Mitochondrial signal transduction

Martin Picard1,2,3, Orian S. Shirihai4,5
1Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, 10032, USA
2New York State Psychiatric Institute, New York, NY 10032, USA
3Department of Neurology, H. Houston Merritt Center, Columbia Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, NY 10032, USA
4Metabolism Theme, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
5Department of Medicine, Endocrinology, and Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA

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Altman, 1890 Mitchell, 1961, Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism, Nature, 191, 144, 10.1038/191144a0 Chance, 1955, Respiratory enzymes in oxidative phosphorylation. V. A mechanism for oxidative phosphorylation, J. Biol. Chem., 217, 439, 10.1016/S0021-9258(19)57193-9 Siekevitz, 1957 Giles, 1980, Maternal inheritance of human mitochondrial DNA, Proc. Natl. Acad. Sci. USA, 77, 6715, 10.1073/pnas.77.11.6715 Holt, 1988, Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies, Nature, 331, 717, 10.1038/331717a0 Wallace, 1988, Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease, Cell, 55, 601, 10.1016/0092-8674(88)90218-8 Nunnari, 1997, Mitochondrial transmission during mating in Saccharomyces cerevisiae is determined by mitochondrial fusion and fission and the intramitochondrial segregation of mitochondrial DNA, Mol. Biol. Cell, 8, 1233, 10.1091/mbc.8.7.1233 Liu, 1996, Induction of apoptotic program in cell-free extracts: requirement for dATP and cytochrome c, Cell, 86, 147, 10.1016/S0092-8674(00)80085-9 Pacher, 2001, Propagation of the apoptotic signal by mitochondrial waves, EMBO J., 20, 4107, 10.1093/emboj/20.15.4107 Ono, 2001, Human cells are protected from mitochondrial dysfunction by complementation of DNA products in fused mitochondria, Nat. Genet., 28, 272, 10.1038/90116 Chen, 2010, Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations, Cell, 141, 280, 10.1016/j.cell.2010.02.026 Twig, 2008, Fission and selective fusion govern mitochondrial segregation and elimination by autophagy, EMBO J., 27, 433, 10.1038/sj.emboj.7601963 Chandel, 2015, Evolution of mitochondria as signaling organelles, Cell Metab., 22, 204, 10.1016/j.cmet.2015.05.013 Nunnari, 2012, Mitochondria: in sickness and in health, Cell, 148, 1145, 10.1016/j.cell.2012.02.035 Tyynismaa, 2010, Mitochondrial myopathy induces a starvation-like response, Hum. Mol. Genet., 19, 3948, 10.1093/hmg/ddq310 Durieux, 2011, The cell-non-autonomous nature of electron transport chain-mediated longevity, Cell, 144, 79, 10.1016/j.cell.2010.12.016 Forsstrom, 2019, Fibroblast growth factor 21 drives dynamics of local and systemic stress responses in mitochondrial myopathy with mtDNA deletions, Cell Metab., 30, 1040, 10.1016/j.cmet.2019.08.019 Nargund, 2012, Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation, Science, 337, 587, 10.1126/science.1223560 Cardamone, 2018, Mitochondrial retrograde signaling in mammals is mediated by the transcriptional cofactor GPS2 via direct mitochondria-to-nucleus translocation, Mol. Cell, 69, 757, 10.1016/j.molcel.2018.01.037 Kim, 2018, The mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress, Cell Metab., 28, 516, 10.1016/j.cmet.2018.06.008 West, 2015, Mitochondrial DNA stress primes the antiviral innate immune response, Nature, 520, 553, 10.1038/nature14156 Picard, 2014, Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming, Proc. Natl. Acad. Sci. USA, 111, E4033, 10.1073/pnas.1414028111 Tian, 2016, Mitochondrial stress induces chromatin reorganization to promote longevity and UPR(mt), Cell, 165, 1197, 10.1016/j.cell.2016.04.011 Lozoya, 2018, Mitochondrial nicotinamide adenine dinucleotide reduced (NADH) oxidation links the tricarboxylic acid (TCA) cycle with methionine metabolism and nuclear DNA methylation, PLoS Biol., 16, 10.1371/journal.pbio.2005707 Smiraglia, 2008, A novel role for mitochondria in regulating epigenetic modifications in the nucleus, Cancer Biol. Ther., 7, 1182, 10.4161/cbt.7.8.6215 Bar-Ziv, 2020, Systemic effects of mitochondrial stress, EMBO Rep., 21, 10.15252/embr.202050094 Berridge, 2018, Mitochondrial transfer between cells: methodological constraints in cell culture and animal models, Anal. Biochem., 552, 75, 10.1016/j.ab.2017.11.008 Levoux, 2021, Platelets facilitate the wound-healing capability of mesenchymal stem cells by mitochondrial transfer and metabolic reprogramming, Cell Metab., 33, 688, 10.1016/j.cmet.2021.02.003 Nicolas-Avila, 2020, A network of macrophages supports mitochondrial homeostasis in the heart, Cell, 183, 94, 10.1016/j.cell.2020.08.031 Sun, 2013, Motile axonal mitochondria contribute to the variability of presynaptic strength, Cell Rep., 4, 413, 10.1016/j.celrep.2013.06.040 Kanellopoulos, 2020, Aralar sequesters GABA into hyperactive mitochondria, causing social behavior deficits, Cell, 180, 1178, 10.1016/j.cell.2020.02.044 Miller, 2013, Steroid hormone synthesis in mitochondria, Mol. Cell. Endocrinol., 379, 62, 10.1016/j.mce.2013.04.014 Hebert-Chatelain, 2016, A cannabinoid link between mitochondria and memory, Nature, 539, 555, 10.1038/nature20127 Rath, 2021, MitoCarta3.0: an updated mitochondrial proteome now with sub-organelle localization and pathway annotations, Nucleic Acids Res., 49, D1541, 10.1093/nar/gkaa1011 Morgenstern, 2021, Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context, Cell Metab., 33, 2464, 10.1016/j.cmet.2021.11.001 Picard, 2019, Mitochondrial psychobiology: foundations and applications, Curr. Opin. Behav. Sci., 28, 142, 10.1016/j.cobeha.2019.04.015 Buck, 2017, Metabolic instruction of immunity, Cell, 169, 570, 10.1016/j.cell.2017.04.004 Hollis, 2015, Mitochondrial function in the brain links anxiety with social subordination, Proc. Natl. Acad. Sci. USA, 112, 15486, 10.1073/pnas.1512653112 Picard, 2015, Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress, Proc. Natl. Acad. Sci. USA, 112, E6614, 10.1073/pnas.1515733112 Gumpp, 2020, Childhood maltreatment is associated with changes in mitochondrial bioenergetics in maternal, but not in neonatal immune cells, Proc. Natl. Acad. Sci. USA, 117, 24778, 10.1073/pnas.2005885117 Picard, 2018, A mitochondrial health index sensitive to mood and caregiving stress, Biol. Psychiatry, 84, 9, 10.1016/j.biopsych.2018.01.012 Hill, 2019, Bioenergetics and translational metabolism: implications for genetics, physiology and precision medicine, Biol. Chem., 401, 3, 10.1515/hsz-2019-0268 McBride, 2006, Mitochondria: more than just a powerhouse, Curr. Biol., 16, R551, 10.1016/j.cub.2006.06.054 Chakrabarty, 2022, Beyond ATP, new roles of mitochondria, Biochemist, 44, 2, 10.1042/bio_2022_119 Kellogg, 2015, Digital signaling decouples activation probability and population heterogeneity, eLife, 4, 10.7554/eLife.08931 Gottschling, 2017, The upsides and downsides of organelle interconnectivity, Cell, 169, 24, 10.1016/j.cell.2017.02.030 Lynn, 2019, The physics of brain network structure, function and control, Nat. Rev. Phys., 1, 318, 10.1038/s42254-019-0040-8 Sagan, 1967, On the origin of mitosing cells, J. Theor. Biol., 14, 225, 10.1016/0022-5193(67)90079-3 Birch, 2017, The multicellular organism as a social phenomenon, 165 Levin, 2021, Bioelectric signaling: reprogrammable circuits underlying embryogenesis, regeneration, and cancer, Cell, 184, 1971, 10.1016/j.cell.2021.02.034 Kerr, 2019, Intracellular energy variability modulates cellular