

    Article  CAS  Google Scholar 

  2. 2.

    Fisher, G. J. et al. Mechanisms of photoaging and chronological skin aging. Arch. Dermatol. 138, 1462–1470 (2002).

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    D’Orazio, J., Jarrett, S., Amaro-Ortiz, A. & Scott, T. UV radiation and the skin. Int. J. Mol. Sci. 14, 12222–12248 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  4. 4.

    Cooper, G. M. The Cell: A Molecular Approach. The Mechanism of Oxidative Phosphorylation 2nd edn, (Sinauer Associates, Sunderland, MA, 2000).

  5. 5.

    Detmer, S. A. & Chan, D. C. Functions and dysfunctions of mitochondrial dynamics. Nat. Rev. Mol. Cell Biol. 8, 870–879 (2007).

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Murphy, M. P. How mitochondria produce reactive oxygen species. Biochem. J. 417, 1–13 (2009).

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Kirkinezos, I. G. & Moraes, C. T. Reactive oxygen species and mitochondrial diseases. Semin Cell Dev. Biol. 12, 449–57 (2001).

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Taanman, J. W. The mitochondrial genome: structure, transcription, translation and replication. Biochim. Biophys. Acta 1410, 103–23 (1999).

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Neiman, M. & Taylor, D. R. The causes of mutation accumulation in mitochondrial genomes. Proc. Biol. Sci. 276, 1201–1209 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. 10.

    Taylor, R. W. & Turnbull, D. M. Mitochondrial DNA mutations in human disease. Nat. Rev. Genet. 6, 389–402 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Bussard, K. M. & Siracusa, L. D. Understanding Mitochondrial Polymorphisms in Cancer. Cancer Res. 77, 6051–6059 (2017).

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Adams, J. C. & Watt, F. M. Changes in keratinocyte adhesion during terminal differentiation: reduction in fibronectin binding precedes alpha 5 beta 1 integrin loss from the cell surface. Cell 63, 425–435 (1990).

    CAS  PubMed  Article  Google Scholar 

  13. 13.

    Lisowski, P., Kannan, P., Mlody, B. & Prigione, A. Mitochondria and the dynamic control of stem cell homeostasis. EMBO Rep. 19, 45432 (2018).

    Article  CAS  Google Scholar 

  14. 14.

    Hamanaka, R. B. et al. Mitochondrial reactive oxygen species promote epidermal differentiation and hair follicle development. Sci. Signal. 6, 261 (2013).

    Article  CAS  Google Scholar 

  15. 15.

    Elias, P., Ahn, S., Brown, B., Crumrine, D. & Feingold, K. R. Origin of the epidermal calcium gradient: regulation by barrier status and role of active vs passive mechanisms. J. Invest. Dermatol. 119, 1269–74 (2002).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Pillai, S., Bikle, D. D., Mancianti, M. L., Cline, P. & Hincenbergs, M. Calcium regulation of growth and differentiation of normal human keratinocytes: modulation of differentiation competence by stages of growth and extracellular calcium. J. Cell Physiol. 143, 294–302 (1990).

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Bhaduri, A. et al. Network analysis identifies mitochondrial regulation of epidermal differentiation by MPZL3 and FDXR. Dev. Cell. 35, 444–57 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Allombert-Blaise, C. et al. Terminal differentiation of human epidermal keratinocytes involves mitochondria- and caspase-dependent cell death pathway. Cell Death Differ. 10, 850–852 (2003).

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Slominski, A. T. et al. Melatonin, mitochondria, and the skin. Cell Mol. Life Sci. 74, 3913–3925 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Slominski, R. M., Reiter, R. J., Schlabritz-Loutsevitch, N., Ostrom, R. S. & Slominski, A. T. Melatonin membrane receptors in peripheral tissues: distribution and functions. Mol. Cell Endocrinol. 351, 152–166 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  21. 21.

    Kleszczynski, K., Tukaj, S., Kruse, N., Zillikens, D. & Fischer, T. W. Melatonin prevents ultraviolet radiation-induced alterations in plasma membrane potential and intracellular pH in human keratinocytes. J. Pineal Res. 54, 89–99 (2013).

