Mitochondrial diseases are among the most common genetic disorders. They can result from mutations in the mitochondrial genome or nuclear genome.
The mitochondrial genome needs to be understood in terms of population genetics, rather than Mendelian genetics; this makes it particularly challenging to understand mitochondrial diseases.
Mutations in mitochondrial DNA (mtDNA) accumulate over the lifetime of an individual and are now implicated in ageing and neurodegeneration.
There is current interest in exploring possible roles of mitochondrial genetic variation in susceptibility to complex diseases, but the evidence remains uncertain at present.
The literature documenting the accumulation of mtDNA mutations in tumours needs to be interpreted with caution.
Mutations in the human mitochondrial genome are known to cause an array of diverse disorders, most of which are maternally inherited, and all of which are associated with defects in oxidative energy metabolism. It is now emerging that somatic mutations in mitochondrial DNA (mtDNA) are also linked to other complex traits, including neurodegenerative diseases, ageing and cancer. Here we discuss insights into the roles of mtDNA mutations in a wide variety of diseases, highlighting the interesting genetic characteristics of the mitochondrial genome and challenges in studying its contribution to pathogenesis.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Heredity Open Access 28 June 2022
Neurochemical Research Open Access 04 June 2022
Orphanet Journal of Rare Diseases Open Access 17 May 2022
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Sagan, L. On the origin of mitosing cells. J. Theor. Biol. 14, 255–274 (1967).
Garcia-Rodriguez, L. J. Appendix 1. Basic properties of mitochondria. Methods Cell Biol. 80, 809–812 (2007).
Calvo, S. E. et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci. Transl. Med. 4, 118ra10 (2012). This was one of the first applications of sequencing the 'mitochondrial exome' (that is, ∼1,500 nuclear genes encoding mitochondrial-targeted proteins) to identify pathogenic mutations causing mitochondrial disease.
Schaefer, A. M. et al. Prevalence of mitochondrial DNA disease in adults. Ann. Neurol. 63, 35–39 (2008).
Greaves, L. C., Reeve, A. K., Taylor, R. W. & Turnbull, D. M. Mitochondrial DNA and disease. J. Pathol. 226, 274–286 (2012).
Koopman, W. J., Willems, P. H. & Smeitink, J. A. Monogenic mitochondrial disorders. N. Engl. J. Med. 366, 1132–1141 (2012).
Ylikallio, E. & Suomalainen, A. Mechanisms of mitochondrial diseases. Ann. Med. 44, 41–59 (2012). This is a comprehensive overview of mitochondrial respiratory chain disorders.
Anderson, S. et al. Sequence and organization of the human mitochondrial genome. Nature 290, 457–465 (1981).
DiMauro, S. & Schon, E. A. Mitochondrial respiratory-chain diseases. N. Engl. J. Med. 348, 2656–2668 (2003).
Sacconi, S. et al. A functionally dominant mitochondrial DNA mutation. Hum. Mol. Genet. 17, 1814–1820 (2008).
Yoneda, M., Miyatake, T. & Attardi, G. Heteroplasmic mitochondrial tRNALys mutation and its complementation in MERRF patient-derived mitochondrial transformants. Muscle Nerve 3, S95–S101 (1995).
Sciacco, M., Bonilla, E., Schon, E. A., DiMauro, S. & Moraes, C. T. Distribution of wild-type and common deletion forms of mtDNA in normal and respiration-deficient muscle fibers from patients with mitochondrial myopathy. Hum. Mol. Genet. 3, 13–19 (1994).
Santorelli, F. M., Shanske, S., Macaya, A., DeVivo, D. C. & DiMauro, S. The mutation at nt 8993 of mitochondrial DNA is a common cause of Leigh's syndrome. Ann. Neurol. 34, 827–834 (1993).
Holt, I. J., Harding, A. E., Petty, R. K. & Morgan-Hughes, J. A. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am. J. Hum. Genet. 46, 428–433 (1990).
Elliott, H. R., Samuels, D. C., Eden, J. A., Relton, C. L. & Chinnery, P. F. Pathogenic mitochondrial DNA mutations are common in the general population. Am. J. Hum. Genet. 83, 254–260 (2008). This was the first large-scale epidemiological survey of the prevalence of common pathological mtDNA mutations in the normal population.