decision-making capacity, Sci. Rep., 9, 10.1038/s41598-019-56587-5 Katajisto, 2015, Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness, Science, 348, 340, 10.1126/science.1260384 Nijhout, 2017, Systems biology of phenotypic robustness and plasticity, Integr. Comp. Biol., 57, 171, 10.1093/icb/icx076 Sterling, 2020 Rubalcava-Gracia, 2022, No role for nuclear transcription regulators in mammalian mitochondria?, Mol. Cell, 10.1016/j.molcel.2022.09.010 Wrutniak-Cabello, 2001, Thyroid hormone action in mitochondria, J. Mol. Endocrinol., 26, 67, 10.1677/jme.0.0260067 Sterling, 1984, Purification of the mitochondrial triiodothyronine (T3) receptor from rat liver, Acta Endocrinol., 105, 391, 10.1530/acta.0.1050391 Sterling, 1978, Mitochondrial thyroid hormone receptor: localization and physiological significance, Science, 201, 1126, 10.1126/science.210507 Sterling, 1977, Thyroid hormone action: the mitochondrial pathway, Science, 197, 996, 10.1126/science.196334 Wrutniak, 1995, A 43-kDa protein related to c-Erb A alpha 1 is located in the mitochondrial matrix of rat liver, J. Biol. Chem., 270, 16347, 10.1074/jbc.270.27.16347 Casas, 1999, A variant form of the nuclear triiodothyronine receptor c-ErbAα1 plays a direct role in regulation of mitochondrial RNA synthesis, Mol. Cell Biol., 19, 7913, 10.1128/MCB.19.12.7913 Enriquez, 1999, Direct regulation of mitochondrial RNA synthesis by thyroid hormone, Mol. Cell Biol., 19, 657, 10.1128/MCB.19.1.657 Fernandez-Vizarra, 2008, Mitochondrial gene expression is regulated at multiple levels and differentially in the heart and liver by thyroid hormones, Curr. Genet., 54, 13, 10.1007/s00294-008-0194-x Casas, 2008, Overexpression of the mitochondrial T3 receptor p43 induces a shift in skeletal muscle fiber types, PLoS One, 3, 10.1371/journal.pone.0002501 Wrutniak-Cabello, 2018, Thyroid hormone action: the p43 mitochondrial pathway, Methods Mol. Biol., 1801, 163, 10.1007/978-1-4939-7902-8_14 Mosselman, 1996, ERβ: identification and characterization of a novel human estrogen receptor, FEBS Lett., 392, 49, 10.1016/0014-5793(96)00782-X Klinge, 2017, Estrogens regulate life and death in mitochondria, J. Bioenerg. Biomembr., 49, 307, 10.1007/s10863-017-9704-1 Yang, 2004, Mitochondrial localization of estrogen receptor β, Proc. Natl. Acad. Sci. USA, 101, 4130, 10.1073/pnas.0306948101 Solakidi, 2005, Differential subcellular distribution of estrogen receptor isoforms: localization of ERα in the nucleoli and ERβ in the mitochondria of human osteosarcoma SaOS-2 and hepatocarcinoma HepG2 cell lines, Biochim. Biophys. Acta, 1745, 382, 10.1016/j.bbamcr.2005.05.010 Zhang, 2010, Ligand-independent antiapoptotic function of estrogen receptor-beta in lung cancer cells, Mol. Endocrinol., 24, 1737, 10.1210/me.2010-0125 Giordano, 2011, Oestrogens ameliorate mitochondrial dysfunction in Leber's hereditary optic neuropathy, Brain, 134, 220, 10.1093/brain/awq276 Bajpai, 2019, Mitochondrial localization, import, and mitochondrial function of the androgen receptor, J. Biol. Chem., 294, 6621, 10.1074/jbc.RA118.006727 Solakidi, 2005, Estrogen receptors α and β (ERα and ERβ) and androgen receptor (AR) in human sperm: localization of ERβ and AR in mitochondria of the midpiece, Hum. Reprod., 20, 3481, 10.1093/humrep/dei267 Ventura-Clapier, 2017, Mitochondria: a central target for sex differences in pathologies, Clin. Sci. (Lond.), 131, 803, 10.1042/CS20160485 Junker, 2022, Human studies of mitochondrial biology demonstrate an overall lack of binary sex differences: a multivariate meta-analysis, FASEB J., 36, 10.1096/fj.202101628R Hollenberg, 1985, Primary structure and expression of a functional human glucocorticoid receptor cDNA, Nature, 318, 635, 10.1038/318635a0 Rivers, 1999, Insertion of an amino acid in the DNA-binding domain of the glucocorticoid receptor as a result of alternative splicing, J. Clin. Endocrinol. Metab., 84, 4283, 10.1210/jcem.84.11.6235 Yu, 1970, A comparative study of RNA synthesis in rat hepatic nuclei and mitochondria under the influence of cortisone, Biochim. Biophys. Acta, 213, 134, 10.1016/0005-2787(70)90014-6 Demonacos, 1995, The mitochondrion as a primary site of action of glucocorticoids: the interaction of the glucocorticoid receptor with mitochondrial DNA sequences showing partial similarity to the nuclear glucocorticoid responsive elements, J. Steroid Biochem. Mol. Biol., 55, 43, 10.1016/0960-0760(95)00159-W Tsiriyotis, 1997, The mitochondrion as a primary site of action of glucocorticoids: mitochondrial nucleotide sequences, showing similarity to hormone response elements, confer dexamethasone inducibility to chimaeric genes transfected in LATK- cells, Biochem. Biophys. Res. Commun., 235, 349, 10.1006/bbrc.1997.6787 Polman, 2012, A genome-wide signature of glucocorticoid receptor binding in neuronal PC12 cells, BMC Neurosci., 13, 118, 10.1186/1471-2202-13-118 Morgan, 2016, Glucocorticoid receptor isoforms direct distinct mitochondrial programs to regulate ATP production, Sci. Rep., 6, 10.1038/srep26419 Psarra, 2011, Glucocorticoids induce mitochondrial gene transcription in HepG2 cells: role of the mitochondrial glucocorticoid receptor, Biochim. Biophys. Acta, 1813, 1814, 10.1016/j.bbamcr.2011.05.014 Simoes, 2012, Glucocorticoid and estrogen receptors are reduced in mitochondria of lung epithelial cells in asthma, PLoS One, 7, 10.1371/journal.pone.0039183 Abadir, 2011, Identification and characterization of a functional mitochondrial angiotensin system, Proc. Natl. Acad. Sci. USA, 108, 14849, 10.1073/pnas.1101507108 Suofu, 2017, Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release, Proc. Natl. Acad. Sci. USA, 114, E7997, 10.1073/pnas.1705768114 Benard, 2012, Mitochondrial CB(1) receptors regulate neuronal energy metabolism, Nat. Neurosci., 15, 558, 10.1038/nn.3053 Belous, 2006, Mitochondrial calcium transport is regulated by P2Y1- and P2Y2-like mitochondrial receptors, J. Cell. Biochem., 99, 1165, 10.1002/jcb.20985 Jong, 2018, Intracellular GPCRs play key roles in synaptic plasticity, ACS Chem. Neurosci., 9, 2162, 10.1021/acschemneuro.7b00516 Abadir, 2012, Subcellular characteristics of functional intracellular renin-angiotensin systems, Peptides, 38, 437, 10.1016/j.peptides.2012.09.016 Reiter, 2021, Melatonin synthesis in and uptake by mitochondria: implications for diseased cells with dysfunctional mitochondria, Future Med. Chem., 13, 335, 10.4155/fmc-2020-0326 Guo, 2014, Melatonin improves mitochondrial function by promoting MT1/SIRT1/PGC-1 alpha-dependent mitochondrial biogenesis in cadmium-induced hepatotoxicity in vitro, Toxicol. Sci., 142, 182, 10.1093/toxsci/kfu164 Gutierrez-Rodriguez, 2018, Localization of the cannabinoid type-1 receptor in subcellular astrocyte compartments of mutant mouse hippocampus, Glia, 66, 1417, 10.1002/glia.23314 Mendizabal-Zubiaga, 2016, Cannabinoid CB1 receptors are localized in striated muscle mitochondria and regulate mitochondrial respiration, Front. Physiol., 7, 476, 10.3389/fphys.2016.00476 Belous, 2004, Mitochondrial P2Y-like receptors link cytosolic adenosine nucleotides to mitochondrial calcium uptake, J. Cell. Biochem., 92, 1062, 10.1002/jcb.20144 Sarti, 2021, Mitochondrial P2X7 receptor localization modulates energy metabolism enhancing physical performance, Function (Oxf)., 2, zqab005, 10.1093/function/zqab005 Wyant, 2022, Mitochondrial remodeling and ischemic protection by G protein-coupled receptor 35 agonists, Science, 