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Fischer, T. W., Kleszczynski, K., Hardkop, L. H., Kruse, N. & Zillikens, D. Melatonin enhances antioxidative enzyme gene expression (CAT, GPx, SOD), prevents their UVR-induced depletion, and protects against the formation of DNA damage (8-hydroxy-2′-deoxyguanosine) in ex-vivo human skin. J. Pineal Res. 54, 303–312 (2013).

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Kilanczyk, E. & Bryszewska, M. The effect of melatonin on antioxidant enzymes in human diabetic skin fibroblasts. Cell Mol. Biol. Lett. 8, 333–336 (2003).

    CAS  PubMed  Google Scholar 

  24. 24.

    Reiter, R. J. et al. Melatonin Mitigates Mitochondrial Meltdown: Interactions with SIRT3. Int. J. Mol. Sci. 19, 2439 (2018).

    PubMed Central  Article  CAS  Google Scholar 

  25. 25.

    He, C. et al. Mitochondria synthesize melatonin to ameliorate its function and improve mice oocyte’s quality under in-vitro conditions. Int. J. Mol. Sci. 17, 939 (2016).

    PubMed Central  Article  CAS  Google Scholar 

  26. 26.

    Reiter, R. J. et al. Mitochondria: central organelles for melatonin’s antioxidant and anti-aging actions. Molecules 23, 509 (2018).

    PubMed Central  Article  CAS  Google Scholar 

  27. 27.

    Fernández, A., Ordóñez, R., Reiter, R. J., González-Gallego, J. & Mauriz, J. L. Melatonin and endoplasmic reticulum stress: relation to autophagy and apoptosis. J. Pineal Res. 59, 292–307 (2015).

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Kim, T. K. et al. Metabolism of melatonin and biological activity of intermediates of melatoninergic pathway in human skin cells. FASEB J. 27, 2742–55 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Romić, M. D. et al. Melatonin-loaded chitosan/Pluronic® F127 microspheres as in situ forming hydrogel: an innovative antimicrobial wound dressing. Eur. J. Pharm. Biopharm. 107, 67–79 (2016).

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Kimmel, H. M., Grant, A. & Ditata, J. The presence of oxygen in wound healing. Wounds 28, 264–70 (2016).

    PubMed  Google Scholar 

  31. 31.

    Krutmann, J., & Gilchrest, B. A. Photoaging of skin. In: Skin Aging (eds Gilchrest, B. A. & Krutmann, J.) 33-43. (Springer, New York 2006).

  32. 32.

    Krutmann, J. & Schroeder, P. Role of mitochondria in photoaging of human skin: the defective powerhouse model. J. Investigative Dermatol. Symp. Proc. 14, 44–49 (2009).

    CAS  Article  Google Scholar 

  33. 33.

    Richter, C. Oxidative damage to mitochondrial DNA and its relationship to ageing. Int. J. Biochem. Cell Biol. 27, 647–53 (1995).

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Yang, J. H., Lee, H. C. & Wei, Y. H. Photoageing-associated mitochondrial DNA length mutations in human skin. Arch. Dermatol. Res. 287, 641–8 (1995).

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Kaneko, N. et al. Mitochondrial common deletion mutation and extrinsic skin ageing in German and Japanese women. Exp. Dermatol. 21, 26–30 (2012).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Singh, B., Schoeb, T. R., Bajpai, P., Slominski, A. & Singh, K. K. Reversing wrinkled skin and hair loss in mice by restoring mitochondrial function. Cell Death Dis. 9, 735 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  37. 37.

    Prahl, S. et al. Aging skin is functionally anaerobic: importance of coenzyme Q10 for anti-aging skin care. Biofactors 32, 245–55 (2008).

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    Bowman, A. & Birch-Machin, M. A. Age-dependent decrease of mitochondrial complex II activity in human skin fibroblasts. J. Invest. Dermatol. 136, 912–919 (2016).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Lemasters, J. J. Selective mitochondrial autophagy, or mitophagy, as a targeted defense against oxidative stress, mitochondrial dysfunction, and aging. Rejuvenation Res. 8, 3–5 (2005).

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Aymard, E. et al. Autophagy in human keratinocytes: an early step of the differentiation? Exp. Dermatol. 20, 263–8 (2011).