Stewart, J. B. et al. Strong purifying selection in transmission of mammalian mitochondrial DNA. PLoS Biol. 6, e10 (2008).
Prezant, T. R. et al. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nature Genet. 4, 289–294 (1993).
Raimundo, N. et al. Mitochondrial stress engages E2F1 apoptotic signaling to cause deafness. Cell 148, 716–726 (2012).
Gilkerson, R. W. et al. Mitochondrial autophagy in cells with mtDNA mutations results from synergistic loss of transmembrane potential and mTORC1 inhibition. Hum. Mol. Genet. 21, 978–990 (2012).
Gilkerson, R. W., Schon, E. A., Hernandez, E. & Davidson, M. M. Mitochondrial nucleoids maintain genetic autonomy but allow for functional complementation. J. Cell Biol. 181, 1117–1128 (2008).
Sgarbi, G. et al. Inefficient coupling between proton transport and ATP synthesis may be the pathogenic mechanism for NARP and Leigh syndrome resulting from the T8993G mutation in mtDNA. Biochem. J. 395, 493–500 (2006).
Holt, I. J., Harding, A. E. & Morgan-Hughes, J. A. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature 331, 717–719 (1988).
Lestienne, P. & Ponsot, G. Kearns-Sayre syndrome with muscle mitochondrial DNA deletion. Lancet 331, 885–886 (1988).
Damas, J. et al. Mitochondrial DNA deletions are associated with non-B DNA conformations. Nucleic Acids Res. 40, 7606–7621 (2012).
Kearns, T. P. & Sayre, G. P. Retinitis pigmentosa, external ophthalmophegia, and complete heart block: unusual syndrome with histologic study in one of two cases. AMA Arch. Ophthalmol. 60, 280–289 (1958).
Moraes, C. T. et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns–Sayre syndrome. N. Engl. J. Med. 320, 1293–1299 (1989).
Pearson, H. A. et al. A new syndrome of refractory sideroblastic anemia with vacuolization of marrow precursors and exocrine pancreatic dysfunction. J. Pediatr. 95, 976–984 (1979).
Nakase, H. et al. Transcription and translation of deleted mitochondrial genomes in Kearns–Sayre syndrome: implications for pathogenesis. Am. J. Hum. Genet. 46, 418–427 (1990). This was one of the first studies providing insight into the pathomechanism of mtDNA deletion disorders.
Mita, S., Schmidt, B., Schon, E. A., DiMauro, S. & Bonilla, E. Detection of “deleted” mitochondrial genomes in cytochrome-c oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome. Proc. Natl Acad. Sci. USA 86, 9509–9513 (1989).
Moraes, C. T. et al. Molecular analysis of the muscle pathology associated with mitochondrial DNA deletions. Nature Genet. 1, 359–367 (1992).
Ashley, N. et al. Defects in maintenance of mitochondrial DNA are associated with intramitochondrial nucleotide imbalances. Hum. Mol. Genet. 16, 1400–1411 (2007).
Moraes, C. T. et al. Mitochondrial DNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases. Am. J. Hum. Genet. 48, 492–501 (1991). This was the first description of a quantitative defect in mtDNA copy number causing disease.
Nishigaki, Y., Marti, R., Copeland, W. C. & Hirano, M. Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency. J. Clin. Invest. 111, 1913–1921 (2003). This was the first description of a secondary mitochondrial disorder causing mtDNA point mutations.
Nishino, I., Spinazzola, A. & Hirano, M. Thymidine phosphorylase gene mutations in MNGIE, a human mitochondrial disorder. Science 283, 689–692 (1999).
Kaukonen, J. et al. Role of adenine nucleotide translocator 1 in mtDNA maintenance. Science 289, 782–785 (2000).
Van Goethem, G., Dermaut, B., Lofgren, A., Martin, J. J. & Van Broeckhoven, C. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nature Genet. 28, 211–212 (2001).
Spelbrink, J. N. et al. Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria. Nature Genet. 28, 223–231 (2001).
