Abstract
Our cells operate based on two distinct genomes that are enclosed in the nucleus and mitochondria. The mitochondrial genome presumably originates from endosymbiotic bacteria. With time, a large portion of the original genes in the bacterial genome is considered to have been lost or transferred to the nuclear genome, leaving a reduced 16.5 Kb circular mitochondrial DNA (mtDNA). Traditionally only 37 genes, including 13 proteins, were thought to be encoded within mtDNA, its genetic repertoire is expanding with the identification of mitochondrial-derived peptides (MDPs). The biology of aging has been largely unveiled to be regulated by genes that are encoded in the nuclear genome, whereas the mitochondrial genome remained more cryptic. However, recent studies position mitochondria and mtDNA as an important counterpart to the nuclear genome, whereby the two organelles constantly regulate each other. Thus, the genomic network that regulates lifespan and/or healthspan is likely constituted by two unique, yet co-evolved, genomes. Here, we will discuss aspects of mitochondrial biology, especially mitochondrial communication that may add substantial momentum to aging research by accounting for both mitonuclear genomes to more comprehensively and inclusively map the genetic and molecular networks that govern aging and age-related diseases.
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Abbott MJ, Turcotte LP (2014) AMPK-alpha2 is involved in exercise training-induced adaptations in insulin-stimulated metabolism in skeletal muscle following high-fat diet. J Appl Physiol 117:869–79. https://doi.org/10.1152/japplphysiol.01380.2013
Adam-Vizi V (2005) Production of reactive oxygen species in brain mitochondria: contribution by electron transport chain and non-electron transport chain sources. Antioxid Redox Signal 7:1140–1149. https://doi.org/10.1089/ars.2005.7.1140
Ahmed ZM, Smith TN, Riazuddin S, Makishima T, Ghosh M, Bokhari S, Menon PS, Deshmukh D, Griffith AJ, Riazuddin S, Friedman TB, Wilcox ER (2002) Nonsyndromic recessive deafness DFNB18 and Usher syndrome type IC are allelic mutations of USHIC. Hum Genet 110:527–531. https://doi.org/10.1007/s00439-002-0732-4
Ameur A, Stewart JB, Freyer C, Hagstrom E, Ingman M, Larsson NG, Gyllensten U (2011) Ultra-deep sequencing of mouse mitochondrial DNA: mutational patterns and their origins. PLoS Genet 7:e1002028. https://doi.org/10.1371/journal.pgen.1002028
Amrita C, Mark DP (2015) Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPRmt. Mol Cell 58:123–133. https://doi.org/10.1016/j.molcel.2015.02.008
Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, Schreier PH, Smith AJ, Staden R, Young IG (1981) Sequence and organization of the human mitochondrial genome. Nature 290:457–465. https://doi.org/10.1038/290457a0
Andrews SJ, Rothnagel JA (2014) Emerging evidence for functional peptides encoded by short open reading frames. Nat Rev Genet 15:193–204. https://doi.org/10.1038/nrg3520
Bachar AR, Scheffer L, Schroeder AS, Nakamura HK, Cobb LJ, Oh YK, Lerman LO, Pagano RE, Cohen P, Lerman A (2010) Humanin is expressed in human vascular walls and has a cytoprotective effect against oxidized LDL-induced oxidative stress. Cardiovasc Res 88:360–366. https://doi.org/10.1093/cvr/cvq191
Bajpai P, Koc E, Sonpavde G, Singh R, Singh KK (2019) Mitochondrial localization, import, and mitochondrial function of the androgen receptor. J Biol Chem 294:6621–6634. https://doi.org/10.1074/jbc.RA118.006727
Bazzini AA, Johnstone TG, Christiano R, Mackowiak SD, Obermayer B, Fleming ES, Vejnar CE, Lee MT, Rajewsky N, Walther TC, Giraldez AJ (2014) Identification of small ORFs in vertebrates using ribosome footprinting and evolutionary conservation. EMBO J 33:981–993. https://doi.org/10.1002/embj.201488411
Bellizzi D, D'Aquila P, Giordano M, Montesanto A, Passarino G (2012) Global DNA methylation levels are modulated by mitochondrial DNA variants. Epigenomics 4:17–27. https://doi.org/10.2217/epi.11.109
Benayoun BA, Pollina EA, Brunet A (2015) Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Nat Rev Mol Cell Biol 16:593–610. https://doi.org/10.1038/nrm4048
Bensasson D, Feldman MW, Petrov DA (2003) Rates of DNA duplication and mitochondrial DNA insertion in the human genome. J Mol Evol 57:343–354. https://doi.org/10.1007/s00239-003-2485-7
Betancourt AM, King AL, Fetterman JL, Millender-Swain T, Finley RD, Oliva CR, Crowe DR, Ballinger SW, Bailey SM (2014) Mitochondrial-nuclear genome interactions in non-alcoholic fatty liver disease in mice. Biochem J 461:223–232. https://doi.org/10.1042/BJ20131433
Bi P, Ramirez-Martinez A, Li H, Cannavino J, McAnally JR, Shelton JM, Sanchez-Ortiz E, Bassel-Duby R, Olson EN (2017) Control of muscle formation by the fusogenic micropeptide myomixer. Science 356:323–327. https://doi.org/10.1126/science.aam9361
Bock R (2017) Witnessing genome evolution: experimental reconstruction of endosymbiotic and horizontal gene transfer. Annu Rev Genet 51:1–22. https://doi.org/10.1146/annurev-genet-120215-035329
Bohr VA, Stevnsner T, De Souza-Pinto NC (2002) Mitochondrial DNA repair of oxidative damage in mammalian cells. Gene 286:127–134. https://doi.org/10.1016/s0378-1119(01)00813-7
Boveris A, Chance B (1973) The mitochondrial generation of hydrogen peroxide. General properties and effect of hyperbaric oxygen. Biochem J 134:707–716. https://doi.org/10.1042/bj1340707
Breton CV, Song AY, Xiao J, Kim SJ, Mehta HH, Wan J, Yen K, Sioutas C, Lurmann F, Xue S, Morgan TE, Zhang J, Cohen P (2019) Effects of air pollution on mitochondrial function, mitochondrial DNA methylation, and mitochondrial peptide expression. Mitochondrion 46:22–29. https://doi.org/10.1016/j.mito.2019.04.001
Calabrese FM, Balacco DL, Preste R, Diroma MA, Forino R, Ventura M, Attimonelli M (2017) NumtS colonization in mammalian genomes. Sci Rep 7:16357. https://doi.org/10.1038/s41598-017-16750-2
Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J (2009) AMPK regulates energy expenditure by modulating NAD + metabolism and SIRT1 activity. Nature 458:1056–1060. https://doi.org/10.1038/nature07813
Cardamone MD, Krones A, Tanasa B, Taylor H, Ricci L, Ohgi KA, Glass CK, Rosenfeld MG, Perissi V (2012) A protective strategy against hyperinflammatory responses requiring the nontranscriptional actions of GPS2. Mol Cell 46:91–104. https://doi.org/10.1016/j.molcel.2012.01.025
Cardamone MD, Tanasa B, Cederquist CT, Huang J, Mahdaviani K, Li W, Rosenfeld MG, Liesa M, Perissi V (2018) Mitochondrial retrograde signaling in mammals is mediated by the transcriptional cofactor GPS2 via direct mitochondria-to-nucleus translocation. Mol Cell 69(757–772):e7. https://doi.org/10.1016/j.molcel.2018.01.037
Cataldo LR, Fernández-Verdejo R, Santos JL, Galgani JE (2018) Plasma MOTS-c levels are associated with insulin sensitivity in lean but not in obese individuals. J Investig Med 66:1019–1022. https://doi.org/10.1136/jim-2017-000681
Cederquist CT, Lentucci C, Martinez-Calejman C, Hayashi V, Orofino J, Guertin D, Fried SK, Lee MJ, Cardamone MD, Perissi V (2017) Systemic insulin sensitivity is regulated by GPS2 inhibition of AKT ubiquitination and activation in adipose tissue. Mol Metab 6:125–137. https://doi.org/10.1016/j.molmet.2016.10.007