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Mellem, D. et al. Fragmentation of the mitochondrial network in skin in vivo. PLoS One 12, 1462–1470 (2017).

    Article  CAS  Google Scholar 

  42. 42.

    Jugé, R. et al. Quantification and characterization of UVB-induced mitochondrial fragmentation in normal primary human keratinocytes. Sci. Rep. 6, 35065 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. 43.

    Bentinger, M., Tekle, M. & Dallner, G. Coenzyme Q—biosynthesis and functions. Biochem. Biophys. Res. Commun. 396, 74–79 (2010).

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Hoppe. et al. Coenzyme Q10, a cutaneous antioxidant and energizer. Biofactors 9, 371–378 (1999).

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Blatt, T. & Littarru, G. P. Biochemical rationale and experimental data on the antiaging properties of CoQ(10) at skin level. Biofactors 37, 381–385 (2011).

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Marcheggiani, F. et al. Modulation of coenzyme Q(10) content and oxidative status in human dermal fibroblasts using HMG-CoA reductase inhibitor over a broad range of concentrations. From mitohormesis to mitochondrial dysfunction and accelerated aging. Aging 11, 2565–2582 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. 47.

    Fisher, G. J. et al. Pathophysiology of premature skin aging induced by ultraviolet light. N. Engl. J. Med. 337, 1419–28 (1997).

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Berneburg, M. et al. Chronically ultraviolet-exposed human skin shows a higher mutation frequency of mitochondrial DNA as compared to unexposed skin and the hematopoietic system. Photochem. Photobiol. 66, 271–5 (1997).

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Berneburg, M. et al. Induction of the photoaging-associated mitochondrial common deletion in vivo in normal human skin. J. Invest. Dermatol. 122, 1277–83 (2004).

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Krishnan, K. J., Harbottle, A. & Birch-Machin, M. A. The use of a 3895 bp mitochondrial DNA deletion as a marker for sunlight exposure in human skin. J. Invest. Dermatol. 123, 1020–4 (2005).

    Article  Google Scholar 

  51. 51.

    Powers, J. M., Murphy, G., Ralph, N., O’Gorman, S. M., Murphy, J. E. & Mitochondrial, D. N. A. deletion percentage in sun exposed and non-sun exposed skin. J. Photochem. Photobiol. B 165, 277–82 (2016).

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Berneburg, M. & Lehmann, A. R. Xeroderma pigmentosum and related disorders: defects in DNA repair and transcription. Adv. Genet. 43, 71–102 (2001).

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Berneburg, M. & Krutmann, J. Photoaging-associated large-scale deletions of mitochondrial DNA. Methods Enzymol. 319, 366–76 (2000).

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Balaban, R. S., Nemoto, S. & Finkel, T. Mitochondria, oxidants, and aging. Cell 25, 483–95 (2005).

    Article  CAS  Google Scholar 

  55. 55.

    Schroeder, P., Gremmel, T., Berneburg, M. & Krutmann, J. Partial depletion of mitochondrial DNA from human skin fibroblasts induces a gene expression profile reminiscent of photoaged skin. J. Invest. Dermatol. 128, 2297–303 (2008).

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Majora, M. et al. Functional consequences of mitochondrial DNA deletions in human skin fibroblasts: increased contractile strength in collagen lattices is due to oxidative stress-induced lysyl oxidase activity. Am. J. Pathol. 175, 1019–29 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57.

    Oyewole, A. O., Wilmot, M. C., Fowler, M. & Birch-Machin, M. A. Comparing the effects of mitochondrial targeted and localized antioxidants with cellular antioxidants in human skin cells exposed to UVA and hydrogen peroxide. FASEB J. 28, 485–94 (2014).

    CAS  PubMed  Article  Google Scholar 

  58. 58.

    Schieke, S. et al. Infrared-A radiation-induced matrix metalloproteinase 1 expression is mediated through extracellular signal-regulated kinase 1/2 activation in human dermal fibroblasts. J. Invest. Dermatol. 119, 1323–9 (2002).

    CAS  PubMed  Article  Google Scholar 

  59. 59.

    Kim, H. H. et al. Augmentation of UV-induced skin wrinkling by infrared irradiation in hairless mice. Mech. Ageing Dev. 126, 1170–7 (2005).