Naviaux, R. K. & Nguyen, K. V. POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion. Ann. Neurol. 55, 706–712 (2004).
Moraes, C. T. et al. Phenotype-genotype correlations in skeletal muscle of patients with mtDNA deletions. Muscle Nerve 3, S150–S153 (1995).
Cortopassi, G. A., Shibata, D., Soong, N. W. & Arnheim, N. A pattern of accumulation of a somatic deletion of mitochondrial DNA in aging human tissues. Proc. Natl Acad. Sci. USA 89, 7370–7374 (1992). This was among the first reports that called attention to the accumulation of somatic mtDNA deletions in normal ageing.
Corral-Debrinski, M. et al. Mitochondrial DNA deletions in human brain: regional variability and increase with advanced age. Nature Genet. 2, 324–329 (1992).
Meissner, C. et al. The 4977 bp deletion of mitochondrial DNA in human skeletal muscle, heart and different areas of the brain: a useful biomarker or more? Exp. Gerontol. 43, 645–652 (2008).
Pallotti, F., Chen, X., Bonilla, E. & Schon, E. A. Evidence that specific mtDNA point mutations may not accumulate in skeletal muscle during normal human aging. Am. J. Hum. Genet. 59, 591–602 (1996).
Simonetti, S., Chen, X., DiMauro, S. & Schon, E. A. Accumulation of deletions in human mitochondrial DNA during normal aging: analysis by quantitative PCR. Biochim. Biophys. Acta 1180, 113–122 (1992).
Oldfors, A. et al. Mitochondrial DNA deletions and cytochrome c oxidase deficiency in muscle fibres. J. Neurol. Sci. 110, 169–177 (1992).
Bodyak, N. D., Nekhaeva, E., Wei, J. Y. & Khrapko, K. Quantification and sequencing of somatic deleted mtDNA in single cells: evidence for partially duplicated mtDNA in aged human tissues. Hum. Mol. Genet. 10, 17–24 (2001).
Vu, T. H. et al. Analysis of mtDNA deletions in muscle by in situ hybridization. Muscle Nerve 23, 80–85 (2000).
Petruzzella, V. et al. Extremely high levels of mutant mtDNAs co-localize with cytochrome c oxidase-negative ragged-red fibers in patients harboring a point mutation at nt-3243. Hum. Mol. Genet. 3, 449–454 (1994).
Bua, E. et al. Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers. Am. J. Hum. Genet. 79, 469–480 (2006).
Schon, E. A. & Przedborski, S. Mitochondria: the next (neurode) generation. Neuron 70, 1033–1053 (2011).
Vives-Bauza, C. et al. Control of mitochondrial integrity in Parkinson's disease. Prog. Brain Res. 183, 99–113 (2010).
Narendra, D. P. & Youle, R. J. Targeting mitochondrial dysfunction: role for PINK1 and Parkin in mitochondrial quality control. Antioxid. Redox Signal. 14, 1929–1938 (2011).
Bender, A. et al. High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease. Nature Genet. 38, 515–517 (2006). This was the first report of correlating a neurodegenerative disease with the accumulation of mtDNA mutations in the clinically relevant target tissue.
Kraytsberg, Y. et al. Mitochondrial DNA deletions are abundant and cause functional impairment in aged human substantia nigra neurons. Nature Genet. 38, 518–520 (2006).
Ekstrand, M. I. et al. Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons. Proc. Natl Acad. Sci. USA 104, 1325–1330 (2007).
De Coo, I. F. et al. A 4-base pair deletion in the mitochondrial cytochrome b gene associated with parkinsonism/MELAS overlap syndrome. Ann. Neurol. 45, 130–133 (1999).
Inoue, K. et al. Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes. Nature Genet. 26, 176–181 (2000).
Tyynismaa, H. et al. Mutant mitochondrial helicase Twinkle causes multiple mtDNA deletions and a late-onset mitochondrial disease in mice. Proc. Natl Acad. Sci. USA 102, 17687–17692 (2005).
Cann, R. L., Stoneking, M. & Wilson, A. C. Mitochondrial DNA and human evolution. Nature 325, 31–36 (1987).