Cermakian N, Ikeda TM, Cedergren R, Gray MW (1996) Sequences homologous to yeast mitochondrial and bacteriophage T3 and T7 RNA polymerases are widespread throughout the eukaryotic lineage. Nucleic Acids Res 24:648–654. https://doi.org/10.1093/nar/24.4.648
Chandel NS (2015) Evolution of mitochondria as signaling organelles. Cell Metab 22:204–206. https://doi.org/10.1016/j.cmet.2015.05.013
Chanut-Delalande H, Hashimoto Y, Pelissier-Monier A, Spokony R, Dib A, Kondo T, Bohere J, Niimi K, Latapie Y, Inagaki S, Dubois L, Valenti P, Polesello C, Kobayashi S, Moussian B, White KP, Plaza S, Kageyama Y, Payre F (2014) Pri peptides are mediators of ecdysone for the temporal control of development. Nat Cell Biol 16:1035–1044. https://doi.org/10.1038/ncb3052
Chen H, Vermulst M, Wang YE, Chomyn A, Prolla TA, McCaffery JM, Chan DC (2010) Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations. Cell 141:280–289. https://doi.org/10.1016/j.cell.2010.02.026
Clay Montier LL, Deng JJ, Bai Y (2009) Number matters: control of mammalian mitochondrial DNA copy number. J Genet Genom 36:125–131. https://doi.org/10.1016/s1673-8527(08)60099-5
Cobb LJ, Lee C, Xiao J, Yen K, Wong RG, Nakamura HK, Mehta HH, Gao Q, Ashur C, Huffman DM, Wan J, Muzumdar R, Barzilai N, Cohen P (2016) Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers. Aging (Albany NY) 8:796–809. https://doi.org/10.18632/aging.100943
Cogliati S, Enriquez JA, Scorrano L (2016) Mitochondrial cristae: where beauty meets functionality. Trends Biochem Sci 41:261–273
Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M, Cipolat S, Costa V, Casarin A, Gomes LC (2013) Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respiratory efficiency. Cell 155:160–171
Cortopassi GA, Arnheim N (1990) Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res 18:6927–6933. https://doi.org/10.1093/nar/18.23.6927
Couvillion MT, Soto IC, Shipkovenska G, Churchman LS (2016) Synchronized mitochondrial and cytosolic translation programs. Nature 533:499–503. https://doi.org/10.1038/nature18015
Dahlmans D, Houzelle A, Andreux P, Wang X, Jorgensen JA, Moullan N, Daemen S, Kersten S, Auwerx J, Hoeks J (2019) MicroRNA-382 silencing induces a mitonuclear protein imbalance and activates the mitochondrial unfolded protein response in muscle cells. J Cell Physiol 234:6601–6610. https://doi.org/10.1002/jcp.27401
DeBalsi KL, Hoff KE, Copeland WC (2017) Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases. Ageing Res Rev 33:89–104. https://doi.org/10.1016/j.arr.2016.04.006
DeLuca SZ, O'Farrell PH (2012) Barriers to male transmission of mitochondrial DNA in sperm development. Dev Cell 22:660–668. https://doi.org/10.1016/j.devcel.2011.12.021
Deng Y, Bamigbade AT, Hammad MA, Xu S, Liu P (2018) Identification of small ORF-encoded peptides in mouse serum. Biophys Rep 4:39–49. https://doi.org/10.1007/s41048-018-0048-0
Dobler R, Dowling DK, Morrow EH, Reinhardt K (2018) A systematic review and meta-analysis reveals pervasive effects of germline mitochondrial replacement on components of health. Hum Reprod Update 24:519–534. https://doi.org/10.1093/humupd/dmy018
Doonan R, McElwee JJ, Matthijssens F, Walker GA, Houthoofd K, Back P, Matscheski A, Vanfleteren JR, Gems D (2008) Against the oxidative damage theory of aging: superoxide dismutases protect against oxidative stress but have little or no effect on life span in Caenorhabditis elegans. Genes Dev 22:3236–3241. https://doi.org/10.1101/gad.504808
Drummond E, Short E, Clancy D (2019) Mitonuclear gene X environment effects on lifespan and health: how common, how big? Mitochondrion 49:12–18. https://doi.org/10.1016/j.mito.2019.06.009
Du C, Zhang C, Wu W, Liang Y, Wang A, Wu S, Zhao Y, Hou L, Ning Q, Luo X (2018) Circulating MOTS-c levels are decreased in obese male children and adolescents and associated with insulin resistance. Pediatr Diabetes. https://doi.org/10.1111/pedi.12685
Dunham-Snary KJ, Ballinger SW (2015) GENETICS. Mitochondrial-nuclear DNA mismatch matters. Science 349:1449–1450. https://doi.org/10.1126/science.aac5271
Dunham-Snary KJ, Sandel MW, Sammy MJ, Westbrook DG, Xiao R, McMonigle RJ, Ratcliffe WF, Penn A, Young ME, Ballinger SW (2018) Mitochondrial—nuclear genetic interaction modulates whole body metabolism, adiposity and gene expression in vivo. EBioMedicine 36:316–328. https://doi.org/10.1016/j.ebiom.2018.08.036
Eckel RH, Krauss RM (1998) American Heart Association Call to Action: obesity as a major risk factor for coronary heart disease. Circulation 97:2099–2100
Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, Asara JM, Fitzpatrick J, Dillin A, Viollet B, Kundu M, Hansen M, Shaw RJ (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–461. https://doi.org/10.1126/science.1196371
Ekstrand MI, Falkenberg M, Rantanen A, Park CB, Gaspari M, Hultenby K, Rustin P, Gustafsson CM, Larsson NG (2004) Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum Mol Genet 13:935–944. https://doi.org/10.1093/hmg/ddh109
Fabrizio P, Liou LL, Moy VN, Diaspro A, Valentine JS, Gralla EB, Longo VD (2003) SOD2 functions downstream of Sch9 to extend longevity in yeast. Genetics 163:35–46
Falkenberg M, Larsson NG, Gustafsson CM (2007) DNA replication and transcription in mammalian mitochondria. Annu Rev Biochem 76:679–699. https://doi.org/10.1146/annurev.biochem.76.060305.152028
Faye G, Sor F (1977) Analysis of mitochondrial ribosomal proteins of Saccharomyces cerevisiae by two dimensional polyacrylamide gel electrophoresis. Mol Gen Genet 155:27–34. https://doi.org/10.1007/bf00268557
Fazzini F, Schöpf B, Blatzer M, Coassin S, Hicks AA, Kronenberg F, Fendt L (2018) Plasmid-normalized quantification of relative mitochondrial DNA copy number. Sci Rep. https://doi.org/10.1038/s41598-018-33684-5
Fetterman JL, Ballinger SW (2019) Mitochondrial genetics regulate nuclear gene expression through metabolites. Proc Natl Acad Sci 116:15763–15765. https://doi.org/10.1073/pnas.1909996116
Fetterman JL, Zelickson BR, Johnson LW, Moellering DR, Westbrook DG, Pompilius M, Sammy MJ, Johnson M, Dunham-Snary KJ, Cao X, Bradley WE, Zhang J, Wei CC, Chacko B, Schurr TG, Kesterson RA, Dell'italia LJ, Darley-Usmar VM, Welch DR, Ballinger SW (2013) Mitochondrial genetic background modulates bioenergetics and susceptibility to acute cardiac volume overload. Biochem J 455:157–167. https://doi.org/10.1042/BJ20130029
Fiorese CJ, Schulz AM, Lin YF, Rosin N, Pellegrino MW, Haynes CM (2016) The transcription factor ATF5 mediates a mammalian mitochondrial UPR. Curr Biol 26:2037–2043. https://doi.org/10.1016/j.cub.2016.06.002
Fuku N, Pareja-Galeano H, Zempo H, Alis R, Arai Y, Lucia A, Hirose N (2015) The mitochondrial-derived peptide MOTS-c: a player in exceptional longevity? Aging Cell 14:921–923. https://doi.org/10.1111/acel.12389
Galindo MI, Pueyo JI, Fouix S, Bishop SA, Couso JP (2007) Peptides encoded by short ORFs control development and define a new eukaryotic gene family. PLoS Biol 5:e106. https://doi.org/10.1371/journal.pbio.0050106
Garcia-Roves PM, Osler ME, Holmstrom MH, Zierath JR (2008) Gain-of-function R225Q mutation in AMP-activated protein kinase gamma3 subunit increases mitochondrial biogenesis in glycolytic skeletal muscle. J Biol Chem 283:35724–35734. https://doi.org/10.1074/jbc.M805078200