377, 621, 10.1126/science.abm1638 Lykhmus, 2014, Mitochondria express several nicotinic acetylcholine receptor subtypes to control various pathways of apoptosis induction, Int. J. Biochem. Cell Biol., 53, 246, 10.1016/j.biocel.2014.05.030 Lu, 2014, α7 nicotinic acetylcholine receptor signaling inhibits inflammasome activation by preventing mitochondrial DNA release, Mol. Med., 20, 350, 10.2119/molmed.2013.00117 Nicholls, 2013 Ruprecht, 2019, The molecular mechanism of transport by the mitochondrial ADP/ATP carrier, Cell, 176, 435, 10.1016/j.cell.2018.11.025 Nelson, 2021, Intrinsic OXPHOS limitations underlie cellular bioenergetics in leukemia, eLife, 10, e63104, 10.7554/eLife.63104 Hackenbrock, 1968, Ultrastructural bases for metabolically linked mechanical activity in mitochondria. II. Electron transport-linked ultrastructural transformations in mitochondria, J. Cell Biol., 37, 345, 10.1083/jcb.37.2.345 Taylor, 2017, Functional properties of the mitochondrial carrier system, Trends Cell Biol., 27, 633, 10.1016/j.tcb.2017.04.004 Ruprecht, 2020, The SLC25 mitochondrial carrier family: structure and mechanism, Trends Biochem. Sci., 45, 244, 10.1016/j.tibs.2019.11.001 Bricker, 2012, A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans, Science, 337, 96, 10.1126/science.1218099 Herzig, 2012, Identification and functional expression of the mitochondrial pyruvate carrier, Science, 337, 93, 10.1126/science.1218530 Kory, 2020, MCART1/SLC25A51 is required for mitochondrial NAD transport, Sci. Adv., 6, eabe5310, 10.1126/sciadv.abe5310 Yoo, 2020, A variant of SLC1A5 is a mitochondrial glutamine transporter for metabolic reprogramming in cancer cells, Cell Metab., 31, 267, 10.1016/j.cmet.2019.11.020 Abdullah, 2022, Mitochondrial hyperfusion via metabolic sensing of regulatory amino acids, Cell Rep., 40, 10.1016/j.celrep.2022.111198 Lane, 2022 Sharma, 2021, Circulating markers of NADH-reductive stress correlate with mitochondrial disease severity, J. Clin. Invest., 131, 136055, 10.1172/JCI136055 Goodman, 2020, Hepatic NADH reductive stress underlies common variation in metabolic traits, Nature, 583, 122, 10.1038/s41586-020-2337-2 Khan, 2017, mTORC1 regulates mitochondrial integrated stress response and mitochondrial myopathy progression, Cell Metab., 26, 419, 10.1016/j.cmet.2017.07.007 Nikkanen, 2016, Mitochondrial DNA replication defects disturb cellular dNTP pools and remodel one-carbon metabolism, Cell Metab., 23, 635, 10.1016/j.cmet.2016.01.019 Wellen, 2009, ATP-citrate lyase links cellular metabolism to histone acetylation, Science, 324, 1076, 10.1126/science.1164097 Carrico, 2018, The mitochondrial acylome emerges: proteomics, regulation by sirtuins, and metabolic and disease implications, Cell Metab., 27, 497, 10.1016/j.cmet.2018.01.016 Spinelli, 2018, The multifaceted contributions of mitochondria to cellular metabolism, Nat. Cell Biol., 20, 745, 10.1038/s41556-018-0124-1 Baughman, 2011, Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter, Nature, 476, 341, 10.1038/nature10234 De Stefani, 2011, A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter, Nature, 476, 336, 10.1038/nature10230 Glancy, 2012, Role of mitochondrial ca(2+) in the regulation of cellular energetics, Biochemistry, 51, 2959, 10.1021/bi2018909 Wescott, 2019, Voltage-energized calcium-sensitive ATP production by mitochondria, Nat. Metab., 1, 975, 10.1038/s42255-019-0126-8 Koval, 2019, Loss of MCU prevents mitochondrial fusion in G1-S phase and blocks cell cycle progression and proliferation, Sci. Signal., 12, eaav1439, 10.1126/scisignal.aav1439 Palty, 2004, Lithium-calcium exchange is mediated by a distinct potassium-independent sodium-calcium exchanger, J. Biol. Chem., 279, 25234, 10.1074/jbc.M401229200 Nita, 2014, Pancreatic beta-cell Na+ channels control global Ca2+ signaling and oxidative metabolism by inducing Na+ and Ca2+ responses that are propagated into mitochondria, FASEB J., 28, 3301, 10.1096/fj.13-248161 Luongo, 2017, The mitochondrial Na(+)/Ca(2+) exchanger is essential for Ca(2+) homeostasis and viability, Nature, 545, 93, 10.1038/nature22082 Assali, 2020, NCLX prevents cell death during adrenergic activation of the brown adipose tissue, Nat. Commun., 11, 3347, 10.1038/s41467-020-16572-3 Hernansanz-Agustin, 2020, Na(+) controls hypoxic signalling by the mitochondrial respiratory chain, Nature, 586, 287, 10.1038/s41586-020-2551-y de Sousa, 2015, Lithium increases leukocyte mitochondrial complex I activity in bipolar disorder during depressive episodes, Psychopharmacology (Berl), 232, 245, 10.1007/s00213-014-3655-6 Lundberg, 2022, Nitric oxide signaling in health and disease, Cell, 185, 2853, 10.1016/j.cell.2022.06.010 Arias-Mayenco, 2018, Acute O2 sensing: role of coenzyme QH2/Q ratio and mitochondrial ROS compartmentalization, Cell Metab., 28, 145, 10.1016/j.cmet.2018.05.009 Fernández-Agüera, 2015, Oxygen sensing by arterial chemoreceptors depends on mitochondrial complex I signaling, Cell Metab., 22, 825, 10.1016/j.cmet.2015.09.004 Guzy, 2005, Mitochondrial complex III is required for hypoxia-induced ROS production and cellular oxygen sensing, Cell Metab., 1, 401, 10.1016/j.cmet.2005.05.001 Semenza, 2009, Regulation of oxygen homeostasis by hypoxia-inducible factor 1, Physiology, 24, 97, 10.1152/physiol.00045.2008 Gustafsson, 2016, Maintenance and expression of mammalian mitochondrial DNA, Annu. Rev. Biochem., 85, 133, 10.1146/annurev-biochem-060815-014402 Merry, 2020, Mitochondrial-derived peptides in energy metabolism, Am. J. Physiol. Endocrinol. Metab., 319, E659, 10.1152/ajpendo.00249.2020 Chomyn, 1992, MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts, Proc. Natl. Acad. Sci. USA, 89, 4221, 10.1073/pnas.89.10.4221 Payne, 2011, Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations, Nat. Genet., 43, 806, 10.1038/ng.863 Gorman, 2016, Mitochondrial diseases, Nat. Rev. Dis. Primers, 2, 10.1038/nrdp.2016.80 Taylor, 2005, Mitochondrial DNA mutations in human disease, Nat. Rev. Genet., 6, 389, 10.1038/nrg1606 Shaham, 2010, A plasma signature of human mitochondrial disease revealed through metabolic profiling of spent media from cultured muscle cells, Proc. Natl. Acad. Sci. USA, 107, 1571, 10.1073/pnas.0906039107 Vincent, 2018, Subcellular origin of mitochondrial DNA deletions in human skeletal muscle, Ann. Neurol., 84, 289, 10.1002/ana.25288 Cai, 2021, Mitochondrial DNA variants modulate N-formylmethionine, proteostasis and risk of late-onset human diseases, Nat. Med., 27, 1564, 10.1038/s41591-021-01441-3 Latorre-Pellicer, 2016, Mitochondrial and nuclear DNA matching shapes metabolism and healthy ageing, Nature, 535, 561, 10.1038/nature18618 Yonova-Doing, 2021, An atlas of mitochondrial DNA genotype-phenotype associations in the UK Biobank, Nat. Genet., 53, 982, 10.1038/s41588-021-00868-1 Wu, 2019, Mitochondrial DNA stress signalling protects the nuclear genome, Nat. Metab., 1, 1209, 10.1038/s42255-019-0150-8 Chanprasert, 2013, Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene, Mol. Genet. Metab., 110, 153, 10.1016/j.ymgme.2013.07.009 Sassone-Corsi, 2012, The cyclic AMP pathway, Cold Spring Harbor Perspect. Biol., 4, a011148, 10.1101/cshperspect.a011148 Kandel, 2021 Keidar Haran, 2022, From genes to modules, from cells to ecosystems, Mol. Syst. Biol., 18, 10.15252/msb.202110726 Picard, 2021, The social nature of mitochondria: implications for human health, Neurosci. Biobehav. Rev., 120, 595, 