Ruiz-Pesini, E., Mishmar, D., Brandon, M., Procaccio, V. & Wallace, D. C. Effects of purifying and adaptive selection on regional variation in human mtDNA. Science 303, 223–226 (2004).
Amo, T. & Brand, M. D. Were inefficient mitochondrial haplogroups selected during migrations of modern humans? A test using modular kinetic analysis of coupling in mitochondria from cybrid cell lines. Biochem. J. 404, 345–351 (2007).
Saxena, R. et al. Comprehensive association testing of common mitochondrial DNA variation in metabolic disease. Am. J. Hum. Genet. 79, 54–61 (2006).
Kadowaki, T. et al. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N. Engl. J. Med. 330, 962–968 (1994). This was an important survey that demonstrated the importance of a specific mtDNA mutation as a cause of diabetes mellitus.
Bitner-Glindzicz, M. et al. Prevalence of mitochondrial 1555A→G mutation in European children. N. Engl. J. Med. 360, 640–642 (2009).
Vandebona, H. et al. Prevalence of mitochondrial 1555A→G mutation in adults of European descent. N. Engl. J. Med. 360, 642–644 (2009).
Andreu, A. L. et al. Exercise intolerance due to mutations in the cytochrome b gene of mitochondrial DNA. N. Engl. J. Med. 341, 1037–1044 (1999).
Elson, J. L., Majamaa, K., Howell, N. & Chinnery, P. F. Associating mitochondrial DNA variation with complex traits. Am. J. Hum. Genet. 80, 378–382; author reply 382–383 (2007).
Carelli, V. et al. Haplogroup effects and recombination of mitochondrial DNA: novel clues from the analysis of Leber hereditary optic neuropathy pedigrees. Am. J. Hum. Genet. 78, 564–574 (2006). This paper provieds a good example of the 'synergistic' relationship between specific mtDNA haplotypes and the severity of pathogenic mtDNA point mutations.
Hudson, G. et al. Clinical expression of Leber hereditary optic neuropathy is affected by the mitochondrial DNA-haplogroup background. Am. J. Hum. Genet. 81, 228–233 (2007).
Ghelli, A. et al. The background of mitochondrial DNA haplogroup J increases the sensitivity of Leber's hereditary optic neuropathy cells to 2,5-hexanedione toxicity. PLoS ONE 4, e7922 (2009).
Anderson, C. D. et al. Common mitochondrial sequence variants in ischemic stroke. Ann. Neurol. 69, 471–480 (2011).
Arning, L. et al. Mitochondrial haplogroup H correlates with ATP levels and age at onset in Huntington disease. J. Mol. Med. 88, 431–436 (2010).
Ingram, C. J. et al. Analysis of European case-control studies suggests that common inherited variation in mitochondrial DNA is not involved in susceptibility to amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 13, 341–346 (2012).
Hiona, A. & Leeuwenburgh, C. The role of mitochondrial DNA mutations in aging and sarcopenia: implications for the mitochondrial vicious cycle theory of aging. Exp. Gerontol. 43, 24–33 (2008).
Khusnutdinova, E. et al. A mitochondrial etiology of neurodegenerative diseases: evidence from Parkinson's disease. Ann. NY Acad. Sci. 1147, 1–20 (2008).
Mancuso, M., Filosto, M., Orsucci, D. & Siciliano, G. Mitochondrial DNA sequence variation and neurodegeneration. Hum. Genom. 3, 71–78 (2008).
Nishigaki, Y., Fuku, N. & Tanaka, M. Mitochondrial haplogroups associated with lifestyle-related diseases and longevity in the Japanese population. Geriatr. Gerontol. Int. 10, S221–S235 (2010).
Rose, G. et al. No evidence of association between frontotemporal dementia and major European mtDNA haplogroups. Eur. J. Neurol. 15, 1006–1008 (2008).
SanGiovanni, J. P. et al. Mitochondrial DNA variants of respiratory complex I that uniquely characterize haplogroup T2 are associated with increased risk of age-related macular degeneration. PLoS ONE 4, e5508 (2009).