Gershoni M, Levin L, Ovadia O, Toiw Y, Shani N, Dadon S, Barzilai N, Bergman A, Atzmon G, Wainstein J, Tsur A, Nijtmans L, Glaser B, Mishmar D (2014) Disrupting mitochondrial-nuclear coevolution affects OXPHOS complex I integrity and impacts human health. Genome Biol Evol 6:2665–2680. https://doi.org/10.1093/gbe/evu208
Gilkerson R, Bravo L, Garcia I, Gaytan N, Herrera A, Maldonado A, Quintanilla B (2013) The mitochondrial nucleoid: integrating mitochondrial DNA into cellular homeostasis. Cold Spring Harbor Perspect Biol 5:a011080–a011080. https://doi.org/10.1101/cshperspect.a011080
Goldin E, Stahl S, Cooney AM, Kaneski CR, Gupta S, Brady RO, Ellis JR, Schiffmann R (2004) Transfer of a mitochondrial DNA fragment to MCOLN1 causes an inherited case of mucolipidosis IV. Hum Mutat 24:460–465. https://doi.org/10.1002/humu.20094
Grazina M, Pratas J, Silva F, Oliveira S, Santana I, Oliveira C (2006) Genetic basis of Alzheimer's dementia: role of mtDNA mutations. Genes Brain Behav 5(Suppl 2):92–107. https://doi.org/10.1111/j.1601-183X.2006.00225.x
Grazioli S, Pugin J (2018) Mitochondrial damage-associated molecular patterns: from inflammatory signaling to human diseases. Front Immunol 9:832. https://doi.org/10.3389/fimmu.2018.00832
Guo B, Zhai D, Cabezas E, Welsh K, Nouraini S, Satterthwait AC, Reed JC (2003) Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature 423:456–461. https://doi.org/10.1038/nature01627
Guo F, Jing W, Ma CG, Wu MN, Zhang JF, Li XY, Qi JS (2010) [Gly(14)]-humanin rescues long-term potentiation from amyloid beta protein-induced impairment in the rat hippocampal CA1 region in vivo. Synapse 64:83–91. https://doi.org/10.1002/syn.20707
Gustafsson CM, Falkenberg M, Larsson NG (2016) Maintenance and expression of mammalian mitochondrial DNA. Annu Rev Biochem 85:133–160. https://doi.org/10.1146/annurev-biochem-060815-014402
Harman D (1956) Aging: a theory based on free radical and radiation chemistry. J Gerontol 11:298–300
Harman D (2009) Origin and evolution of the free radical theory of aging: a brief personal history, 1954–2009. Biogerontology 10:773–781. https://doi.org/10.1007/s10522-009-9234-2
Hashimoto Y, Ito Y, Niikura T, Shao Z, Hata M, Oyama F, Nishimoto I (2001a) Mechanisms of neuroprotection by a novel rescue factor humanin from Swedish mutant amyloid precursor protein. Biochem Biophys Res Commun 283:460–468. https://doi.org/10.1006/bbrc.2001.4765
Hashimoto Y, Niikura T, Tajima H, Yasukawa T, Sudo H, Ito Y, Kita Y, Kawasumi M, Kouyama K, Doyu M, Sobue G, Koide T, Tsuji S, Lang J, Kurokawa K, Nishimoto I (2001b) A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Abeta. Proc Natl Acad Sci USA 98:6336–6341. https://doi.org/10.1073/pnas.101133498
Havird JC, Sloan DB (2016) The roles of mutation, selection, and expression in determining relative rates of evolution in mitochondrial versus nuclear genomes. Mol Biol Evol 33:3042–3053. https://doi.org/10.1093/molbev/msw185
Hazkani-Covo E, Covo S (2008) Numt-mediated double-strand break repair mitigates deletions during primate genome evolution. PLoS Genet 4:e1000237. https://doi.org/10.1371/journal.pgen.1000237
Hazkani-Covo E, Zeller RM, Martin W (2010) Molecular poltergeists: mitochondrial DNA copies (numts) in sequenced nuclear genomes. PLoS Genet 6:e1000834. https://doi.org/10.1371/journal.pgen.1000834
Hill GE, Havird JC, Sloan DB, Burton RS, Greening C, Dowling DK (2019) Assessing the fitness consequences of mitonuclear interactions in natural populations. Biol Rev Camb Philos Soc 94:1089–1104. https://doi.org/10.1111/brv.12493
Hill S, Sataranatarajan K, Remmen HV (2018) Role of signaling molecules in mitochondrial stress response. Front Genet. https://doi.org/10.3389/fgene.2018.00225
Houtkooper RH, Mouchiroud L, Ryu D, Moullan N, Katsyuba E, Knott G, Williams RW, Auwerx J (2013) Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497:451–457. https://doi.org/10.1038/nature12188
Huang CY, Grunheit N, Ahmadinejad N, Timmis JN, Martin W (2005) Mutational decay and age of chloroplast and mitochondrial genomes transferred recently to angiosperm nuclear chromosomes. Plant Physiol 138:1723–1733. https://doi.org/10.1104/pp.105.060327
Hubert HB, Feinleib M, McNamara PM, Castelli WP (1983) Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 67:968–977. https://doi.org/10.1161/01.cir.67.5.968
Ikonen M, Liu B, Hashimoto Y, Ma L, Lee KW, Niikura T, Nishimoto I, Cohen P (2003) Interaction between the Alzheimer's survival peptide humanin and insulin-like growth factor-binding protein 3 regulates cell survival and apoptosis. Proc Natl Acad Sci USA 100:13042–13047. https://doi.org/10.1073/pnas.2135111100
Imai SI, Guarente L (2016) It takes two to tango: NAD(+) and sirtuins in aging/longevity control. NPJ Aging Mech Dis 2:16017. https://doi.org/10.1038/npjamd.2016.17
Immonen E, Collet M, Goenaga J, Arnqvist G (2016) Direct and indirect genetic effects of sex-specific mitonuclear epistasis on reproductive ageing. Heredity (Edinb) 116:338–347. https://doi.org/10.1038/hdy.2015.112
Ingelsson B, Söderberg D, Strid T, Söderberg A, Bergh A-C, Loitto V, Lotfi K, Segelmark M, Spyrou G, Rosén A (2018) Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C. Proc Natl Acad Sci 115:E478–E487. https://doi.org/10.1073/pnas.1711950115
Ingolia NT, Brar GA, Stern-Ginossar N, Harris MS, Talhouarne GJ, Jackson SE, Wills MR, Weissman JS (2014) Ribosome profiling reveals pervasive translation outside of annotated protein-coding genes. Cell Rep 8:1365–1379. https://doi.org/10.1016/j.celrep.2014.07.045
International Human Genome Sequencing C (2004) Finishing the euchromatic sequence of the human genome. Nature 431:931–945. https://doi.org/10.1038/nature03001
Jackson R, Kroehling L, Khitun A, Bailis W, Jarret A, York AG, Khan OM, Brewer JR, Skadow MH, Duizer C, Harman CCD, Chang L, Bielecki P, Solis AG, Steach HR, Slavoff S, Flavell RA (2018) The translation of non-canonical open reading frames controls mucosal immunity. Nature 564:434–438. https://doi.org/10.1038/s41586-018-0794-7
Jakobsson T, Venteclef N, Toresson G, Damdimopoulos AE, Ehrlund A, Lou X, Sanyal S, Steffensen KR, Gustafsson JA, Treuter E (2009) GPS2 is required for cholesterol efflux by triggering histone demethylation, LXR recruitment, and coregulator assembly at the ABCG1 locus. Mol Cell 34:510–518. https://doi.org/10.1016/j.molcel.2009.05.006
Ji Z, Song R, Regev A, Struhl K (2015) Many lncRNAs, 5’UTRs, and pseudogenes are translated and some are likely to express functional proteins. eLife. https://doi.org/10.7554/elife.08890
Johnston IG, Williams BP (2016) Evolutionary inference across eukaryotes identifies specific pressures favoring mitochondrial gene retention. Cell Syst 2:101–111. https://doi.org/10.1016/j.cels.2016.01.013
Ju YS, Tubio JMC, Mifsud W, Fu B, Davies HR, Ramakrishna M, Li Y, Yates L, Gundem G, Tarpey PS, Behjati S, Papaemmanuil E, Martin S, Fullam A, Gerstung M, Nangalia J, Green AR, Caldas C, Borg Å, Tutt A, Lee MTM, Van'T Veer LJ, Tan BKT, Aparicio S, Span PN, Martens JWM, Knappskog S, Vincent-Salomon A, Børresen-Dale A-L, Eyfjörd JE, Myklebost O, Flanagan AM, Foster C, Neal DE, Cooper C, Eeles R, Bova GS, Lakhani SR, Desmedt C, Thomas G, Richardson AL, Purdie CA, Thompson AM, McDermott U, Yang F, Nik-Zainal S, Campbell PJ, Stratton MR (2015) Frequent somatic transfer of mitochondrial DNA into the nuclear genome of human cancer cells. Genome Res 25:814–824. https://doi.org/10.1101/gr.190470.115