10.1016/j.neubiorev.2020.04.017 Hein, 2015, The evolution of distributed sensing and collective computation in animal populations, eLife, 4, 10.7554/eLife.10955 Sosna, 2019, Individual and collective encoding of risk in animal groups, Proc. Natl. Acad. Sci. USA, 116, 20556, 10.1073/pnas.1905585116 Barabasi, 2004, Network biology: understanding the cell's functional organization, Nat. Rev. Genet., 5, 101, 10.1038/nrg1272 Kadushin, 2012 Arimura, 2004, Frequent fusion and fission of plant mitochondria with unequal nucleoid distribution, Proc. Natl. Acad. Sci. USA, 101, 7805, 10.1073/pnas.0401077101 Liu, 2009, Mitochondrial 'kiss-and-run': interplay between mitochondrial motility and fusion-fission dynamics, EMBO J., 28, 3074, 10.1038/emboj.2009.255 Yang, 2015, Mitochondrial fusion provides an 'initial metabolic complementation' controlled by mtDNA, Cell. Mol. Life Sci., 72, 2585, 10.1007/s00018-015-1863-9 Bakeeva, 1983, Intermitochondrial contacts in myocardiocytes, J. Mol. Cell. Cardiol., 15, 413, 10.1016/0022-2828(83)90261-4 Amchenkova, 1988, Coupling membranes as energy-transmitting cables. I. Filamentous mitochondria in fibroblasts and mitochondrial clusters in cardiomyocytes, J. Cell Biol., 107, 481, 10.1083/jcb.107.2.481 Picard, 2013, Acute exercise remodels mitochondrial membrane interactions in mouse skeletal muscle, J. Appl. Physiol., 115, 1562, 10.1152/japplphysiol.00819.2013 Picard, 2015, Trans-mitochondrial coordination of cristae at regulated membrane junctions, Nat. Commun., 6, 6259, 10.1038/ncomms7259 Vernay, 2017, MitoNEET-dependent formation of intermitochondrial junctions, Proc. Natl. Acad. Sci. USA, 114, 8277, 10.1073/pnas.1706643114 Santo-Domingo, 2013, OPA1 promotes pH flashes that spread between contiguous mitochondria without matrix protein exchange, EMBO J., 32, 1927, 10.1038/emboj.2013.124 Glancy, 2017, Power grid protection of the muscle mitochondrial reticulum, Cell Rep., 19, 487, 10.1016/j.celrep.2017.03.063 Vincent, 2017, Mitochondrial nanotunnels, Trends Cell Biol., 27, 787, 10.1016/j.tcb.2017.08.009 Huang, 2013, Kissing and nanotunneling mediate intermitochondrial communication in the heart, Proc. Natl. Acad. Sci. USA, 110, 2846, 10.1073/pnas.1300741110 Wang, 2015, Dynamic tubulation of mitochondria drives mitochondrial network formation, Cell Res., 25, 1108, 10.1038/cr.2015.89 Vincent, 2019, Quantitative 3D mapping of the human skeletal muscle mitochondrial network, Cell Rep., 26, 996, 10.1016/j.celrep.2019.01.010 Lavorato, 2017, Increased mitochondrial nanotunneling activity, induced by calcium imbalance, affects intermitochondrial matrix exchanges, Proc. Natl. Acad. Sci. USA, 114, E849, 10.1073/pnas.1617788113 Ji, 2021, Brain microvasculature has a common topology with local differences in geometry that match metabolic load, Neuron, 109, 1168, 10.1016/j.neuron.2021.02.006 Han, 2004, Evidence for dynamically organized modularity in the yeast protein-protein interaction network, Nature, 430, 88, 10.1038/nature02555 Brady, 2004, Coordinated behavior of mitochondria in both space and time: a reactive oxygen species-activated wave of mitochondrial depolarization, Biophys. J., 87, 2022, 10.1529/biophysj.103.035097 Zhou, 2010, A reaction-diffusion model of ROS-induced ROS release in a mitochondrial network, PLoS Comput. Biol., 6, 10.1371/journal.pcbi.1000657 Friedman, 2014, Mitochondrial form and function, Nature, 505, 335, 10.1038/nature12985 Twig, 2006, Tagging and tracking individual networks within a complex mitochondrial web with photoactivatable GFP, Am. J. Physiol. Cell Physiol., 291, C176, 10.1152/ajpcell.00348.2005 Eisner, 2017, Mitochondrial fusion dynamics is robust in the heart and depends on calcium oscillations and contractile activity, Proc. Natl. Acad. Sci. USA, 114, E859, 10.1073/pnas.1617288114 Molina, 2009, Monitoring mitochondrial dynamics with photoactivatable [corrected] green fluorescent protein., Methods Enzymol., 457, 289, 10.1016/S0076-6879(09)05016-2 Eisner, 2014, Mitochondrial fusion is frequent in skeletal muscle and supports excitation-contraction coupling, J. Cell Biol., 205, 179, 10.1083/jcb.201312066 Schauss, 2010, A novel cell-free mitochondrial fusion assay amenable for high-throughput screenings of fusion modulators, BMC Biol., 8, 100, 10.1186/1741-7007-8-100 Paltauf-Doburzynska, 2004, Hyperglycemic conditions affect shape and Ca2+ homeostasis of mitochondria in endothelial cells, J. Cardiovasc. Pharmacol., 44, 423, 10.1097/01.fjc.0000139449.64337.1b Shenouda, 2011, Altered mitochondrial dynamics contributes to endothelial dysfunction in diabetes mellitus, Circulation, 124, 444, 10.1161/CIRCULATIONAHA.110.014506 Yu, 2006, Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology, Proc. Natl. Acad. Sci. USA, 103, 2653, 10.1073/pnas.0511154103 Kleele, 2021, Distinct fission signatures predict mitochondrial degradation or biogenesis, Nature, 593, 435, 10.1038/s41586-021-03510-6 Liesa, 2013, Mitochondrial dynamics in the regulation of nutrient utilization and energy expenditure, Cell Metab., 17, 491, 10.1016/j.cmet.2013.03.002 Picard, 2013, Linking the metabolic state and mitochondrial DNA in chronic disease, health, and aging, Diabetes, 62, 672, 10.2337/db12-1203 Gomes, 2011, During autophagy mitochondria elongate, are spared from degradation and sustain cell viability, Nat. Cell Biol., 13, 589, 10.1038/ncb2220 Rambold, 2011, Tubular network formation protects mitochondria from autophagosomal degradation during nutrient starvation, Proc. Natl. Acad. Sci. USA, 108, 10190, 10.1073/pnas.1107402108 Wang, 2012, Mitochondrial fission triggered by hyperglycemia is mediated by ROCK1 activation in podocytes and endothelial cells, Cell Metab., 15, 186, 10.1016/j.cmet.2012.01.009 Molina, 2009, Mitochondrial networking protects beta-cells from nutrient-induced apoptosis, Diabetes, 58, 2303, 10.2337/db07-1781 Picard, 2015, Mechanical ventilation triggers abnormal mitochondrial dynamics and morphology in the diaphragm, J. Appl. Physiol., 118, 1161, 10.1152/japplphysiol.00873.2014 Cogliati, 2013, Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency, Cell, 155, 160, 10.1016/j.cell.2013.08.032 Wikstrom, 2014, Hormone-induced mitochondrial fission is utilized by brown adipocytes as an amplification pathway for energy expenditure, EMBO J., 33, 418 Liston, 2013, Circadian glucocorticoid oscillations promote learning-dependent synapse formation and maintenance, Nat. Neurosci., 16, 698, 10.1038/nn.3387 Twig, 2010, Biophysical properties of mitochondrial fusion events in pancreatic beta-cells and cardiac cells unravel potential control mechanisms of its selectivity, Am. J. Physiol. Cell Physiol., 299, C477, 10.1152/ajpcell.00427.2009 Al-Mehdi, 2012, Perinuclear mitochondrial clustering creates an oxidant-rich nuclear domain required for hypoxia-induced transcription, Sci. Signal., 5, ra47, 10.1126/scisignal.2002712 Oikawa, 2021, Mitochondrial movement during its association with chloroplasts in Arabidopsis thaliana, Commun. Biol., 4, 292, 10.1038/s42003-021-01833-8 Eisner, 2018, Mitochondrial dynamics in adaptive and maladaptive cellular stress responses, Nat. Cell Biol., 20, 755, 10.1038/s41556-018-0133-0 Kruppa, 2021, Motor proteins at the mitochondria-cytoskeleton interface, J. Cell Sci., 134, jcs226084, 10.1242/jcs.226084 Pekkurnaz, 2022, Mitochondrial heterogeneity and homeostasis through the lens of a neuron, Nat. Metab., 4, 802, 10.1038/s42255-022-00594-w Yi, 2004, Control of