Sanchez-Ferrero, E. et al. Mitochondrial DNA polymorphisms/haplogroups in hereditary spastic paraplegia. J. Neurol. 259, 246–250.
Santoro, A. et al. Evidence for sub-haplogroup h5 of mitochondrial DNA as a risk factor for late onset Alzheimer's disease. PLoS ONE 5, e12037 (2012).
Sequeira, A. et al. Mitochondrial mutations and polymorphisms in psychiatric disorders. Front. Genet. 3, 103 (2012).
Tranah, G. J. Mitochondrial-nuclear epistasis: implications for human aging and longevity. Ageing Res. Rev. 10, 238–252 (2012).
McRae, A. F., Byrne, E. M., Zhao, Z. Z., Montgomery, G. W. & Visscher, P. M. Power and SNP tagging in whole mitochondrial genome association studies. Genome Res. 18, 911–917 (2008).
Battersby, B. J. & Shoubridge, E. A. Selection of a mtDNA sequence variant in hepatocytes of heteroplasmic mice is not due to differences in respiratory chain function or efficiency of replication. Hum. Mol. Genet. 10, 2469–2479 (2001).
Warburg, O., Wind, F. & Negelein, E. The metabolism of tumors in the body. J. Gen. Physiol. 8, 519–530 (1927).
Polyak, K. et al. Somatic mutations of the mitochondrial genome in human colorectal tumours. Nature Genet. 20, 291–293 (1998).
Yu, M. Generation, function and diagnostic value of mitochondrial DNA copy number alterations in human cancers. Life Sci. 89, 65–71 (2011).
Melnick, P. J. Enzyme patterns of tumors demonstrated histochemically in cryostat sections. Ann. NY Acad. Sci. 125, 689–715 (1965).
Pelicano, H. et al. Mitochondrial respiration defects in cancer cells cause activation of Akt survival pathway through a redox-mediated mechanism. J. Cell Biol. 175, 913–923 (2006).
Yu, M. et al. Reduced mitochondrial DNA copy number is correlated with tumor progression and prognosis in Chinese breast cancer patients. IUBMB Life 59, 450–457 (2007).
Bai, R. K. et al. Mitochondrial DNA content varies with pathological characteristics of breast cancer. J. Oncol. 2011, 496189 (2011).
King, M. P., Koga, Y., Davidson, M. & Schon, E. A. Defects in mitochondrial protein synthesis and respiratory chain activity segregate with the tRNALeu(UUR) mutation associated with mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. Mol. Cell. Biol. 12, 480–490 (1992).
Miller, R. W. Dihydroorotate-quinone reductase of Neurospora crassa mitochondria. Arch. Biochem. Biophys. 146, 256–270 (1971).
Hayashi, J., Takemitsu, M. & Nonaka, I. Recovery of the missing tumorigenicity in mitochondrial DNA-less HeLa cells by introduction of mitochondrial DNA from normal human cells. Somat. Cell. Mol. Genet. 18, 123–129 (1992).
Morais, R. et al. Tumor-forming ability in athymic nude mice of human cell lines devoid of mitochondrial DNA. Cancer Res. 54, 3889–3896 (1994).
Peters, G. J. et al. In vivo inhibition of the pyrimidine de novo enzyme dihydroorotic acid dehydrogenase by brequinar sodium (DUP-785; NSC 368390) in mice and patients. Cancer Res. 50, 4644–4649 (1990).
Mourier, T., Hansen, A. J., Willerslev, E. & Arctander, P. The Human Genome Project reveals a continuous transfer of large mitochondrial fragments to the nucleus. Mol. Biol. Evol. 18, 1833–1837 (2001).
Ramos, A. et al. Nuclear insertions of mitochondrial origin: database updating and usefulness in cancer studies. Mitochondrion 11, 946–953 (2011).
Hazkani-Covo, E., Zeller, R. M. & Martin, W. Molecular poltergeists: mitochondrial DNA copies (numts) in sequenced nuclear genomes. PLoS Genet. 6, e1000834 (2010).
Lang, M. et al. Polymorphic Numts trace human population relationships. Hum. Genet. 131, 757–771 (2012).