Kanki T, Ohgaki K, Gaspari M, Gustafsson CM, Fukuoh A, Sasaki N, Hamasaki N, Kang D (2004) Architectural role of mitochondrial transcription factor A in maintenance of human mitochondrial DNA. Mol Cell Biol 24:9823–9834. https://doi.org/10.1128/mcb.24.22.9823-9834.2004
Kariya S, Takahashi N, Hirano M, Ueno S (2003) Humanin improves impaired metabolic activity and prolongs survival of serum-deprived human lymphocytes. Mol Cell Biochem 254:83–89
Karpac J, Jasper H (2013) Aging: seeking mitonuclear balance. Cell 154:271–273. https://doi.org/10.1016/j.cell.2013.06.046
Kaufman BA, Durisic N, Mativetsky JM, Costantino S, Hancock MA, Grutter P, Shoubridge EA (2007) The mitochondrial transcription factor TFAM coordinates the assembly of multiple DNA molecules into nucleoid-like structures. Mol Biol Cell 18:3225–3236. https://doi.org/10.1091/mbc.e07-05-0404
Kelly JL, Lehman IR (1986) Yeast mitochondrial RNA polymerase. Purification and properties of the catalytic subunit. J Biol Chem 261:10340–10347
Kennedy SR, Salk JJ, Schmitt MW, Loeb LA (2013) Ultra-sensitive sequencing reveals an age-related increase in somatic mitochondrial mutations that are inconsistent with oxidative damage. PLoS Genet 9:e1003794. https://doi.org/10.1371/journal.pgen.1003794
Khrapko K, Vijg J (2009) Mitochondrial DNA mutations and aging: devils in the details? Trends Genet 25:91–98. https://doi.org/10.1016/j.tig.2008.11.007
Kim KH, Son JM, Benayoun BA, Lee C (2018a) The Mitochondrial-encoded peptide MOTS-c translocates to the nucleus to regulate nuclear gene expression in response to metabolic stress. Cell Metab 28(516–524):e7. https://doi.org/10.1016/j.cmet.2018.06.008
Kim SJ, Mehta HH, Wan J, Kuehnemann C, Chen J, Hu JF, Hoffman AR, Cohen P (2018b) Mitochondrial peptides modulate mitochondrial function during cellular senescence. Aging (Albany NY) 10:1239–1256. https://doi.org/10.18632/aging.101463
Kim J, Gupta R, Blanco LP, Yang S, Shteinfer-Kuzmine A, Wang K, Zhu J, Yoon HE, Wang X, Kerkhofs M (2019a) VDAC oligomers form mitochondrial pores to release mtDNA fragments and promote lupus-like disease. Science 366:1531–1536
Kim SJ, Miller B, Mehta HH, Xiao J, Wan J, Arpawong TE, Yen K, Cohen P (2019b) The mitochondrial-derived peptide MOTS-c is a regulator of plasma metabolites and enhances insulin sensitivity. Physiol Rep 7:e14171. https://doi.org/10.14814/phy2.14171
Kim SJ, Xiao J, Wan J, Cohen P, Yen K (2017) Mitochondrially derived peptides as novel regulators of metabolism. J Physiol 595:6613–6621. https://doi.org/10.1113/JP274472
Klein LE, Cui L, Gong Z, Su K, Muzumdar R (2013) A humanin analog decreases oxidative stress and preserves mitochondrial integrity in cardiac myoblasts. Biochem Biophys Res Commun 440:197–203. https://doi.org/10.1016/j.bbrc.2013.08.055
Kondo T, Hashimoto Y, Kato K, Inagaki S, Hayashi S, Kageyama Y (2007) Small peptide regulators of actin-based cell morphogenesis encoded by a polycistronic mRNA. Nat Cell Biol 9:660–665. https://doi.org/10.1038/ncb1595
Kondo T, Plaza S, Zanet J, Benrabah E, Valenti P, Hashimoto Y, Kobayashi S, Payre F, Kageyama Y (2010) Small peptides switch the transcriptional activity of Shavenbaby during Drosophila embryogenesis. Science 329:336–339. https://doi.org/10.1126/science.1188158
Kopek BG, Shtengel G, Xu CS, Clayton DA, Hess HF (2012) Correlative 3D superresolution fluorescence and electron microscopy reveal the relationship of mitochondrial nucleoids to membranes. Proc Natl Acad Sci 109:6136–6141. https://doi.org/10.1073/pnas.1121558109
Kopinski PK, Janssen KA, Schaefer PM, Trefely S, Perry CE, Potluri P, Tintos-Hernandez JA, Singh LN, Karch KR, Campbell SL, Doan MT, Jiang H, Nissim I, Nakamaru-Ogiso E, Wellen KE, Snyder NW, Garcia BA, Wallace DC (2019) Regulation of nuclear epigenome by mitochondrial DNA heteroplasmy. Proc Natl Acad Sci 116:16028–16035. https://doi.org/10.1073/pnas.1906896116
Lane N (2011) Mitonuclear match: optimizing fitness and fertility over generations drives ageing within generations. BioEssays 33:860–869. https://doi.org/10.1002/bies.201100051
Lane N (2017) Serial endosymbiosis or singular event at the origin of eukaryotes? J Theor Biol 434:58–67. https://doi.org/10.1016/j.jtbi.2017.04.031
Larsson NG (2010) Somatic mitochondrial DNA mutations in mammalian aging. Annu Rev Biochem 79:683–706. https://doi.org/10.1146/annurev-biochem-060408-093701
Lee C, Wan J, Miyazaki B, Fang Y, Guevara-Aguirre J, Yen K, Longo V, Bartke A, Cohen P (2014) IGF-I regulates the age-dependent signaling peptide humanin. Aging Cell 13:958–961. https://doi.org/10.1111/acel.12243
Lee C, Yen K, Cohen P (2013) Humanin: a harbinger of mitochondrial-derived peptides? Trends Endocrinol Metab 24:222–228. https://doi.org/10.1016/j.tem.2013.01.005
Lee C, Zeng J, Drew BG, Sallam T, Martin-Montalvo A, Wan J, Kim SJ, Mehta H, Hevener AL, de Cabo R, Cohen P (2015) The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab 21:443–454. https://doi.org/10.1016/j.cmet.2015.02.009
Lee SR, Han J (2017) Mitochondrial nucleoid: shield and switch of the mitochondrial genome. Oxid Med Cell Longev 2017:8060949. https://doi.org/10.1155/2017/8060949
Lee WT, Sun X, Tsai TS, Johnson JL, Gould JA, Garama DJ, Gough DJ, McKenzie M, Trounce IA, St John JC (2017) Mitochondrial DNA haplotypes induce differential patterns of DNA methylation that result in differential chromosomal gene expression patterns. Cell Death Discov 3:17062. https://doi.org/10.1038/cddiscovery.2017.62
Li Q, Lu H, Hu G, Ye Z, Zhai D, Yan Z, Wang L, Xiang A, Lu Z (2019) Earlier changes in mice after d-galactose treatment were improved by mitochondria derived small peptide MOTS-c. Biochem Biophys Res Commun 513:439–445. https://doi.org/10.1016/j.bbrc.2019.03.194
Liu C, Gidlund EK, Witasp A, Qureshi AR, Soderberg M, Thorell A, Nader GA, Barany P, Stenvinkel P, von Walden F (2019) Reduced skeletal muscle expression of mitochondrial derived peptides humanin and MOTS-C and Nrf2 in chronic kidney disease. Am J Physiol Renal Physiol. https://doi.org/10.1152/ajprenal.00202.2019
Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, Curiel TJ, de Cabo R, Franceschi C, Gems D, Ingram DK, Johnson TE, Kennedy BK, Kenyon C, Klein S, Kopchick JJ, Lepperdinger G, Madeo F, Mirisola MG, Mitchell JR, Passarino G, Rudolph KL, Sedivy JM, Shadel GS, Sinclair DA, Spindler SR, Suh Y, Vijg J, Vinciguerra M, Fontana L (2015) Interventions to slow aging in humans: are we ready? Aging Cell 14:497–510. https://doi.org/10.1111/acel.12338
Longo VD, Gralla EB, Valentine JS (1996) Superoxide dismutase activity is essential for stationary phase survival in Saccharomyces cerevisiae. Mitochondrial production of toxic oxygen species in vivo. J Biol Chem 271:12275–12280. https://doi.org/10.1074/jbc.271.21.12275
Lopez JV, Yuhki N, Masuda R, Modi W, O'Brien SJ (1994) Numt, a recent transfer and tandem amplification of mitochondrial DNA to the nuclear genome of the domestic cat. J Mol Evol 39:174–190. https://doi.org/10.1007/bf00163806
Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–1217. https://doi.org/10.1016/j.cell.2013.05.039
Lopez-Otin C, Galluzzi L, Freije JM, Madeo F, Kroemer G (2016) Metabolic control of longevity. Cell 166:802–821. https://doi.org/10.1016/j.cell.2016.07.031
Lu H, Tang S, Xue C, Liu Y, Wang J, Zhang W, Luo W, Chen J (2019a) Mitochondrial-derived peptide MOTS-c increases adipose thermogenic activation to promote cold adaptation. Int J Mol Sci 20:2456. https://doi.org/10.3390/ijms20102456
Lu H, Wei M, Zhai Y, Li Q, Ye Z, Wang L, Luo W, Chen J, Lu Z (2019b) MOTS-c peptide regulates adipose homeostasis to prevent ovariectomy-induced metabolic dysfunction. J Mol Med (Berl) 97:473–485. https://doi.org/10.1007/s00109-018-01738-w
Luo S, Valencia CA, Zhang J, Lee N-C, Slone J, Gui B, Wang X, Li Z, Dell S, Brown J, Chen SM, Chien Y-H, Hwu W-L, Fan P-C, Wong L-J, Atwal PS, Huang T (2018) Biparental inheritance of mitochondrial DNA in humans. Proc Natl Acad Sci 115:13039–13044. https://doi.org/10.1073/pnas.1810946115
Lutz-Bonengel S, Parson W (2019) No further evidence for paternal leakage of mitochondrial DNA in humans yet. Proc Natl Acad Sci 116:1821–1822. https://doi.org/10.1073/pnas.1820533116
Magny EG, Pueyo JI, Pearl FM, Cespedes MA, Niven JE, Bishop SA, Couso JP (2013) Conserved regulation of cardiac calcium uptake by peptides encoded in small open reading frames. Science 341:1116–1120. https://doi.org/10.1126/science.1238802
Makarewich CA, Olson EN (2017) Mining for micropeptides. Trends Cell Biol. https://doi.org/10.1016/j.tcb.2017.04.006
Mamiya T, Ukai M (2001) [Gly(14)]-Humanin improved the learning and memory impairment induced by scopolamine in vivo. Br J Pharmacol 134:1597–1599. https://doi.org/10.1038/sj.bjp.0704429
Mangalhara KC, Shadel GS (2018) A mitochondrial-derived peptide exercises the nuclear option. Cell Metab 28:330–331. https://doi.org/10.1016/j.cmet.2018.08.017
Martijn J, Vosseberg J, Guy L, Offre P, Ettema TJG (2018) Deep mitochondrial origin outside the sampled alphaproteobacteria. Nature 557:101–105. https://doi.org/10.1038/s41586-018-0059-5
Martin I, Jones MA, Rhodenizer D, Zheng J, Warrick JM, Seroude L, Grotewiel M (2009) Sod2 knockdown in the musculature has whole-organism consequences in Drosophila. Free Radic Biol Med 47:803–813. https://doi.org/10.1016/j.freeradbiomed.2009.06.021
Martinus RD, Garth GP, Webster TL, Cartwright P, Naylor DJ, Høj PB, Hoogenraad NJ (1996) Selective induction of mitochondrial chaperones in response to loss of the mitochondrial genome. Eur J Biochem 240:98–103. https://doi.org/10.1111/j.1432-1033.1996.0098h.x
Masters BS, Stohl LL, Clayton DA (1987) Yeast mitochondrial RNA polymerase is homologous to those encoded by bacteriophages T3 and T7. Cell 51:89–99. https://doi.org/10.1016/0092-8674(87)90013-4
McManus MJ, Picard M, Chen HW, De Haas HJ, Potluri P, Leipzig J, Towheed A, Angelin A, Sengupta P, Morrow RM, Kauffman BA, Vermulst M, Narula J, Wallace DC (2019) Mitochondrial DNA variation dictates expressivity and progression of nuclear DNA mutations causing cardiomyopathy. Cell Metab 29(78–90):e5. https://doi.org/10.1016/j.cmet.2018.08.002
Melber A, Haynes CM (2018) UPR(mt) regulation and output: a stress response mediated by mitochondrial-nuclear communication. Cell Res 28:281–295. https://doi.org/10.1038/cr.2018.16
Melov S, Ravenscroft J, Malik S, Gill MS, Walker DW, Clayton PE, Wallace DC, Malfroy B, Doctrow SR, Lithgow GJ (2000) Extension of life-span with superoxide dismutase/catalase mimetics. Science 289:1567–1569. https://doi.org/10.1126/science.289.5484.1567
Menzies KJ, Zhang H, Katsyuba E, Auwerx J (2016) Protein acetylation in metabolism—metabolites and cofactors. Nat Rev Endocrinol 12:43–60. https://doi.org/10.1038/nrendo.2015.181
Mercer TR, Neph S, Dinger ME, Crawford J, Smith MA, Shearwood AM, Haugen E, Bracken CP, Rackham O, Stamatoyannopoulos JA, Filipovska A, Mattick JS (2011) The human mitochondrial transcriptome. Cell 146:645–658. https://doi.org/10.1016/j.cell.2011.06.051
Merkwirth C, Jovaisaite V, Durieux J, Matilainen O, Sabine P, Kristan E, Mouchiroud L, Sarah MV, Suzanne R, Auwerx J, Dillin A (2016) Two conserved histone demethylases regulate mitochondrial stress-induced longevity. Cell 165:1209–1223. https://doi.org/10.1016/j.cell.2016.04.012
Merry TL, Ristow M (2015) Do antioxidant supplements interfere with skeletal muscle adaptation to exercise training? J Physiol. https://doi.org/10.1113/jp270654
Milenkovic D, Blaza JN, Larsson NG, Hirst J (2017) The enigma of the respiratory chain supercomplex. Cell Metab 25:765–776. https://doi.org/10.1016/j.cmet.2017.03.009
Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, Yoshino J, Imai SI (2016) Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab 24:795–806. https://doi.org/10.1016/j.cmet.2016.09.013
Ming W, Lu G, Xin S, Huanyu L, Yinghao J, Xiaoying L, Chengming X, Banjun R, Li W, Zifan L (2016) Mitochondria related peptide MOTS-c suppresses ovariectomy-induced bone loss via AMPK activation. Biochem Biophys Res Commun 476:412–419. https://doi.org/10.1016/j.bbrc.2016.05.135
Morava E, Kozicz T, Wallace DC (2019) The phenotype modifier: is the mitochondrial DNA background responsible for individual differences in disease severity. J Inherit Metab Dis 42:3–4. https://doi.org/10.1002/jimd.12050
Mossman JA, Biancani LM, Rand DM (2019) Mitochondrial genomic variation drives differential nuclear gene expression in discrete regions of Drosophila gene and protein interaction networks. BMC Genom. https://doi.org/10.1186/s12864-019-6061-y
Mottis A, Herzig S, Auwerx J (2019) Mitocellular communication: shaping health and disease. Science 366:827–832. https://doi.org/10.1126/science.aax3768
Mouchiroud L, Houtkooper RH, Moullan N, Katsyuba E, Ryu D, Canto C, Mottis A, Jo YS, Viswanathan M, Schoonjans K, Guarente L, Auwerx J (2013) The NAD(+)/Sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154:430–441. https://doi.org/10.1016/j.cell.2013.06.016
Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13. https://doi.org/10.1042/BJ20081386
Muzumdar RH, Huffman DM, Atzmon G, Buettner C, Cobb LJ, Fishman S, Budagov T, Cui L, Einstein FH, Poduval A, Hwang D, Barzilai N, Cohen P (2009) Humanin: a novel central regulator of peripheral insulin action. PLoS ONE 4:e6334. https://doi.org/10.1371/journal.pone.0006334
Muzumdar RH, Huffman DM, Calvert JW, Jha S, Weinberg Y, Cui L, Nemkal A, Atzmon G, Klein L, Gundewar S, Ji SY, Lavu M, Predmore BL, Lefer DJ (2010) Acute humanin therapy attenuates myocardial ischemia and reperfusion injury in mice. Arterioscler Thromb Vasc Biol 30:1940–1948. https://doi.org/10.1161/ATVBAHA.110.205997
Nargund AM, Fiorese CJ, Pellegrino MW, Deng P, Haynes CM (2015) Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPR(mt). Mol Cell 58:123–133. https://doi.org/10.1016/j.molcel.2015.02.008
Nargund AM, Pellegrino MW, Fiorese CJ, Baker BM, Haynes CM (2012) Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 337:587–590. https://doi.org/10.1126/science.1223560
Nicholas G, Stern-Ginossar N, Michael G, Sarah M (2014) Ribosome profiling reveals pervasive translation outside of annotated protein-coding genes. Cell Reports 8:1365–1379. https://doi.org/10.1016/j.celrep.2014.07.045
