Focus on mitochondrial form and function

Mitochondria are critical to cellular metabolism, homeostasis and stress responses, and their dysfunction is linked to human disease and pathology. In this issue, we present a Focus of specially commissioned Review articles that discuss recent discoveries and emerging questions in this rapidly advancing field.

Mitochondria sense and respond to many stressors and can support cell survival or death through energy production and signalling pathways. Mitochondrial responses depend on fusion–fission dynamics that dilute and segregate damaged mitochondria. Mitochondrial motility and inter-organellar interactions, such as with the endoplasmic reticulum, also function in cellular adaptation to stress. In this Review, we discuss how stressors influence these components, and how they contribute to the complex adaptive and pathological responses that lead to disease.

Garcia-Bermudez et al. and Sullivan et al. show that endogenous aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours, and that metformin depletes aspartate to limit tumour growth.

Garcia-Bermudez et al. and Sullivan et al. show that endogenous aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours, and that metformin depletes aspartate to limit tumour growth.

The metabolic phenotype of tumours is shaped by a complex interplay between cancer cells and their microenvironment. Two studies now show that aspartate acquisition is a metabolic limitation encountered by certain tumours in their native in vivo environment, and that overcoming this limitation is advantageous for tumour growth.

Hawk et al. show that RIPK1 activation during extracellular matrix detachment induces mitophagy through mitochondrial phosphatase PGAM5 to increase reactive oxygen species and non-apoptotic cell death, and that antagonizing RIPK1/PGAM5 enhances tumour formation.

Ahier et al. describe a method to isolate intact mitochondria from specific cells in Caenorhabditis elegans and show that the germline is more prone to propagating deleterious mitochondrial genomes than somatic lineages.

RIP3 regulates mitochondrial metabolism. Yang et al. show that RIP3 activates the pyruvate dehydrogenase complex to enhance aerobic respiration and increase mitochondrial ROS during necroptosis, and MLKL is required for RIP3 translocation to mitochondria.

Floros et al. show that mtDNA copy number is reduced and non-synonymous mtDNA mutations are eliminated to prevent mtDNA mutation accumulation in germ cells during human primordial germ cell development.

By analysing the exonuclease EXD2, Silva et al. find that it localizes to mitochondria, and that its loss alters metabolism by affecting mitochondrial translation and causes developmental delay and lifespan extension in flies.

Sato et al. identify ALLO-1 as an autophagy receptor required for paternal organelle clearance in Caenorhabditis elegans, and this process is dependent on ALLO-1 phosphorylation by the TBK1 family kinase IKKE-1.

Liu et al. find that PKM2 methylated by CARM1 inhibits Ca²⁺ influx from endoplasmic reticulum to mitochondria, thus restraining mitochondrial oxidative phosphorylation while promoting aerobic glycolysis and breast cancer growth.

Tait and colleagues show that caspase-independent cell death induced by mitochondrial permeabilization stimulates NF-κB activity through downregulation of inhibitor of apoptosis, and enhances anti-tumour effects.

Cancer treatments often focus on killing tumour cells through apoptosis, which is thought to typically require mitochondrial outer membrane permeabilization (MOMP) and subsequent caspase activation. A study now shows that MOMP can trigger TNF-dependent, but caspase-independent cell death, suggesting a different approach to improve cancer therapy.

Schell et al. demonstrate that inactivation of the mitochondrial pyruvate carrier in mouse and fly intestinal stem cells (ISCs) locks the cell into a glycolytic metabolic program and promotes the expansion of the stem cell compartment.

Flores et al. show that hair follicle stem cells rely on the production of lactate via the LDHA enzyme to become activated. Inducing Ldha through Mpc1 inhibition or Myc activation successfully reactivates the hair cycle in quiescent follicles.

Ban et al. show that optic atrophy 1 (OPA1) and cardiolipin mediate mitochondrial fusion. In contrast, a homotypic trans-OPA1 interaction independent of cardiolipin mediates membrane tethering to form mitochondrial cristae.

Fusion between the inner membranes of two mitochondria requires the GTPase optic atrophy 1 (OPA1), but the molecular mechanism is poorly understood. A study now shows that fusion of two liposomes can be performed by OPA1 tethered to just one liposome, through an interaction with the phospholipid cardiolipin on the opposing liposome.

Two papers by Liu et al. and Ansó et al. study the post-transcriptional regulation of mitochondrial factors in erythropoiesis and the role of RISP-mediated mitochondrial respiration in fetal and adult HSC function via metabolites and epigenetic changes.

Two papers by Liu et al. and Ansó et al. study the post-transcriptional regulation of mitochondrial factors in erythropoiesis and the role of RISP-mediated mitochondrial respiration in fetal and adult HSC function via metabolites and epigenetic changes.

Due to their varied metabolic and signalling roles, mitochondria are important in mediating cell behaviour. By altering mitochondrial function, two studies now identify metabolite-induced epigenetic changes that have profound effects on haematopoietic stem cell fate and function.

Lin and Wang show that methionine deprivation reprogrammes bacterial metabolism to regulate host mitochondrial dynamics and lipid metabolism in Caenorhabditis elegans through nuclear receptor and Hedgehog signalling.

Fujita et al. find that normal epithelial cells induce metabolic changes in adjacent transformed cells, causing their apical extrusion. The effect is conveyed non-cell-autonomously and relies on PDK4-mediated inhibition of mitochondrial function.

Donato et al. show that Fbxo15 targets acetylated KBP for degradation to limit mitochondrial expansion, whereas KBP accumulation promotes mitochondrial biogenesis in a Kif1Bα-dependent manner.

Saita et al. show that PARL cleaves Smac (also known as DIABLO) to generate an IAP-binding motif required for its apoptotic activity, identifying PARL-mediated Smac processing as a pro-apoptotic mitochondrial pathway.

Although the mitochondrial inner membrane rhomboid peptidase PARL is known to participate in critical signalling cascades, its role in apoptosis has remained unclear. PARL is now shown to process the mitochondrial pro-apoptotic protein Smac (also known as DIABLO) for its subsequent release into the cytosol where it antagonizes XIAP-mediated caspase inhibition to promote apoptosis.

Torrano et al. use bioinformatics analyses to identify PGC1α as a transcriptional regulator of a metabolic program downstream of ERRα that opposes metastatic dissemination in prostate cancer.