Wang, D., Lloyd, A. H. & Timmis, J. N. Environmental stress increases the entry of cytoplasmic organellar DNA into the nucleus in plants. Proc. Natl Acad. Sci. USA 109, 2444–2448 (2012).
Cheng, X. & Ivessa, A. S. The migration of mitochondrial DNA fragments to the nucleus affects the chronological aging process of Saccharomyces cerevisiae. Aging Cell 9, 919–923 (2010). This is a fascinating example of how mtDNA fragments can be transferred to the nucleus in 'real time' (that is, during the lifetime of an individual).
Caro, P. et al. Mitochondrial DNA sequences are present inside nuclear DNA in rat tissues and increase with age. Mitochondrion 10, 479–486 (2010).
Goldin, E. et al. Transfer of a mitochondrial DNA fragment to MCOLN1 causes an inherited case of mucolipidosis IV. Hum. Mutat. 24, 460–465 (2004).
Turner, C. et al. Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer. Hum. Genet. 112, 303–309 (2003).
Willett-Brozick, J. E., Savul, S. A., Richey, L. E. & Baysal, B. E. Germ line insertion of mtDNA at the breakpoint junction of a reciprocal constitutional translocation. Hum. Genet. 109, 216–223 (2001).
Storlazzi, C. T. et al. Gene amplification as double minutes or homogeneously staining regions in solid tumors: origin and structure. Genome Res. 20, 1198–1206 (2010).
Valsesia, A. et al. Network-guided analysis of genes with altered somatic copy number and gene expression reveals pathways commonly perturbed in metastatic melanoma. PLoS ONE 6, e18369 (2011).
Hirano, T. et al. Co-localization of mitochondrial and double minute DNA in the nuclei of HL-60 cells but not normal cells. Mutat. Res. 425, 195–204 (1999).
Lee, J. H., Ryu, T. Y., Cho, C. H. & Kim, D. K. Different characteristics of mitochondrial microsatellite instability between uterine leiomyomas and leiomyosarcomas. Pathol. Oncol. Res. 17, 201–205 (2011).
Ellinger, J. et al. Circulating mitochondrial DNA in serum: A universal diagnostic biomarker for patients with urological malignancies. Urol. Oncol. 30, 509–515 (2012).
Kiebish, M. A. & Seyfried, T. N. Absence of pathogenic mitochondrial DNA mutations in mouse brain tumors. BMC Cancer 5, 102 (2005).
Ericson, N. G. et al. Decreased mitochondrial DNA mutagenesis in human colorectal cancer. PLoS Genet. 8, e1002689 (2012).
Chinnery, P. F., Samuels, D. C., Elson, J. & Turnbull, D. M. Accumulation of mitochondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism? Lancet 360, 1323–1325 (2002).
Parr, R. L. et al. The pseudo-mitochondrial genome influences mistakes in heteroplasmy interpretation. BMC Genomics 7, 185 (2006).
Maki, J. et al. Mitochondrial genome deletion aids in the identification of false- and true-negative prostate needle core biopsy specimens. Am. J. Clin. Pathol. 129, 57–66 (2008).
Parr, R. L. et al. Somatic mitochondrial DNA mutations in prostate cancer and normal appearing adjacent glands in comparison to age-matched prostate samples without malignant histology. J. Mol. Diagn. 8, 312–319 (2006).
DiMauro, S. & Andreu, A. L. Mutations in mtDNA: are we scraping the bottom of the barrel? Brain Pathol. 10, 431–441 (2000).
Giordano, C. et al. Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy. Brain 134, 220–234 (2011).
Kaufmann, P. et al. Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype. Neurology 77, 1965–1971 (2011).
Tay, S. H. et al. Aortic rupture in mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes. Arch. Neurol. 63, 281–283 (2006).
Chong, P. S., Vucic, S., Hedley-Whyte, E. T., Dreyer, M. & Cros, D. Multiple symmetric lipomatosis (Madelung's disease) caused by the MERRF (A8344G) mutation: a report of two cases and review of the literature. J. Clin. Neuromuscul. Dis. 5, 1–7 (2003).