Oh YK, Bachar AR, Zacharias DG, Kim SG, Wan J, Cobb LJ, Lerman LO, Cohen P, Lerman A (2011) Humanin preserves endothelial function and prevents atherosclerotic plaque progression in hypercholesterolemic ApoE deficient mice. Atherosclerosis 219:65–73. https://doi.org/10.1016/j.atherosclerosis.2011.06.038
Ojala D, Montoya J, Attardi G (1981) tRNA punctuation model of RNA processing in human mitochondria. Nature 290:470–474. https://doi.org/10.1038/290470a0
Okada AK, Teranishi K, Lobo F, Isas JM, Xiao J, Yen K, Cohen P, Langen R (2017) The mitochondrial-derived peptides, HumaninS14G and small humanin-like peptide 2, exhibit chaperone-like activity. Sci Rep. https://doi.org/10.1038/s41598-017-08372-5
Onyango I, Khan S, Miller B, Swerdlow R, Trimmer P, Bennett P Jr (2006) Mitochondrial genomic contribution to mitochondrial dysfunction in Alzheimer's disease. J Alzheimers Dis 9:183–193. https://doi.org/10.3233/jad-2006-9210
Perna NT, Kocher TD (1996) Mitochondrial DNA: molecular fossils in the nucleus. Curr Biol 6:128–129. https://doi.org/10.1016/s0960-9822(02)00441-4
Pichaud N, Berube R, Cote G, Belzile C, Dufresne F, Morrow G, Tanguay RM, Rand DM, Blier PU (2019) Age dependent dysfunction of mitochondrial and ROS metabolism induced by mitonuclear mismatch. Front Genet 10:130. https://doi.org/10.3389/fgene.2019.00130
Pickles S, Vigie P, Youle RJ (2018) Mitophagy and quality control mechanisms in mitochondrial maintenance. Curr Biol 28:R170–R185. https://doi.org/10.1016/j.cub.2018.01.004
Pinti M, Cevenini E, Nasi M, De Biasi S, Salvioli S, Monti D, Benatti S, Gibellini L, Cotichini R, Stazi MA, Trenti T, Franceschi C, Cossarizza A (2014) Circulating mitochondrial DNA increases with age and is a familiar trait: Implications for “inflamm-aging”. Eur J Immunol 44:1552–1562. https://doi.org/10.1002/eji.201343921
Pohjoismaki JLO, Forslund JME, Goffart S, Torregrosa-Munumer R, Wanrooij S (2018) Known unknowns of mammalian mitochondrial DNA maintenance. BioEssays 40:e1800102. https://doi.org/10.1002/bies.201800102
Pomatto LCD, Davies KJA (2018) Adaptive homeostasis and the free radical theory of ageing. Free Radic Biol Med 124:420–430. https://doi.org/10.1016/j.freeradbiomed.2018.06.016
Pozzi A, Dowling DK (2019) The genomic origins of small mitochondrial RNAs: are they transcribed by the mitochondrial DNA or by mitochondrial pseudogenes within the nucleus (NUMTs)? Genome Biol Evol 11:1883–1896. https://doi.org/10.1093/gbe/evz132
Prevost CT, Peris N, Seger C, Pedeville DR, Wershing K, Sia EA, Sia RAL (2018) The influence of mitochondrial dynamics on mitochondrial genome stability. Curr Genet 64:199–214. https://doi.org/10.1007/s00294-017-0717-4
Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, Agarwal B, Ye L, Ramadori G, Teodoro JS, Hubbard BP, Varela AT, Davis JG, Varamini B, Hafner A, Moaddel R, Rolo AP, Coppari R, Palmeira CM, de Cabo R, Baur JA, Sinclair DA (2012) SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab 15:675–690. https://doi.org/10.1016/j.cmet.2012.04.003
Qin Q, Delrio S, Wan J, Jay Widmer R, Cohen P, Lerman LO, Lerman A (2018a) Downregulation of circulating MOTS-c levels in patients with coronary endothelial dysfunction. Int J Cardiol 254:23–27. https://doi.org/10.1016/j.ijcard.2017.12.001
Qin Q, Mehta H, Yen K, Navarrete G, Brandhorst S, Wan J, Delrio S, Zhang X, Lerman LO, Cohen P, Lerman A (2018b) Chronic treatment with the mitochondrial peptide humanin prevents age-related myocardial fibrosis in mice. Am J Physiol Heart Circ Physiol 315:H1127–H1136. https://doi.org/10.1152/ajpheart.00685.2017
Quirós PM, Mottis A, Auwerx J (2016) Mitonuclear communication in homeostasis and stress. Nat Rev Mol Cell Biol 17:213–226. https://doi.org/10.1038/nrm.2016.23
Raijmakers RPH, Jansen AFM, Keijmel SP, Ter Horst R, Roerink ME, Novakovic B, Joosten LAB, van der Meer JWM, Netea MG, Bleeker-Rovers CP (2019) A possible role for mitochondrial-derived peptides humanin and MOTS-c in patients with Q fever fatigue syndrome and chronic fatigue syndrome. J Transl Med 17:157. https://doi.org/10.1186/s12967-019-1906-3
Raj A, Wang SH, Shim H, Harpak A, Li YI, Engelmann B, Stephens M, Gilad Y, Pritchard JK (2016) Thousands of novel translated open reading frames in humans inferred by ribosome footprint profiling. Elife. https://doi.org/10.7554/eLife.13328
Ramanjaneya M, Bettahi I, Jerobin J, Chandra P, Abi Khalil C, Skarulis M, Atkin SL, Abou-Samra AB (2019a) Mitochondrial-derived peptides are down regulated in diabetes subjects. Front Endocrinol (Lausanne) 10:331. https://doi.org/10.3389/fendo.2019.00331
Ramanjaneya M, Jerobin J, Bettahi I, Bensila M, Aye M, Siveen KS, Sathyapalan T, Skarulis M, Abou-Samra AB, Atkin SL (2019b) Lipids and insulin regulate mitochondrial-derived peptide (MOTS-c) in PCOS and healthy subjects. Clin Endocrinol (Oxf). https://doi.org/10.1111/cen.14007
Reinhardt K, Dowling DK, Morrow EH (2013) Medicine. Mitochondrial replacement, evolution, and the clinic. Science 341:1345–1346. https://doi.org/10.1126/science.1237146
Ricchetti M, Tekaia F, Dujon B (2004) Continued colonization of the human genome by mitochondrial DNA. PLoS Biol 2:E273. https://doi.org/10.1371/journal.pbio.0020273
Ringel R, Sologub M, Morozov YI, Litonin D, Cramer P, Temiakov D (2011) Structure of human mitochondrial RNA polymerase. Nature 478:269–273. https://doi.org/10.1038/nature10435
Ristow M, Schmeisser K (2014) Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS). Dose Response 12:288–341. https://doi.org/10.2203/dose-response.13-035.Ristow
Ristow M, Schmeisser S (2011) Extending life span by increasing oxidative stress. Free Radical Biol Med 51:327–336. https://doi.org/10.1016/j.freeradbiomed.2011.05.010
Rojansky R, Cha MY, Chan DC (2016) Elimination of paternal mitochondria in mouse embryos occurs through autophagic degradation dependent on PARKIN and MUL1. Elife. https://doi.org/10.7554/eLife.17896
Rothnagel J, Menschaert G (2018) Short open reading frames and their encoded peptides. Proteomics 18:1700035. https://doi.org/10.1002/pmic.201700035
Rubio MAT, Rinehart JJ, Krett B, Duvezin-Caubet S, Reichert AS, Söll D, Alfonzo JD (2008) Mammalian mitochondria have the innate ability to import tRNAs by a mechanism distinct from protein import. Proc Natl Acad Sci 105:9186–9191. https://doi.org/10.1073/pnas.0804283105
Ruiz-Orera J, Albà MM (2019) Translation of small open reading frames: roles in regulation and evolutionary innovation. Trends Genet 35:186–198. https://doi.org/10.1016/j.tig.2018.12.003
Sagan L (1967) On the origin of mitosing cells. J Theor Biol 14:255–274. https://doi.org/10.1016/0022-5193(67)90079-3
Saghatelian A, Couso JP (2015) Discovery and characterization of smORF-encoded bioactive polypeptides. Nat Chem Biol 11:909–916. https://doi.org/10.1038/nchembio.1964
Salinas-Giegé T, Giegé R, Giegé P (2015) tRNA Biology in mitochondria. Int J Mol Sci 16:4518–4559. https://doi.org/10.3390/ijms16034518
Schneider A (2011) Mitochondrial tRNA import and its consequences for mitochondrial translation. Annu Rev Biochem 80:1033–1053. https://doi.org/10.1146/annurev-biochem-060109-092838