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Schauen, M., Hornig-Do, H. T., Schomberg, S., Herrmann, G. & Wiesner, R. J. Mitochondrial electron transport chain activity is not involved in ultraviolet A (UVA)-induced cell death. Free Radic. Biol. Med. 42, 499–509 (2007).

    CAS  PubMed  Article  Google Scholar 

  61. 61.

    Schroeder, P. et al. Cellular response to infrared radiation involves retrograde mitochondrial signaling. Free Radic. Biol. Med. 43, 128–35 (2007).

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Karu, T. I., Pyatibrat, L. V. & Afanasyeva, N. I. A novel mitochondrial signaling pathway activated by visible-to-near infrared radiation. Photochem. Photobiol. 80, 366–72 (2004).

    CAS  PubMed  Article  Google Scholar 

  63. 63.

    Sander, C. S. et al. Photoaging is associated with protein oxidation in human skin in vivo. J. Invest. Dermatol. 118, 618–25 (2002).

    CAS  Article  PubMed  Google Scholar 

  64. 64.

    Ortonne, J. P. Pigmentary changes of the ageing skin. Br. J. Dermatol. 122, 21–8 (1990).

    PubMed  Article  Google Scholar 

  65. 65.

    Hardman, J. A. et al. The peripheral clock regulates human pigmentation. J. Invest. Dermatol. 135, 1053–1064 (2015).

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Severi, G. & English, D. J. Prevention of Skin Cancer, Cancer Prevention—Cancer Causes Vol. 3 (eds Hill, D, Elwood, J. M, & English, D. J) 73–88 (Kluwer Academic Publishers. Dordrecht, 2004).

  67. 67.

    Armstrong, B. K. & Kricker, A. The epidemiology of UV induced skin cancer. J. Photochem. Photobiol. B 63, 8–18 (2001).

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Takeuchi, H., Fujimoto, A. & Hoon, D. S. Detection of mitochondrial DNA alterations in plasma of malignant melanoma patients. Ann. N. Y Acad. Sci. 1022, 50–54 (2004).

    CAS  PubMed  Article  Google Scholar 

  69. 69.

    Mithani, S. K., Smith, I. M., Topalian, S. L. & Califano, J. A. Nonsynonymous somatic mitochondrial mutations occur in the majority of cutaneous melanomas. Melanoma Res. 18, 214–219 (2008).

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Deichmann, M. et al. Somatic mitochondrial mutations in melanoma resection specimens. Int. J. Oncol. 24, 137–141 (2004).

    CAS  PubMed  Google Scholar 

  71. 71.

    Ebner, S. et al. Mitochondrial haplogroups, control region polymorphisms and malignant melanoma: a study in middle European Caucasians. PLoS One 6, 12 (2011).

    Article  CAS  Google Scholar 

  72. 72.

    Zhang, W. et al. Single nucleotide polymorphisms in the mitochondrial displacement loop region modifies malignant melanoma: a study in Chinese Han population. Mitochondrial DNA 26, 205–7 (2015).

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Durham, S. E., Krishnan, K. J., Betts, J., Birch-Machin, M. A. & Mitochondrial, D. N. A. damage in non-melanoma skin cancer. Brit J. Cancer 88, 90–95 (2003).

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Yang, J. H., Lee, H. C., Chung, J. G., Wei, Y. H. & Mitochondrial, D. N. A. mutations in light-associated skin tumors. Anticancer Res. 24, 1753–1758 (2004).

    CAS  PubMed  Google Scholar 

  75. 75.

    Hu, L., Yao, X. & Shen, Y. Altered mitochondrial DNA copy number contributes to human cancer risk: evidence from an updated meta-analysis. Sci. Rep. 6, 35859 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Robbins, D. & Zhao, Y. Manganese superoxide dismutase in cancer prevention. Antioxid. Redox Signal. 20, 1628–45 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Zhao, Y. et al. A mechanism-based antioxidant approach for the reduction of skin carcinogenesis. Cancer Res. 65, 1401–5 (2005).

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Ibarrola-Villava, M. et al. Role of glutathione S-transferases in melanoma susceptibility: association with GSTP1 rs1695 polymorphism. Br. J. Dermatol. 166, 1176–83 (2012).