mitochondrial motility and distribution by the calcium signal: a homeostatic circuit, J. Cell Biol., 167, 661, 10.1083/jcb.200406038 Pekkurnaz, 2014, Glucose regulates mitochondrial motility via Milton modification by O-GlcNAc transferase, Cell, 158, 54, 10.1016/j.cell.2014.06.007 Wong, 2019, Lysosomal regulation of inter-mitochondrial contact fate and motility in Charcot-Marie-Tooth type 2, Dev. Cell, 50, 339, 10.1016/j.devcel.2019.05.033 English, 2019, Knowing when to let go: lysosomes regulate inter-mitochondrial tethering, Dev. Cell, 50, 259, 10.1016/j.devcel.2019.07.019 Murley, 2016, The emerging network of mitochondria-organelle contacts, Mol. Cell, 61, 648, 10.1016/j.molcel.2016.01.031 Csordas, 2018, Endoplasmic reticulum-mitochondrial contactology: structure and signaling functions, Trends Cell Biol., 28, 523, 10.1016/j.tcb.2018.02.009 Selvaraj, 2018, Current knowledge on the acute regulation of steroidogenesis, Biol. Reprod., 99, 13, 10.1093/biolre/ioy102 Kornmann, 2009, An ER-mitochondria tethering complex revealed by a synthetic biology screen, Science, 325, 477, 10.1126/science.1175088 Lahiri, 2014, A conserved endoplasmic reticulum membrane protein complex (EMC) facilitates phospholipid transfer from the ER to mitochondria, PLoS Biol., 12, 10.1371/journal.pbio.1001969 Booth, 2021, Oxidative bursts of single mitochondria mediate retrograde signaling toward the ER, Mol. Cell, 81, 3866, 10.1016/j.molcel.2021.07.014 Kasai, 2021, Spine dynamics in the brain, mental disorders and artificial neural networks, Nat. Rev. Neurosci., 22, 407, 10.1038/s41583-021-00467-3 Kasahara, 2014, Mitochondria: from cell death executioners to regulators of cell differentiation, Trends Cell Biol., 24, 761, 10.1016/j.tcb.2014.08.005 Balaban, 2005, Mitochondria, oxidants, and aging, Cell, 120, 483, 10.1016/j.cell.2005.02.001 Shadel, 2015, Mitochondrial ROS signaling in organismal homeostasis, Cell, 163, 560, 10.1016/j.cell.2015.10.001 Martinez-Reyes, 2020, Mitochondrial TCA cycle metabolites control physiology and disease, Nat. Commun., 11, 102, 10.1038/s41467-019-13668-3 Jiang, 1999, Cytochrome c-mediated apoptosis in cells lacking mitochondrial DNA, J. Biol. Chem., 274, 29905, 10.1074/jbc.274.42.29905 Picard, 2013, Mitochondrial morphology transitions and functions: implications for retrograde signaling?, Am. J. Physiol. Regul. Integr. Comp. Physiol., 304, R393, 10.1152/ajpregu.00584.2012 Bernardi, 2015, The mitochondrial permeability transition pore: channel formation by F-ATP synthase, integration in signal transduction, and role in pathophysiology, Physiol. Rev., 95, 1111, 10.1152/physrev.00001.2015 Wang, 2009, The role of mitochondria in apoptosis, Annu. Rev. Genet., 43, 95, 10.1146/annurev-genet-102108-134850 Kalkavan, 2022, Sublethal cytochrome c release generates drug-tolerant persister cells, Cell, 185, 3356, 10.1016/j.cell.2022.07.025 Gottschalk, 2022, Cristae junction as a fundamental switchboard for mitochondrial ion signaling and bioenergetics, Cell Calcium, 101, 10.1016/j.ceca.2021.102517 Brookes, 2004, Calcium, ATP, and ROS: a mitochondrial love-hate triangle, Am. J. Physiol. Cell Physiol., 287, C817, 10.1152/ajpcell.00139.2004 Sebastian, 2017, The various metabolic sources of histone acetylation, Trends Endocrinol. Metab., 28, 85, 10.1016/j.tem.2016.11.001 Diehl, 2020, Chromatin as a key consumer in the metabolite economy, Nat. Chem. Biol., 16, 620, 10.1038/s41589-020-0517-x Dai, 2020, The evolving metabolic landscape of chromatin biology and epigenetics, Nat. Rev. Genet., 21, 737, 10.1038/s41576-020-0270-8 Santos, 2021, Mitochondria signaling to the epigenome: a novel role for an old organelle, Free Radic. Biol. Med., 170, 59, 10.1016/j.freeradbiomed.2020.11.016 Mentch, 2016, One-carbon metabolism and epigenetics: understanding the specificity, Ann. N. Y. Acad. Sci., 1363, 91, 10.1111/nyas.12956 Bao, 2016, Mitochondrial dysfunction remodels one-carbon metabolism in human cells, eLife, 5, e10575, 10.7554/eLife.10575 Zhang, 2019, Metabolic regulation of gene expression by histone lactylation, Nature, 574, 575, 10.1038/s41586-019-1678-1 Lepack, 2020, Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking, Science, 368, 197, 10.1126/science.aaw8806 Graves, 2020, Dopamine metabolism by a monoamine oxidase mitochondrial shuttle activates the electron transport chain, Nat. Neurosci., 23, 15, 10.1038/s41593-019-0556-3 Huang, 2021, The regulatory enzymes and protein substrates for the lysine beta-hydroxybutyrylation pathway, Sci. Adv., 7, eabe2771, 10.1126/sciadv.abe2771 Kopinski, 2019, Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy, Proc. Natl. Acad. Sci. USA, 116, 16028, 10.1073/pnas.1906896116 Lozoya, 2019, Mitochondrial acetyl-CoA reversibly regulates locus-specific histone acetylation and gene expression, Life Sci. Alliance, 2, e201800228, 10.26508/lsa.201800228 Sturm, 2021, OxPhos dysfunction causes hypermetabolism and reduces lifespan in cells and in patients with mitochondrial diseases, Preprint at bioRxiv Sturm, 2022, A multi-omics and bioenergetics longitudinal aging dataset in primary human fibroblasts with mitochondrial perturbations, Preprint at bioRxiv Kafkia, 2022, Operation of a TCA cycle subnetwork in the mammalian nucleus, Sci. Adv., 8, 10.1126/sciadv.abq5206 Lampropoulou, 2016, Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation, Cell Metab., 24, 158, 10.1016/j.cmet.2016.06.004 Bambouskova, 2018, Electrophilic properties of itaconate and derivatives regulate the IκBζ–ATF3 inflammatory axis, Nature, 556, 501, 10.1038/s41586-018-0052-z Intlekofer, 2017, L-2-hydroxyglutarate production arises from noncanonical enzyme function at acidic pH, Nat. Chem. Biol., 13, 494, 10.1038/nchembio.2307 Colvin, 2016, Oncometabolite D-2-hydroxyglurate directly induces epithelial-mesenchymal transition and is associated with distant metastasis in colorectal cancer, Sci. Rep., 6, 10.1038/srep36289 Tyrakis, 2016, S-2-hydroxyglutarate regulates CD8(+) T-lymphocyte fate, Nature, 540, 236, 10.1038/nature20165 Funai, 2020, Reign in the membrane: how common lipids govern mitochondrial function, Curr. Opin. Cell Biol., 63, 162, 10.1016/j.ceb.2020.01.006 Dudek, 2017, Role of cardiolipin in mitochondrial signaling pathways, Front. Cell Dev. Biol., 5, 90, 10.3389/fcell.2017.00090 Pouikli, 2021, Metabolism and chromatin: a dynamic duo that regulates development and ageing, Bioessays, 43, 10.1002/bies.202000273 Murphy, 2022, Why succinate? Physiological regulation by a mitochondrial coenzyme Q sentinel, Nat. Chem. Biol., 18, 461, 10.1038/s41589-022-01004-8 Mills, 2021, UCP1 governs liver extracellular succinate and inflammatory pathogenesis, Nat. Metab., 3, 604, 10.1038/s42255-021-00389-5 Gudgeon, 2022, Succinate uptake by T cells suppresses their effector function via inhibition of mitochondrial glucose oxidation, Cell Rep., 40, 10.1016/j.celrep.2022.111193 Paul, 2019, Blunted nocturnal salivary melatonin secretion profiles in military-related posttraumatic stress disorder, Front. Psychiatry, 10, 882, 10.3389/fpsyt.2019.00882 Gandhi, 2015, Melatonin is required for the circadian regulation of sleep, Neuron, 85, 1193, 10.1016/j.neuron.2015.02.016 van Geijlswijk, 2010, The use of exogenous melatonin in delayed sleep phase disorder: a meta-analysis, Sleep, 33, 1605, 10.1093/sleep/33.12.1605 Cipolla-Neto, 2018, Melatonin as a hormone: new physiological and clinical insights, Endocr. Rev., 39, 990, 10.1210/er.2018-00084 Lambert, 