Schulz TJ, Zarse K, Voigt A, Urban N, Birringer M, Ristow M (2007) Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress. Cell Metab 6:280–293. https://doi.org/10.1016/j.cmet.2007.08.011
Sena LA, Chandel NS (2012) Physiological roles of mitochondrial reactive oxygen species. Mol Cell 48:158–167. https://doi.org/10.1016/j.molcel.2012.09.025
Shadel GS, Horvath TL (2015) Mitochondrial ROS signaling in organismal homeostasis. Cell 163:560–569. https://doi.org/10.1016/j.cell.2015.10.001
Shi L, Tu BP (2015) Acetyl-CoA and the regulation of metabolism: mechanisms and consequences. Curr Opin Cell Biol 33:125–131. https://doi.org/10.1016/j.ceb.2015.02.003
Shokolenko IN, Alexeyev MF (2017) Mitochondrial transcription in mammalian cells. Front Biosci (Landmark Ed) 22:835–853. https://doi.org/10.2741/4520
Shpilka T, Haynes CM (2018) The mitochondrial UPR: mechanisms, physiological functions and implications in ageing. Nat Rev Mol Cell Biol 19:109–120. https://doi.org/10.1038/nrm.2017.110
Shutt TE, Gray MW (2006) Bacteriophage origins of mitochondrial replication and transcription proteins. Trends Genet 22:90–95. https://doi.org/10.1016/j.tig.2005.11.007
Singh KK, Choudhury AR, Tiwari HK (2017) Numtogenesis as a mechanism for development of cancer. Semin Cancer Biol 47:101–109. https://doi.org/10.1016/j.semcancer.2017.05.003
Singh PP, Demmitt BA, Nath RD, Brunet A (2019) The genetics of aging: a vertebrate perspective. Cell 177:200–220. https://doi.org/10.1016/j.cell.2019.02.038
Slavoff SA, Heo J, Budnik BA, Hanakahi LA, Saghatelian A (2014) A human short open reading frame (sORF)-encoded polypeptide that stimulates DNA end joining. J Biol Chem 289:10950–10957. https://doi.org/10.1074/jbc.C113.533968
Spang A, Saw JH, Jørgensen SL, Zaremba-Niedzwiedzka K, Martijn J, Lind AE, van Eijk R, Schleper C, Guy L, Ettema TJG (2015) Complex archaea that bridge the gap between prokaryotes and eukaryotes. Nature 521:173. https://doi.org/10.1038/nature14447
Sreekumar PG, Ishikawa K, Spee C, Mehta HH, Wan J, Yen K, Cohen P, Kannan R, Hinton DR (2016) The mitochondrial-derived peptide humanin protects RPE cells from oxidative stress. Senescence Mitochondrial Dysfunct. 57:1238. https://doi.org/10.1167/iovs.15-17053
Srinivasainagendra V, Sandel MW, Singh B, Sundaresan A, Mooga VP, Bajpai P, Tiwari HK, Singh KK (2017) Migration of mitochondrial DNA in the nuclear genome of colorectal adenocarcinoma. Genome Med 9:31. https://doi.org/10.1186/s13073-017-0420-6
Sun N, Youle RJ, Finkel T (2016) The mitochondrial basis of aging. Mol Cell 61:654–666. https://doi.org/10.1016/j.molcel.2016.01.028
Sunnucks P, Morales HE, Lamb AM, Pavlova A, Greening C (2017) Integrative approaches for studying mitochondrial and nuclear genome co-evolution in oxidative phosphorylation. Front Genet 8:25. https://doi.org/10.3389/fgene.2017.00025
Sutendra G, Kinnaird A, Dromparis P, Paulin R, Stenson TH, Haromy A, Hashimoto K, Zhang N, Flaim E, Michelakis ED (2014) A nuclear pyruvate dehydrogenase complex is important for the generation of acetyl-CoA and histone acetylation. Cell 158:84–97. https://doi.org/10.1016/j.cell.2014.04.046
Swerdlow RH, Koppel S, Weidling I, Hayley C, Ji Y, Wilkins HM (2017) Mitochondria, cybrids, aging, and Alzheimer's disease. Prog Mol Biol Transl Sci 146:259–302. https://doi.org/10.1016/bs.pmbts.2016.12.017
Tajima H, Kawasumi M, Chiba T, Yamada M, Yamashita K, Nawa M, Kita Y, Kouyama K, Aiso S, Matsuoka M, Niikura T, Nishimoto I (2005) A humanin derivative, S14G-HN, prevents amyloid-beta-induced memory impairment in mice. J Neurosci Res 79:714–723. https://doi.org/10.1002/jnr.20391
Tatar M, Bartke A, Antebi A (2003) The endocrine regulation of aging by insulin-like signals. Science 299:1346–1351
Tauffenberger A, Vaccaro A, Parker JA (2016) Fragile lifespan expansion by dietary mitohormesis in C. elegans. Aging (Albany NY) 8:50–61. https://doi.org/10.18632/aging.100863
Theurey P, Pizzo P (2018) The aging mitochondria. Genes (Basel). https://doi.org/10.3390/genes9010022
Thorsness PE, Fox TD (1990) Escape of DNA from mitochondria to the nucleus in Saccharomyces cerevisiae. Nature 346:376–379. https://doi.org/10.1038/346376a0
Thummasorn S, Apaijai N, Kerdphoo S, Shinlapawittayatorn K, Chattipakorn SC, Chattipakorn N (2016) Humanin exerts cardioprotection against cardiac ischemia/reperfusion injury through attenuation of mitochondrial dysfunction. Cardiovasc Ther 34:404–414. https://doi.org/10.1111/1755-5922.12210
Thummasorn S, Shinlapawittayatorn K, Khamseekaew J, Jaiwongkam T, Chattipakorn SC, Chattipakorn N (2018) Humanin directly protects cardiac mitochondria against dysfunction initiated by oxidative stress by decreasing complex I activity. Mitochondrion 38:31–40. https://doi.org/10.1016/j.mito.2017.08.001
Tian Y, Garcia G, Bian Q, Steffen KK, Joe L, Wolff S, Meyer BJ, Dillin A (2016) Mitochondrial stress induces chromatin reorganization to promote longevity and UPR(mt). Cell 165:1197–1208. https://doi.org/10.1016/j.cell.2016.04.011
Timmis JN, Ayliffe MA, Huang CY, Martin W (2004) Endosymbiotic gene transfer: organelle genomes forge eukaryotic chromosomes. Nat Rev Genet 5:123–135. https://doi.org/10.1038/nrg1271
Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly YM, Gidlof S, Oldfors A, Wibom R, Tornell J, Jacobs HT, Larsson NG (2004) Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429:417–423. https://doi.org/10.1038/nature02517
Trumpff C, Marsland AL, Basualto-Alarcón C, Martin JL, Carroll JE, Sturm G, Vincent AE, Mosharov EV, Gu Z, Kaufman BA, Picard M (2019) Acute psychological stress increases serum circulating cell-free mitochondrial DNA. Psychoneuroendocrinology 106:268–276. https://doi.org/10.1016/j.psyneuen.2019.03.026
Tsuzuki T, Nomiyama H, Setoyama C, Maeda S, Shimada K, Pestka S (1983) The majority of cDNA clones with strong positive signals for the interferon-induction-specific sequences resemble mitochondrial ribosomal RNA genes. Biochem Biophys Res Commun 114:670–676
Turner C, Killoran C, Thomas NS, Rosenberg M, Chuzhanova NA, Johnston J, Kemel Y, Cooper DN, Biesecker LG (2003) Human genetic disease caused by de novo mitochondrial-nuclear DNA transfer. Hum Genet 112:303–309. https://doi.org/10.1007/s00439-002-0892-2
Tyynismaa H, Sembongi H, Bokori-Brown M, Granycome C, Ashley N, Poulton J, Jalanko A, Spelbrink JN, Holt IJ, Suomalainen A (2004) Twinkle helicase is essential for mtDNA maintenance and regulates mtDNA copy number. Hum Mol Genet 13:3219–3227. https://doi.org/10.1093/hmg/ddh342
Unlu ES, Koc A (2007) Effects of deleting mitochondrial antioxidant genes on life span. Ann N Y Acad Sci 1100:505–509. https://doi.org/10.1196/annals.1395.055
van Oven M, Kayser M (2009) Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation. Hum Mutat 30:E386–E394. https://doi.org/10.1002/humu.20921
Vermulst M, Bielas JH, Kujoth GC, Ladiges WC, Rabinovitch PS, Prolla TA, Loeb LA (2007) Mitochondrial point mutations do not limit the natural lifespan of mice. Nat Genet 39:540–543. https://doi.org/10.1038/ng1988
Vermulst M, Wanagat J, Kujoth GC, Bielas JH, Rabinovitch PS, Prolla TA, Loeb LA (2008) DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice. Nat Genet 40:392–394. https://doi.org/10.1038/ng.95