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Valverde, P. et al. Melatonin antagonizes alpha-melanocyte-stimulating hormone enhancement of melanogenesis in mouse melanoma cells by blocking the hormone-induced accumulation of the c locus tyrosinase. Eur. J. Biochem. 232, 257–63 (1995).

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Lissoni, P. et al. A phase II study of chemoneuroimmunotherapy with platinum, subcutaneous low-dose interleukin-2 and the pineal neurohormone melatonin (P.I.M.) as a second-line therapy in metastatic melanoma patients progressing on dacarbazine plus interferon-alpha. In Vivo 16, 93–6 (2002).

    CAS  PubMed  Google Scholar 

  81. 81.

    Ghaderi, R., Sehatbakhsh, S., Bakhshaee, M. & Sharifzadeh, G. R. Urinary melatonin levels and skin malignancy. Iran J. Med. Sci. 39, 64–67 (2014).

    PubMed  PubMed Central  Google Scholar 

  82. 82.

    Warburg, O. Versuche am überlebenden Karzinomgewebe. Biochem. Z. 142, 317–333 (1923).

    CAS  Google Scholar 

  83. 83.

    DeBerardinis, R. J., Lum, J. J., Hatzivassiliou, G. & Thompson, C. B. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7, 11–20 (2008).

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Papandreou, I., Cairns, R. A., Fontana, L., Lim, A. L. & Denko, N. C. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 3, 187–197 (2006).

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Hall, A. et al. Dysfunctional oxidative phosphorylation makes malignant melanoma cells addicted to glycolysis driven by the (V600E) BRAF oncogene. Oncotarget 4, 584–599 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Mamelak, A. J. et al. Downregulation of NDUFA1 and other oxidative phosphorylation-related genes is a consistent feature of basal cell carcinoma. Exp. Dermatol. 14, 336–48 (2005).

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Feichtinger, R. G., Sperl, W., Bauer, J. W. & Kofler, B. Mitochondrial dysfunction: a neglected component of skin diseases. Exp. Dermatol. 23, 607–14 (2014).

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Bodemer, C. et al. Hair and skin disorders as signs of mitochondrial disease. Pediatrics 103, 428–33 (1999).

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Sonam, K. et al. Clinical and magnetic resonance imaging findings in patients with Leigh syndrome and SURF1 mutations. Brain Dev. 36, 807–12 (2014).

    PubMed  Article  Google Scholar 

  90. 90.

    McPherson, E. & Zabel, C. Mitochondrial mutation in a child with distal arthrogryposis. Am. J. Med. Genet. A 140, 184–5 (2006).

    PubMed  Article  Google Scholar 

  91. 91.

    Kakourou, T. et al. Kearns Sayre syndrome initially presenting as hypomelanosis of Ito. Arch. Dis. Child 81, 280–1 (1999).

    CAS  PubMed  Google Scholar 

  92. 92.

    Campuzano-García, A. E., Rodríguez-Arámbula, A., Torres-Alvarez, B. & Castanedo-Cázares, J. P. Hyperpigmentation and atrophy in folds as cutaneous manifestation in a case of mitochondrial myopathy. Dermatol. Online J. 21, 5 (2015).

    Google Scholar 

  93. 93.

    AlSaman, A., Tomoum, H., Invernizzi, F. & Zeviani, M. Hepatocerebral form of mitochondrial DNA depletion syndrome due to mutation in MPV17 gene. Saudi J. Gastroenterol. 18, 285–9 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  94. 94.

    Rahman, A. et al. Hutchinson-Gilford progeria syndrome (HGPS) with mitochondrial dna (mtDNA) HV1 control region mutations. Unique J. Pharm. Biol. Sci. 2, 1 (2014).

    CAS  Google Scholar 

  95. 95.

    Rivera-Torres, J. et al. Identification of mitochondrial dysfunction in Hutchinson-Gilford progeria syndrome through use of stable isotope labeling with amino acids in cell culture. J. Proteom. 91, 466–477 (2013).

    CAS  Article  Google Scholar 

  96. 96.

    Maasz, A. et al. Phenotypic variants of the deafness-associated mitochondrial DNA A7445G mutation. Curr. Med. Chem. 15, 1257–1262 (2008).