2009, Reactive oxygen species production by mitochondria, Methods Mol. Biol., 554, 165, 10.1007/978-1-59745-521-3_11 Desai, 2020, Mitochondria form contact sites with the nucleus to couple prosurvival retrograde response, Sci. Adv., 6, eabc9955, 10.1126/sciadv.abc9955 Murphy, 2022, Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo, Nat. Metab., 4, 651, 10.1038/s42255-022-00591-z Chouchani, 2016, Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1, Nature, 532, 112, 10.1038/nature17399 Shum, 2021, ABCB10 exports mitochondrial biliverdin, driving metabolic maladaptation in obesity, Sci. Transl. Med., 13, eabd1869, 10.1126/scitranslmed.abd1869 Pi, 2007, Reactive oxygen species as a signal in glucose-stimulated insulin secretion, Diabetes, 56, 1783, 10.2337/db06-1601 Vizioli, 2020, Mitochondria-to-nucleus retrograde signaling drives formation of cytoplasmic chromatin and inflammation in senescence, Genes Dev., 34, 428, 10.1101/gad.331272.119 Qian, 2019, Chemoptogenetic damage to mitochondria causes rapid telomere dysfunction, Proc. Natl. Acad. Sci. USA, 116, 18435, 10.1073/pnas.1910574116 Cox, 2018, Mitohormesis in mice via sustained basal activation of mitochondrial and antioxidant signaling, Cell Metab., 28, 776, 10.1016/j.cmet.2018.07.011 Lozoya, 2020, Single nucleotide resolution analysis reveals pervasive, long-lasting DNA methylation changes by developmental exposure to a mitochondrial toxicant, Cell Rep., 32, 10.1016/j.celrep.2020.108131 Nelson, 2018, The senescent bystander effect is caused by ROS-activated NF-κB signalling, Mech. Ageing Dev., 170, 30, 10.1016/j.mad.2017.08.005 Correia-Melo, 2016, Mitochondria are required for pro-ageing features of the senescent phenotype, EMBO J., 35, 724, 10.15252/embj.201592862 da Silva, 2019, The bystander effect contributes to the accumulation of senescent cells in vivo, Aging Cell, 18, 10.1111/acel.12848 Zhang, 2018, The mitochondrial unfolded protein response is mediated cell-non-autonomously by retromer-dependent Wnt signaling, Cell, 174, 870, 10.1016/j.cell.2018.06.029 Fu, 2017, Dendritic mitoflash as a putative signal for stabilizing long-term synaptic plasticity, Nat. Commun., 8, 31, 10.1038/s41467-017-00043-3 Horn, 2020, Mitochondrial fragmentation enables localized signaling required for cell repair, J. Cell Biol., 219, e201909154, 10.1083/jcb.201909154 Miller, 1988, Molecular biology of steroid hormone synthesis, Endocr. Rev., 9, 295, 10.1210/edrv-9-3-295 Reddy, 2010, Neurosteroids: endogenous role in the human brain and therapeutic potentials, Prog. Brain Res., 186, 113, 10.1016/B978-0-444-53630-3.00008-7 Crivello, 1980, Intracellular movement of cholesterol in rat adrenal cells. Kinetics and effects of inhibitors, J. Biol. Chem., 255, 8144, 10.1016/S0021-9258(19)70620-6 Bose, 2002, The steroidogenic acute regulatory protein, StAR, works only at the outer mitochondrial membrane, Endocr. Res., 28, 295, 10.1081/ERC-120016800 Bose, 2002, Rapid regulation of steroidogenesis by mitochondrial protein import, Nature, 417, 87, 10.1038/417087a Prasad, 2015, Mitochondria-associated endoplasmic reticulum membrane (MAM) regulates steroidogenic activity via steroidogenic acute regulatory protein (StAR)-voltage-dependent anion channel 2 (VDAC2) interaction, J. Biol. Chem., 290, 2604, 10.1074/jbc.M114.605808 Rajapaksha, 2016, An outer mitochondrial translocase, Tom22, is crucial for inner mitochondrial steroidogenic regulation in adrenal and gonadal tissues, Mol. Cell Biol., 36, 1032, 10.1128/MCB.01107-15 Papadopoulos, 2012, Role of mitochondria in steroidogenesis, Best Pract. Res. Clin. Endocrinol. Metab., 26, 771, 10.1016/j.beem.2012.05.002 Black, 1994, The mitochondrial environment is required for activity of the cholesterol side-chain cleavage enzyme, cytochrome P450scc, Proc. Natl. Acad. Sci. USA, 91, 7247, 10.1073/pnas.91.15.7247 Meimaridou, 2012, Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency, Nat. Genet., 44, 740, 10.1038/ng.2299 Riley, 2020, Mitochondrial DNA in inflammation and immunity, EMBO Rep., 21, 10.15252/embr.201949799 West, 2017, Mitochondrial DNA in innate immune responses and inflammatory pathology, Nat. Rev. Immunol., 17, 363, 10.1038/nri.2017.21 Xu, 2014, Structural basis for the prion-like MAVS filaments in antiviral innate immunity, eLife, 3, 10.7554/eLife.01489 Seth, 2005, Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF3, Cell, 122, 669, 10.1016/j.cell.2005.08.012 Koshiba, 2011, Mitochondrial membrane potential is required for MAVS-mediated antiviral signaling, Sci. Signal., 4, ra7, 10.1126/scisignal.2001147 Marchi, 2022, Mitochondrial control of inflammation, Nat. Rev. Immunol., 10.1038/s41577-022-00760-x Kim, 2019, VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease, Science, 366, 1531, 10.1126/science.aav4011 Xian, 2022, Oxidized DNA fragments exit mitochondria via mPTP- and VDAC-dependent channels to activate NLRP3 inflammasome and interferon signaling, Immunity, 55, 1370, 10.1016/j.immuni.2022.06.007 McArthur, 2018, BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis, Science, 359, eaao6047, 10.1126/science.aao6047 Tigano, 2021, Nuclear sensing of breaks in mitochondrial DNA enhances immune surveillance, Nature, 591, 477, 10.1038/s41586-021-03269-w Dhir, 2018, Mitochondrial double-stranded RNA triggers antiviral signalling in humans, Nature, 560, 238, 10.1038/s41586-018-0363-0 Vincent, 2016, The spectrum of mitochondrial ultrastructural defects in mitochondrial myopathy, Sci. Rep., 6, 10.1038/srep30610 Gaziev, 2010, [Nuclear mitochondrial pseudogenes], Mol. Biol. (Mosk)., 44, 358, 10.1134/S0026893310030027 Quammen, 2018 Srinivasainagendra, 2017, Migration of mitochondrial DNA in the nuclear genome of colorectal adenocarcinoma, Genome Med., 9, 31, 10.1186/s13073-017-0420-6 Bock, 2017, Witnessing genome evolution: experimental reconstruction of endosymbiotic and horizontal gene transfer, Annu. Rev. Genet., 51, 1, 10.1146/annurev-genet-120215-035329 Anand, 2014, The i-AAA protease YME1L and OMA1 cleave OPA1 to balance mitochondrial fusion and fission, J. Cell Biol., 204, 919, 10.1083/jcb.201308006 Cheng, 2010, The migration of mitochondrial DNA fragments to the nucleus affects the chronological aging process of Saccharomyces cerevisiae, Aging Cell, 9, 919, 10.1111/j.1474-9726.2010.00607.x Srinivasainagendra, 2017, Migration of mitochondrial DNA in the nuclear genome of colorectal adenocarcinoma, Genome Med., 9, 31, 10.1186/s13073-017-0420-6 Ju, 2015, Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells, Genome Res., 25, 814, 10.1101/gr.190470.115 Rossignol, 2003, Mitochondrial threshold effects, Biochem. J., 370, 751, 10.1042/bj20021594 Trumpff, 2021, Stress and circulating cell-free mitochondrial DNA: a systematic review of human studies, physiological considerations, and technical recommendations, Mitochondrion, 59, 225, 10.1016/j.mito.2021.04.002 Rosa, 2020, A case for measuring both cellular and cell-free mitochondrial DNA as a disease biomarker in human blood, FASEB J., 34, 12278, 10.1096/fj.202000959RR Zhao, 2022, Circulating cell-free mtDNA release is associated with the activation of cGAS-STING pathway and inflammation in mitochondrial diseases, J. Neurol., 269, 4985 Trifunov, 2021, Circulating cell-free mitochondrial DNA in cerebrospinal fluid as a biomarker for mitochondrial diseases, Clin. Chem., 67, 1113, 10.1093/clinchem/hvab091 Maresca, 2020, Expanding and validating the biomarkers for