Suzuki, T., Nagao, A. & Suzuki, T. Human mitochondrial diseases caused by lack of taurine modification in mitochondrial tRNAs. Wiley Interdiscip. Rev. RNA 2, 376–386 (2011).
Hasegawa, H., Matsuoka, T., Goto, Y. & Nonaka, I. Cytochrome c oxidase activity is deficient in blood vessels of patients with myoclonus epilepsy with ragged-red fibers. Acta Neuropathol. 85, 280–284 (1993).
Naini, A. et al. Hypocitrullinemia in patients with MELAS: an insight into the “MELAS paradox”. J. Neurol. Sci. 229–230, 187–193 (2005).
Shiva, S., Brookes, P. S., Patel, R. P., Anderson, P. G. & Darley-Usmar, V. M. Nitric oxide partitioning into mitochondrial membranes and the control of respiration at cytochrome c oxidase. Proc. Natl Acad. Sci. USA 98, 7212–7217 (2001).
Torres, J., Darley-Usmar, V. & Wilson, M. T. Inhibition of cytochrome c oxidase in turnover by nitric oxide: mechanism and implications for control of respiration. Biochem. J. 312, 169–173 (1995).
Rodriguez-Juarez, F., Aguirre, E. & Cadenas, S. Relative sensitivity of soluble guanylate cyclase and mitochondrial respiration to endogenous nitric oxide at physiological oxygen concentration. Biochem. J. 405, 223–231 (2007).
Koga, Y. et al. L-arginine improves the symptoms of strokelike episodes in MELAS. Neurology 64, 710–712 (2005).
Horvath, R. et al. Molecular basis of infantile reversible cytochrome c oxidase deficiency myopathy. Brain 132, 3165–3174 (2009). An unexpected connection is presented in this paper between an mtDNA mutation and a mitochondrial disorder with an unusual course.
Uusimaa, J. et al. Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease. J. Med. Genet. 48, 660–668 (2011).
Umeda, N. et al. Mitochondria-specific RNA-modifying enzymes responsible for the biosynthesis of the wobble base in mitochondrial tRNAs. Implications for the molecular pathogenesis of human mitochondrial diseases. J. Biol. Chem. 280, 1613–1624 (2005).
Yan, Q. et al. Human TRMU encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase is a putative nuclear modifier gene for the phenotypic expression of the deafness-associated 12S rRNA mutations. Biochem. Biophys. Res. Commun. 342, 1130–1136 (2006).
King, M. P. & Attardi, G. Human cells lacking mtDNA: repopulation with exogenous mitochondria by complementation. Science 246, 500–503 (1989). This was the first description of the use of cybrid technology in mammalian cells.
King, M. P. & Attardi, G. Isolation of human cell lines lacking mitochondrial DNA. Methods Enzymol. 264, 304–313 (1996).
Engel, W. K. & Cunningham, G. G. Rapid examination of muscle tissue. An improved trichrome method for fresh-frozen biopsy sections. Neurology 13, 919–923 (1963).
Bonilla, E. et al. New morphological approaches to the study of mitochondrial encephalomyopathies. Brain Pathol. 2, 113–119 (1992). In this paper, a comprehensive survey is presented of morphological approaches used to diagnose and study mitochondrial diseases.
Quinzii, C. M. et al. Reactive oxygen species, oxidative stress, and cell death correlate with level of CoQ10 deficiency. FASEB J. 24, 3733–3743 (2010).
Loveland, B., Wang, C. R., Yonekawa, H., Hermel, E. & Lindahl, K. F. Maternally transmitted histocompatibility antigen of mice: a hydrophobic peptide of a mitochondrially encoded protein. Cell 60, 971–980 (1990).
Gogvadze, V., Orrenius, S. & Zhivotovsky, B. Mitochondria in cancer cells: what is so special about them? Trends Cell Biol. 18, 165–173 (2008).
Madan, E. et al. Regulation of glucose metabolism by p53: emerging new roles for the tumor suppressor. Oncotarget 2, 948–957 (2011).
van Nederveen, F. H. et al. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol. 10, 764–771 (2009).
Tomlinson, I. P. et al. Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nature Genet. 30, 406–410 (2002).