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Michou, L. et al. Genetics of Dupuytren’s disease. Jt. Bone Spine 79, 7–12 (2012).

    CAS  Article  Google Scholar 

  98. 98.

    Indrieri, A. et al. Mutations in COX7B cause microphthalmia with linear skin lesions, an unconventional mitochondrial disease. Am. J. Hum. Genet. 91, 942–9 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Lynn, A. M., King, R. I., Mackay, R. J., Florkowski, C. M. & Wilson, C. J. BCS1L gene mutation presenting with GRACILE-like syndrome and complex III deficiency. Ann. Clin. Biochem. 49, 201–3 (2012).

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Murphy, G. M. The cutaneous porphyrias: a review. The British Photodermatology Group. Br. J. Dermatol. 140, 573–81 (1999).

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Maselli, R. A. et al. Congenital myasthenic syndrome associated with epidermolysis bullosa caused by homozygous mutations in PLEC1 and CHRNE. Clin. Genet. 80, 444–451 (2011).

    CAS  PubMed  Article  Google Scholar 

  102. 102.

    Dimopoulou, A. et al. Genotype-phenotype spectrum of PYCR1-related autosomal recessive cutis laxa. Mol. Genet. Metab. 110, 352–361 (2013).

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Kazak, L., Reyes, A. & Holt, I. J. Minimizing the damage: repair pathways keep mitochondrial DNA intact. Nat. Rev. Mol. Cell Biol. 13, 659–71 (2012).

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Labbé, A. et al. The Werner syndrome gene product (WRN): a repressor of hypoxia-inducible factor-1 activity. Exp. Cell Res. 318, 1620–32 (2012).

    PubMed  Article  CAS  Google Scholar 

  105. 105.

    Sharma, N. K. et al. Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia. DNA Repair 13, 22–31 (2014).

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Sahin, E. et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359–65 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  107. 107.

    Sharma, N. K. et al. Human telomerase acts as a hTR-independent reverse transcriptase in mitochondria. Nucleic Acids Res. 40, 712–25 (2012).

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Perl, A., Gergely, P. Jr. & Banki, K. Mitochondrial dysfunction in T cells of patients with systemic lupus erythematosus. Int Rev. Immunol. 23, 293–313 (2004).

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Di Zenzo, G., Zambruno, G. & Borradori, L. Endemic pemphigus foliaceus: towards understanding autoimmune mechanisms of disease development. J. Invest. Dermatol. 132, 2499–502 (2012).

    PubMed  Article  CAS  Google Scholar 

  110. 110.

    Kalantari-Dehaghi, M. et al. Mechanisms of mitochondrial damage in keratinocytes by pemphigus vulgaris antibodies. J. Biol. Chem. 288, 16916–16925 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Knott, A. et al. Topical treatment with coenzyme Q10-containing formulas improves skin’s Q10 level and provides antioxidative effects. Biofactors 41, 383–90 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Schniertshauer, D. et al. Accelerated Regeneration of ATP Level after Irradiation in Human Skin Fibroblasts by Coenzyme Q10. Photochem. Photobiol. 92, 488–94 (2016).

    CAS  PubMed  Article  Google Scholar 

  113. 113.

    Bains, P., Kaur, M., Kaur, J. & Sharma, S. Nicotinamide: Mechanism of action and indications in dermatology. Indian J. Dermatol. Venereol. Leprol. 84, 234–237 (2018).

    PubMed  Google Scholar 

  114. 114.

    Telang, P. S. Vitamin C in dermatology. Indian Dermatol. Online J. 4(2), 143–6 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Ungvari, Z., Sonntag, W. E., de Cabo, R., Baur, J. A. & Csiszar, A. Mitochondrial protection by resveratrol. Exerc Sport Sci. Rev. 39, 128–32 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Du, J. et al. Flow cytometry analysis of glucocorticoid receptor expression and binding in steroid-sensitive and steroid-resistant patients with systemic lupus erythematosus. Arthritis Res. Ther. 11, R108 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  117. 117.

    Valentin-Vega, Y. A. & Kastan, M. B. A new role for ATM: regulating mitochondrial function and mitophagy. Autophagy 8, 840–841 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118.