mitochondrial diseases, J. Mol. Med. (Berl.), 98, 1467, 10.1007/s00109-020-01967-y Cushen, 2020, Cell-free mitochondrial DNA increases in maternal circulation during healthy pregnancy: a prospective, longitudinal study, Am. J. Physiol. Regul. Integr. Comp. Physiol., 318, R445, 10.1152/ajpregu.00324.2019 Hummel, 2018, Cell-free DNA release under psychosocial and physical stress conditions, Transl. Psychiatry, 8, 236, 10.1038/s41398-018-0264-x Trumpff, 2019, Acute psychological stress increases serum circulating cell-free mitochondrial DNA, Psychoneuroendocrinology, 106, 268, 10.1016/j.psyneuen.2019.03.026 Lindqvist, 2016, Increased plasma levels of circulating cell-free mitochondrial DNA in suicide attempters: associations with HPA-axis hyperactivity, Transl. Psychiatry, 6, 10.1038/tp.2016.236 Trumpff, 2022, Dynamic behavior of cell-free mitochondrial DNA in human saliva, Psychoneuroendocrinology, 143, 10.1016/j.psyneuen.2022.105852 Nakahira, 2013, Circulating mitochondrial DNA in patients in the ICU as a marker of mortality: derivation and validation, PLoS Med., 10, 10.1371/journal.pmed.1001577 Boyapati, 2017, Advances in the understanding of mitochondrial DNA as a pathogenic factor in inflammatory diseases, F1000Res., 6, 169, 10.12688/f1000research.10397.1 Song, 2020, Existence of circulating mitochondria in human and animal peripheral blood, Int. J. Mol. Sci., 21, 2122, 10.3390/ijms21062122 Al Amir Dache, 2020, Blood contains circulating cell-free respiratory competent mitochondria, FASEB J., 34, 3616, 10.1096/fj.201901917RR Caicedo, 2021, Extracellular mitochondria in the cerebrospinal fluid (CSF): potential types and key roles in central nervous system (CNS) physiology and pathogenesis, Mitochondrion, 58, 255, 10.1016/j.mito.2021.02.006 Zhao, 2002, A mitochondrial specific stress response in mammalian cells, EMBO J., 21, 4411, 10.1093/emboj/cdf445 Carreras-Sureda, 2022, Balancing energy and protein homeostasis at ER-mitochondria contact sites, Sci. Signal., 15, 10.1126/scisignal.abm7524 Fessler, 2020, A pathway coordinated by DELE1 relays mitochondrial stress to the cytosol, Nature, 579, 433, 10.1038/s41586-020-2076-4 Guo, 2020, Mitochondrial stress is relayed to the cytosol by an OMA1-DELE1-HRI pathway, Nature, 579, 427, 10.1038/s41586-020-2078-2 Quiros, 2017, Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals, J. Cell Biol., 216, 2027, 10.1083/jcb.201702058 Fiorese, 2016, The transcription factor ATF5 mediates a mammalian mitochondrial UPR, Curr. Biol., 26, 2037, 10.1016/j.cub.2016.06.002 Molenaars, 2020, A conserved mito-cytosolic translational balance links two longevity pathways, Cell Metab., 31, 549, 10.1016/j.cmet.2020.01.011 Replogle, 2022, Mapping information-rich genotype-phenotype landscapes with genome-scale Perturb-seq, Cell, 185, 2559, 10.1016/j.cell.2022.05.013 Dogan, 2014, Tissue-specific loss of DARS2 activates stress responses independently of respiratory chain deficiency in the heart, Cell Metab., 19, 458, 10.1016/j.cmet.2014.02.004 Kim, 2013, Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine, Nat. Med., 19, 83, 10.1038/nm.3014 Keipert, 2014, Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine, Am. J. Physiol. Endocrinol. Metab., 306, E469, 10.1152/ajpendo.00330.2013 Mick, 2020, Distinct mitochondrial defects trigger the integrated stress response depending on the metabolic state of the cell, eLife, 9, e49178, 10.7554/eLife.49178 Kang, 2021, Differential roles of GDF15 and FGF21 in systemic metabolic adaptation to the mitochondrial integrated stress response, iScience, 24, 10.1016/j.isci.2021.102181 Ost, 2016, Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action, Mol. Metabol., 5, 79, 10.1016/j.molmet.2015.11.002 Chung, 2017, Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis, J. Cell Biol., 216, 149, 10.1083/jcb.201607110 Croon, 2022, FGF21 modulates mitochondrial stress response in cardiomyocytes only under mild mitochondrial dysfunction, Sci. Adv., 8, eabn7105, 10.1126/sciadv.abn7105 Luan, 2019, GDF15 is an inflammation-induced central mediator of tissue tolerance, Cell, 178, 1231, 10.1016/j.cell.2019.07.033 Choi, 2020, An adipocyte-specific defect in oxidative phosphorylation increases systemic energy expenditure and protects against diet-induced obesity in mouse models, Diabetologia, 63, 837, 10.1007/s00125-019-05082-7 Ost, 2020, Muscle-derived GDF15 drives diurnal anorexia and systemic metabolic remodeling during mitochondrial stress, EMBO Rep., 21, 10.15252/embr.201948804 Mullican, 2017, GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates, Nat. Med., 23, 1150, 10.1038/nm.4392 Moon, 2020, Growth differentiation factor 15 protects against the aging-mediated systemic inflammatory response in humans and mice, Aging Cell, 19, 10.1111/acel.13195 Klaus, 2020, Mitochondrial uncoupling and longevity - A role for mitokines?, Exp. Gerontol., 130, 10.1016/j.exger.2019.110796 Lockhart, 2020, GDF15: a hormone conveying somatic distress to the brain, Endocr. Rev., 41, bnaa007, 10.1210/endrev/bnaa007 Gil, 2021, Mitochondrial stress-induced GDF15-GFRAL axis promotes anxiety-like behavior and CRH-dependent anorexia, bioRxiv Cimino, 2021, Activation of the hypothalamic-pituitary-adrenal axis by exogenous and endogenous GDF15, Proc. Natl. Acad. Sci. USA, 118, 10.1073/pnas.2106868118 Yatsuga, 2015, Growth differentiation factor 15 as a useful biomarker for mitochondrial disorders, Ann. Neurol., 78, 814, 10.1002/ana.24506 Lehtonen, 2016, FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders, Neurology, 87, 2290, 10.1212/WNL.0000000000003374 Lin, 2020, Accuracy of FGF-21 and GDF-15 for the diagnosis of mitochondrial disorders: a meta-analysis, Ann. Clin. Transl. Neurol., 7, 1204, 10.1002/acn3.51104 Reynolds, 2020, Mitonuclear genomics and aging, Hum. Genet., 139, 381, 10.1007/s00439-020-02119-5 Hashimoto, 2001, A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ, Proc. Natl. Acad. Sci. USA, 98, 6336, 10.1073/pnas.101133498 Yen, 2020, The mitochondrial derived peptide humanin is a regulator of lifespan and healthspan, Aging (Albany NY), 12, 11185, 10.18632/aging.103534 Cobb, 2016, Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers, Aging (Albany NY), 8, 796, 10.18632/aging.100943 Lee, 2015, The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance, Cell Metab., 21, 443, 10.1016/j.cmet.2015.02.009 Kang, 2021, Mitohormesis in hypothalamic POMC neurons mediates regular exercise-induced high-turnover metabolism, Cell Metab., 33, 334, 10.1016/j.cmet.2021.01.003 Reynolds, 2021, MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis, Nat. Commun., 12, 470, 10.1038/s41467-020-20790-0 Woodhead, 2020, High-intensity interval exercise increases humanin, a mitochondrial encoded peptide, in the plasma and muscle of men, J. Appl. Physiol., 128, 1346, 10.1152/japplphysiol.00032.2020 Shamaei-Tousi, 2007, Plasma heat shock protein 60 and cardiovascular disease risk: the role of psychosocial, genetic, and biological factors, Cell Stress Chaperones, 12, 384, 10.1379/CSC-300.1 Julian, 2012, Mitochondrial transcription factor A serves as a danger signal by augmenting plasmacytoid dendritic cell responses to DNA, J. Immunol., 189, 433, 10.4049/jimmunol.1101375 Chaung, 2012, Mitochondrial transcription factor A is a proinflammatory mediator in hemorrhagic shock, Int. J. Mol. Med., 30, 199 Clarke, 2004, Why does metabolism scale with temperature?, Funct. Ecol., 18, 243, 