Wallace DC (1999) Mitochondrial diseases in man and mouse. Science 283:1482–1488. https://doi.org/10.1126/science.283.5407.1482
Wallace DC (2010) Mitochondrial DNA mutations in disease and aging. Environ Mol Mutagen 51:440–450. https://doi.org/10.1002/em.20586
Wallace DC, Chalkia D (2013) Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harbor Perspect Biol 5:a021220–a021220. https://doi.org/10.1101/cshperspect.a021220
Wang D, Li H, Yuan H, Zheng M, Bai C, Chen L, Pei X (2005) Humanin delays apoptosis in K562 cells by downregulation of P38 MAP kinase. Apoptosis 10:963–971. https://doi.org/10.1007/s10495-005-1191-x
Wenceslau CF, McCarthy CG, Szasz T, Spitler K, Goulopoulou S, Webb RC, Working Group on DiCD (2014) Mitochondrial damage-associated molecular patterns and vascular function. Eur Heart J 35:1172–1177. https://doi.org/10.1093/eurheartj/ehu047
Wicks S, Bain N, Duttaroy A, Hilliker AJ, Phillips JP (2009) Hypoxia rescues early mortality conferred by superoxide dismutase deficiency. Free Radic Biol Med 46:176–181. https://doi.org/10.1016/j.freeradbiomed.2008.09.036
Widmer RJ, Flammer AJ, Herrmann J, Rodriguez-Porcel M, Wan J, Cohen P, Lerman LO, Lerman A (2013) Circulating humanin levels are associated with preserved coronary endothelial function. Am J Physiol Heart Circ Physiol 304:H393–H397. https://doi.org/10.1152/ajpheart.00765.2012
Williams BAP, Slamovits CH, Patron NJ, Fast NM, Keeling PJ (2005) A high frequency of overlapping gene expression in compacted eukaryotic genomes. Proc Natl Acad Sci 102:10936–10941. https://doi.org/10.1073/pnas.0501321102
Williams CC, Jan CH, Weissman JS (2014) Targeting and plasticity of mitochondrial proteins revealed by proximity-specific ribosome profiling. Science 346:748–751. https://doi.org/10.1126/science.1257522
Wolff JN, Pichaud N, Camus MF, Cote G, Blier PU, Dowling DK (2016) Evolutionary implications of mitochondrial genetic variation: mitochondrial genetic effects on OXPHOS respiration and mitochondrial quantity change with age and sex in fruit flies. J Evol Biol 29:736–747. https://doi.org/10.1111/jeb.12822
Wong W (2018) Going nuclear with stress. Sci Signal. https://doi.org/10.1126/scisignal.aav4285
Wu Z, Oeck S, West AP, Mangalhara KC, Sainz AG, Newman LE, Zhang X-O, Wu L, Yan Q, Bosenberg M (2019) Mitochondrial DNA stress signalling protects the nuclear genome. Nature Metabolism 1:1–10
Xiao J, Howard L, Wan J, Wiggins E, Vidal A, Cohen P, Freedland SJ (2017) Low circulating levels of the mitochondrial-peptide hormone SHLP2: novel biomarker for prostate cancer risk. Oncotarget 8:94900–94909. https://doi.org/10.18632/oncotarget.20134
Yakes FM, Van Houten B (1997) Mitochondrial DNA damage is more extensive and persists longer than nuclear DNA damage in human cells following oxidative stress. Proc Natl Acad Sci USA 94:514–519. https://doi.org/10.1073/pnas.94.2.514
Yan Z, Zhu S, Wang H, Wang L, Du T, Ye Z, Zhai D, Zhu Z, Tian X, Lu Z, Cao X (2019) MOTS-c inhibits osteolysis in the mouse calvaria by affecting osteocyte-osteoclast crosstalk and inhibiting inflammation. Pharmacol Res 147:104381. https://doi.org/10.1016/j.phrs.2019.104381
Yeasmin F, Yada T, Akimitsu N (2018) Micropeptides encoded in transcripts previously identified as long noncoding RNAs: a new chapter in transcriptomics and proteomics. Front Genet. https://doi.org/10.3389/fgene.2018.00144
Yong CQY, Tang BL (2018) A mitochondrial encoded messenger at the nucleus. Cells. https://doi.org/10.3390/cells7080105
Yoshino J, Mills KF, Yoon MJ, Imai S (2011) Nicotinamide mononucleotide, a key NAD(+) intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab 14:528–536. https://doi.org/10.1016/j.cmet.2011.08.014
Youle RJ (2019) Mitochondria-striking a balance between host and endosymbiont. Science. https://doi.org/10.1126/science.aaw9855
Yousefi S, Gold JA, Andina N, Lee JJ, Kelly AM, Kozlowski E, Schmid I, Straumann A, Reichenbach J, Gleich GJ, Simon H-U (2008) Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nat Med 14:949–953. https://doi.org/10.1038/nm.1855
Zacharias DG, Kim SG, Massat AE, Bachar AR, Oh YK, Herrmann J, Rodriguez-Porcel M, Cohen P, Lerman LO, Lerman A (2012) Humanin, a cytoprotective peptide, is expressed in carotid artherosclerotic plaques in humans. PLoS ONE 7:e31065. https://doi.org/10.1371/journal.pone.0031065
Zaidi AA, Makova KD (2019) Investigating mitonuclear interactions in human admixed populations. Nat Ecol Evol 3:213–222. https://doi.org/10.1038/s41559-018-0766-1
Zempo H, Fuku N, Nishida Y, Higaki Y, Naito H, Hara M, Tanaka K (2016) Relation between type 2 diabetes and m.1382 A%3eC polymorphism which occurs amino acid replacement (K14Q) of mitochondria-derived MOTS-c. FASEB J 30:956-1
Zempo H, Kim S-J, Fuku N, Nishida Y, Higaki Y, Wan J, Yen K, Miller B, Vicinanza R, Miyamoto-Mikami E, Kumagai H, Naito H, Xiao J, Mehta HH, Lee C, Hara M, Patel YM, Setiawan VW, Moore TM, Hevener AL, Sutoh Y, Shimizu A, Kojima K, Kinoshita K, Tanaka K, Cohen P (2019) A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide. MOTS-c. https://doi.org/10.1101/695585
Zhai D, Ye Z, Jiang Y, Xu C, Ruan B, Yang Y, Lei X, Xiang A, Lu H, Zhu Z, Yan Z, Wei D, Li Q, Wang L, Lu Z (2017) MOTS-c peptide increases survival and decreases bacterial load in mice infected with MRSA. Mol Immunol 92:151–160. https://doi.org/10.1016/j.molimm.2017.10.017
Zhang Q, Raoof M, Chen Y, Sumi Y, Sursal T, Junger W, Brohi K, Itagaki K, Hauser CJ (2010) Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 464:104–107. https://doi.org/10.1038/nature08780
Zhang W, Miao J, Hao J, Li Z, Xu J, Liu R, Cao F, Wang R, Chen J (2009) Protective effect of S14G-humanin against beta-amyloid induced LTP inhibition in mouse hippocampal slices. Peptides 30:1197–1202. https://doi.org/10.1016/j.peptides.2009.02.017
Zhang Y, Liu Y, Walsh M, Bokov A, Ikeno Y, Jang YC, Perez VI, Van Remmen H, Richardson A (2016) Liver specific expression of Cu/ZnSOD extends the lifespan of Sod1 null mice. Mech Ageing Dev 154:1–8. https://doi.org/10.1016/j.mad.2016.01.005
Zhang Y, Unnikrishnan A, Deepa SS, Liu Y, Li Y, Ikeno Y, Sosnowska D, Van Remmen H, Richardson A (2017) A new role for oxidative stress in aging: the accelerated aging phenotype in Sod1(−/)(−) mice is correlated to increased cellular senescence. Redox Biol 11:30–37. https://doi.org/10.1016/j.redox.2016.10.014
Zhu CT, Ingelmo P, Rand DM (2014) GxGxE for lifespan in Drosophila: mitochondrial, nuclear, and dietary interactions that modify longevity. PLoS Genet 10:e1004354. https://doi.org/10.1371/journal.pgen.1004354
Acknowledgements
Funding was provided by the American Federation for Aging Research (AFAR), the National Institute on Aging (T32 training grant AG052374, AG052558) and the USC Manning Endowed Fellowship to J.C.R., an American Association of University Women (AAUW) fellowship to C.P.B., and the NIA (R01AG052258), Ellison Medical Foundation (EMF), AFAR, and the Hanson-Thorell Family to C.L.
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Reynolds, J.C., Bwiza, C.P. & Lee, C. Mitonuclear genomics and aging. Hum Genet 139, 381–399 (2020). https://doi.org/10.1007/s00439-020-02119-5
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DOI: https://doi.org/10.1007/s00439-020-02119-5