    Pallardó, F. V. et al. Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome. Biogerontology 11, 401–419 (2010).

    PubMed  Article  CAS  Google Scholar 

  119. 119.

    Hymes, J., Stanley, C. M. & Wolf, B. Mutations in BTD causing biotinidase deficiency. Hum. Mutat. 18, 375–381 (2001).

    CAS  PubMed  Article  Google Scholar 

  120. 120.

    Hernandez-Vazquez, A. et al. Biotinidase knockout mice show cellular energy deficit and altered carbon metabolism gene expression similar to that of nutritional biotin deprivation: clues for the pathogenesis in the human inherited disorder. Mol. Genet. Metab. 110, 248–254 (2013).

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Pedespan, J. M. et al. Menkes disease: study of the mitochondrial respiratory chain in three cases. Eur. J. Paediatr. Neurol. 3, 167–170 (1999).

    CAS  PubMed  Article  Google Scholar 

  122. 122.

    Atamna, H., Newberry, J., Erlitzki, R., Schultz, C. S. & Ames, B. N. Biotin deficiency inhibits heme synthesis and impairs mitochondria in human lung fibroblasts. J. Nutr. 137, 25–30 (2007).

    CAS  PubMed  Article  Google Scholar 

  123. 123.

    Hinson, J. T. et al. Missense mutations in the BCS1L gene as a cause of the Björnstad syndrome. N. Engl. J. Med. 356, 809–819 (2007).

    CAS  PubMed  Article  Google Scholar 

  124. 124.

    Selvaag, E. Pili torti et canaliculi and agenesis of the teeth: report of a new “pure” hair-tooth ectodermal dysplasia in a Norwegian family. J. Med. Genet. 37, 721–723 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Finsterer, J. & Zarrouk-Mahjoub, S. Cardiac manifestations of mitochondrial disorders. Tex. Heart Inst. J. 40, 634–635 (2013).

    PubMed  PubMed Central  Google Scholar 

  126. 126.

    Gronow, S., Noah, C., Blumenthal, A., Lindner, B. & Brade, H. Construction of a deep-rough mutant of Burkholderia cepacia ATCC 25416 and characterization of its chemical and biological properties. J. Biol. Chem. 278, 1647–1655 (2003).

    CAS  PubMed  Article  Google Scholar 

  127. 127.

    Lange, H., Mühlenhoff, U., Denzel, M., Kispal, G. & Lill, R. The heme synthesis defect of mutants impaired in mitochondrial iron-sulfur protein biogenesis is caused by reversible inhibition of ferrochelatase. J. Biol. Chem. 279, 29101–8 (2004).

    CAS  PubMed  Article  Google Scholar 

  128. 128.

    Bareth, B. et al. The heme a synthase Cox15 associates with cytochrome c oxidase assembly intermediates during Cox1 maturation. Mol. Cell Biol. 33, 4128–4137 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Nilsson, R. et al. Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis. Cell Metab. 10, 119–130 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    Zierler, K. A. et al. Functional cardiac lipolysis in mice critically depends on comparative gene identification-58. J. Biol. Chem. 288, 9892–9904 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  131. 131.

    Scheibye-Knudsen, M., Croteau, D. L. & Bohr, V. A. Mitochondrial deficiency in Cockayne syndrome. Mech. Ageing Dev. 134, 275–283 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Scheibye-Knudsen, M. P. et al. Cockayne syndrome group B protein prevents the accumulation of damaged mitochondria by promoting mitochondrial autophagy. J. Exp. Med. 209, 855–869 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Ravera, S. et al. Mitochondrial respiratory chain Complex I defects in Fanconi anemia complementation group A. Biochimie 95, 1828–1837 (2013).

    CAS  PubMed  Article  Google Scholar 

  134. 134.

    Cappelli, E. et al. Mitochondrial respiratory complex I defects in Fanconi anemia. Trends Mol. Med. 19, 513–514 (2013).

    CAS  PubMed  Article  Google Scholar 

  135. 135.

    Kleefstra, T. et al. Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway. Eur. J. Hum. Genet. 19, 138–144 (2011).

    PubMed  Article  Google Scholar 

  136. 136.