10.1111/j.0269-8463.2004.00841.x Nicholls, 1984, Thermogenic mechanisms in brown fat, Physiol. Rev., 64, 1, 10.1152/physrev.1984.64.1.1 Xue, 2022, The mitochondrial calcium uniporter engages UCP1 to form a thermoporter that promotes thermogenesis, Cell Metab., 34, 1325, 10.1016/j.cmet.2022.07.011 Okabe, 2012, Intracellular temperature mapping with a fluorescent polymeric thermometer and fluorescence lifetime imaging microscopy, Nat. Commun., 3, 705, 10.1038/ncomms1714 Nakano, 2017, Genetically encoded ratiometric fluorescent thermometer with wide range and rapid response, PLoS One, 12, 10.1371/journal.pone.0172344 Chretien, 2018, Mitochondria are physiologically maintained at close to 50 °C, PLoS Biol., 16, 10.1371/journal.pbio.2003992 Picard, 2015, Mitochondrial synapses: intracellular communication and signal integration, Trends Neurosci., 38, 468, 10.1016/j.tins.2015.06.001 Kumar, 2010, Mobility of cytoplasmic, membrane, and DNA-binding proteins in Escherichia coli, Biophys. J., 98, 552, 10.1016/j.bpj.2009.11.002 Kekenes-Huskey, 2013, Molecular and subcellular-scale modeling of nucleotide diffusion in the cardiac myofilament lattice, Biophys. J., 105, 2130, 10.1016/j.bpj.2013.09.020 Cossins, 2011, A new view of the bacterial cytosol environment, PLoS Comput. Biol., 7, 10.1371/journal.pcbi.1002066 Courchet, 2013, Terminal axon branching is regulated by the LKB1-NUAK1 kinase pathway via presynaptic mitochondrial capture, Cell, 153, 1510, 10.1016/j.cell.2013.05.021 Faits, 2016, Dendritic mitochondria reach stable positions during circuit development, eLife, 5, 10.7554/eLife.11583 Lewis, 2018, MFF-dependent mitochondrial fission regulates presynaptic release and axon branching by limiting axonal mitochondria size, Nat. Commun., 9, 5008, 10.1038/s41467-018-07416-2 Konig, 2021, MIROs and DRP1 drive mitochondrial-derived vesicle biogenesis and promote quality control, Nat. Cell Biol., 23, 1271, 10.1038/s41556-021-00798-4 Brestoff, 2021, Intercellular mitochondria transfer to macrophages regulates white adipose tissue homeostasis and is impaired in obesity, Cell Metab., 33, 270, 10.1016/j.cmet.2020.11.008 Crewe, 2021, Extracellular vesicle-based interorgan transport of mitochondria from energetically stressed adipocytes, Cell Metab., 33, 1853, 10.1016/j.cmet.2021.08.002 Rodriguez-Nuevo, 2022, Oocytes maintain ROS-free mitochondrial metabolism by suppressing complex I, Nature, 607, 756, 10.1038/s41586-022-04979-5 Pagliarini, 2008, A mitochondrial protein compendium elucidates complex I disease biology, Cell, 134, 112, 10.1016/j.cell.2008.06.016 Fecher, 2019, Cell-type-specific profiling of brain mitochondria reveals functional and molecular diversity, Nat. Neurosci., 22, 1731, 10.1038/s41593-019-0479-z Picard, 2012, Mitochondrial functional specialization in glycolytic and oxidative muscle fibers: tailoring the organelle for optimal function, Am. J. Physiol. Cell Physiol., 302, C629, 10.1152/ajpcell.00368.2011 Rausser, 2021, Mitochondrial phenotypes in purified human immune cell subtypes and cell mixtures, eLife, 10, e70899, 10.7554/eLife.70899 Glancy, 2011, Protein composition and function of red and white skeletal muscle mitochondria, Am. J. Physiol. Cell Physiol., 300, C1280, 10.1152/ajpcell.00496.2010 Rosenberg, 2021, Mouse brain-wide mitochondrial connectivity anchored in gene, brain and behavior, Preprint at bioRxiv Ignatenko, 2018, Loss of mtDNA activates astrocytes and leads to spongiotic encephalopathy, Nat. Commun., 9, 70, 10.1038/s41467-017-01859-9 Vincent, 2018, Multilevel heterogeneity of mitochondrial respiratory chain deficiency, J. Pathol., 246, 261, 10.1002/path.5146 Mito, 2022, Mosaic dysfunction of mitophagy in mitochondrial muscle disease, Cell Metab., 34, 197, 10.1016/j.cmet.2021.12.017 Stauch, 2014, Quantitative proteomics of synaptic and nonsynaptic mitochondria: insights for synaptic mitochondrial vulnerability, J. Proteome Res., 13, 2620, 10.1021/pr500295n Ferreira, 2010, Subsarcolemmal and intermyofibrillar mitochondria proteome differences disclose functional specializations in skeletal muscle, Proteomics, 10, 3142, 10.1002/pmic.201000173 Benador, 2018, Mitochondria bound to lipid droplets have unique bioenergetics, composition, and dynamics that support lipid droplet expansion, Cell Metab., 27, 869, 10.1016/j.cmet.2018.03.003 Sjostedt, 2020, An atlas of the protein-coding genes in the human, pig, and mouse brain, Science, 367, eaay5947, 10.1126/science.aay5947 Faitg, 2021, 3D neuronal mitochondrial morphology in axons, dendrites, and somata of the aging mouse hippocampus, Cell Rep., 36, 10.1016/j.celrep.2021.109509 Lewis, 2016, Progressive decrease of mitochondrial motility during maturation of cortical axons in vitro and in vivo, Curr. Biol., 26, 2602, 10.1016/j.cub.2016.07.064 Wolf, 2019, Individual cristae within the same mitochondrion display different membrane potentials and are functionally independent, EMBO J., 38, 10.15252/embj.2018101056 Berry, 2022, Optogenetic rejuvenation of mitochondrial membrane potential extends C. elegans lifespan, Preprint at bioRxiv Ignatenko, 2020, Mitochondrial spongiotic brain disease: astrocytic stress and harmful rapamycin and ketosis effect, Life Sci. Alliance, 3, 10.26508/lsa.202000797 Johnson, 2013, mTOR inhibition alleviates mitochondrial disease in a mouse model of Leigh syndrome, Science, 342, 1524, 10.1126/science.1244360 Picard, 2016, The rise of mitochondria in medicine, Mitochondrion, 30, 105, 10.1016/j.mito.2016.07.003 Suomalainen, 2018, Mitochondrial diseases: the contribution of organelle stress responses to pathology, Nat. Rev. Mol. Cell Biol., 19, 77, 10.1038/nrm.2017.66 Chernet, 2013, endogenous voltage potentials and the microenvironment: bioelectric signals that reveal, induce and normalize cancer., J. Clin. Exp. Oncol., Suppl 1, S1 López-Otín, 2021, Hallmarks of health, Cell, 184, 33, 10.1016/j.cell.2020.11.034 Chan, 2020, Mitochondrial dynamics and its involvement in disease, Annu. Rev. Pathol., 15, 235, 10.1146/annurev-pathmechdis-012419-032711 Archer, 2013, Mitochondrial dynamics--mitochondrial fission and fusion in human diseases, N. Engl. J. Med., 369, 2236, 10.1056/NEJMra1215233 Hodge, 2019, Conserved cell types with divergent features in human versus mouse cortex, Nature, 573, 61, 10.1038/s41586-019-1506-7 Drucker, 2016, Never waste a good crisis: confronting reproducibility in translational research, Cell Metab., 24, 348, 10.1016/j.cmet.2016.08.006 Enríquez, 2019, Mind your mouse strain, Nat. Metab., 1, 5, 10.1038/s42255-018-0018-3 Sung, 2010, Mitochondrial respiration protects against oxygen-associated DNA damage, Nat. Commun., 1, 5, 10.1038/ncomms1003 Lane, 2010, The energetics of genome complexity, Nature, 467, 929, 10.1038/nature09486 Schavemaker, 2022, The role of mitochondrial energetics in the origin and diversification of eukaryotes, Nat. Ecol. Evol., 6, 1307, 10.1038/s41559-022-01833-9 Ayres, 2020, The biology of physiological health, Cell, 181, 250, 10.1016/j.cell.2020.03.036 Picard, 2018, Psychological stress and mitochondria: a conceptual framework, Psychosom. Med., 80, 126, 10.1097/PSY.0000000000000544 Cole, 2014, Human social genomics, PLoS Genet., 10, 10.1371/journal.pgen.1004601 Snyder-Mackler, 2020, Social determinants of health and survival in humans and other animals, Science, 368, eaax9553, 10.1126/science.aax9553 Picard, 2022, Why do we care more about disease than health?, Phenomics, 2, 145, 10.1007/s43657-021-00037-8