Selak, M. A. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase. Cancer Cell 7, 77–85 (2005).
Lemasters, J. J. & Holmuhamedov, E. Voltage-dependent anion channel (VDAC) as mitochondrial governator — thinking outside the box. Biochim. Biophys. Acta 1762, 181–190 (2006).
Majewski, N., Nogueira, V., Robey, R. B. & Hay, N. Akt inhibits apoptosis downstream of BID cleavage via a glucose-dependent mechanism involving mitochondrial hexokinases. Mol. Cell. Biol. 24, 730–740 (2004).
Jain, M. et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040–1044 (2012).
DiMauro, S., Hirano, M. & Schon, E. A. Approaches to the treatment of mitochondrial diseases. Muscle Nerve 34, 265–283 (2006).
The authors were supported by grants from the US National Institutes of Health (HD32062), the US Department of Defense (W911NF-12-1-0159), the Muscular Dystrophy Association, the Ellison Medical Foundation, the Alzheimer Drug Discovery Foundation and the Marriott Mitochondrial Disorder Clinical Research Fund.
Eric A. Schon is a paid consultant to Mitomics, Inc., which is developing tests to diagnose cancer on the basis of the presence of mutations in tumour mitochondrial DNA (mtDNA). Salvatore DiMauro and Michio Hirano declare no competing financial interests.
- Microarray-based sequencing
DNA sequencing based on the ability of the target DNA to hybridize to an ordered set of defined oligonucleotides immobilized on a chip.
- Monochromosomal transfer
Typically, the transfer of individual human chromosomes (or parts of chromosomes) to rodent cells in order to identify and map human genes responsible for disease.
The morphological properties of mitochondria (for example, fusion, fission, distribution, anchorage, positioning). These properties can change both in space and in time within cells.
- Primary pathogenic mtDNA mutations
Mutations that can compromise OXPHOS function and cause disease. They arise in mtDNA through processes such as random errors during normal mtDNA replication.
An involuntary, quick, rhythmic movement of the eyeball, which can be horizontal, vertical or rotary.
Paralysis of the left or right side of the body owing to a brain lesion affecting motor pathways.
- Strongly SDH-positive vessels
(SSVs). Abnormal, massive accumulation of mitochondria in blood vessels, as visualized by enzyme histochemistry to detect the activity of succinate dehydrogenase (SDH; complex II of the respiratory chain).
A term that describes the presence of two or more mtDNA genotypes within a cell, tissue or organism.
- Lactic acidosis
The abnormal accumulation of lactic acid causing lower pH in blood in a resting individual (that is, not during or immediately after exercise), which is seen in many patients with mitochondrial disease.
Involuntary jerky movement of an area of the body (usually a limb).
- Mitochondrial transmembrane potential
(Δψm). This is the electrical potential generated across the mitochondrial inner membrane due to differences in the distribution of ions (for example, H+, Ca2+, Na+, K+ and ionized ATP species) between the matrix and the intermembrane space.
- Secondary mtDNA mutations
Mutations that can compromise OXPHOS function and cause disease and that arise in mtDNA owing to a mutation in the nuclear genome that compromises mtDNA integrity (for example, a mutation in mitochondrial DNA polymerase-γ causing systemic errors in mtDNA replication).
A term that describes the presence of a single mtDNA genotype within a cell, tissue, or organism.
- Aerobic glycolysis
The conversion of glucose to lactate (and the production of ATP by substrate level phosphorylation) even in the presence of oxygen, especially in tumours.
- Double minute DNAs
(dmDNAs). Tiny fragments of extrachromosomal nuclear DNA found in many tumours, derived from the amplification of small regions of chromosomal DNA.
About this article
Cite this article
Schon, E., DiMauro, S. & Hirano, M. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat Rev Genet 13, 878–890 (2012). https://doi.org/10.1038/nrg3275
ATAD3B and SKIL polymorphisms associated with antipsychotic-induced QTc interval change in patients with schizophrenia: a genome-wide association study
Translational Psychiatry (2022)
Nature Reviews Rheumatology (2022)
Neurochemical Research (2022)
Orphanet Journal of Rare Diseases (2022)