    Aeby, A. et al. Cardiofaciocutaneous (CFC) syndrome associated with muscular coenzyme Q10 deficiency. J. Inherit. Metab. Dis. 30, 827 (2007).

    CAS  PubMed  Article  Google Scholar 

  137. 137.

    Champion, K. J. et al. Germline mutation in BRAF codon 600 is compatible with human development: de novo p.V600G mutation identified in a patient with CFC syndrome. Clin. Genet. 79, 468–474 (2011).

    CAS  PubMed  Article  Google Scholar 

  138. 138.

    Amary, M. F. et al. Ollier disease and Maffucci syndrome are caused by somatic mosaic mutations of IDH1 and IDH2. Nat. Genet. 43, 1262–1265 (2011).

    CAS  PubMed  Article  Google Scholar 

  139. 139.

    Kodama, H., Okabe, I., Yanagisawa, M. & Kodama, Y. Copper deficiency in the mitochondria of cultured skin fibroblasts from patients with Menkes syndrome. J. Inherit. Metab. Dis. 12, 386–389 (1989).

    CAS  PubMed  Article  Google Scholar 

  140. 140.

    Schroder, R. et al. Disorganization of the desmin cytoskeleton and mitochondrial dysfunction in plectin-related epidermolysis bullosa simplex with muscular dystrophy. J. Neuropathol. Exp. Neurol. 61, 520–530 (2002).

    CAS  PubMed  Article  Google Scholar 

  141. 141.

    Banwell, B. L. et al. Myopathy, myasthenic syndrome, and epidermolysis bullosa simplex due to plectin deficiency. J. Neuropathol. Exp. Neurol. 58, 832–846 (1999).

    CAS  PubMed  Article  Google Scholar 

  142. 142.

    Reversade, B. et al. Mutations in PYCR1 cause cutis laxa with progeroid features. Nat. Genet. 41, 1016–1021 (2009).

    CAS  PubMed  Article  Google Scholar 

  143. 143.

    Croteau, D. L. et al. RECQL4 localizes to mitochondria and preserves mitochondrial DNA integrity. Aging Cell 11, 456–466 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Hermanns, P. et al. RMRP mutations in cartilage-hair hypoplasia. Am. J. Med. Genet A 140, 2121–2130 (2006).

    PubMed  Article  CAS  Google Scholar 

  145. 145.

    Robertson, N. J. et al. Brain lactic alkalosis in Aicardi-Goutières syndrome. Neuropediatrics 35, 20–26 (2004).

    CAS  PubMed  Article  Google Scholar 

  146. 146.

    Wu, L. SAMHD1 knockout mice: modeling retrovirus restriction in vivo. Retrovirology 10, 142 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  147. 147.

    Larsson, N. G., Tulinius, M. H., Holme, E. & Oldfors, A. Pathogenetic aspects of the A8344G mutation of mitochondrial DNA associated with MERRF syndrome and multiple symmetric lipomas. Muscle Nerve 18, 102–106 (1995).

    Article  Google Scholar 

  148. 148.

    Dutton-Regester, K. et al. A high-throughput panel for identifying clinically relevant mutation profiles in melanoma. Mol. Cancer Ther. 11, 888–897 (2012).

    CAS  PubMed  Article  Google Scholar 

  149. 149.

    Kamenisch, Y. et al. The mitochondrial DNA common deletion is present in most basal and squamous cell carcinoma samples isolated by laser capture microdissection but generally at reduced rather than increased levels. J. Invest Dermatol. 127, 486–490 (2007).

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

We thank Yuva Biosciences team members for their support. K.K.S. is supported by an NIH grant R01CA204430. We apologize to authors whose work we could not cite due to space limitations.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Keshav K. Singh.

Ethics declarations

Conflict of Interest

K.K.S. is the scientific founder and chief scientific advisor at Yuva Biosciences. A.S., L.A.-A., and K.K.S. hold equity in Yuva Biosciences.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Edited by E. Candi

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sreedhar, A., Aguilera-Aguirre, L. & Singh, K.K. Mitochondria in skin health, aging, and disease. Cell Death Dis 11, 444 (2020). https://doi.org/10.1038/s41419-020-2649-z

Download citation

Further reading

Search

Quick links