Mitonuclear communication in homeostasis and stress (original) (raw)

• Friedman, J. R. & Nunnari, J. Mitochondrial form and function. Nature 505, 335–343 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Wallace, D. C. Mitochondria, bioenergetics, and the epigenome in eukaryotic and human evolution. Cold Spring Harb. Symp. Quant. Biol. 74, 383–393 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Pagliarini, D. J. et al. A mitochondrial protein compendium elucidates complex I disease biology. Cell 134, 112–123 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Mercer, T. R. et al. The human mitochondrial transcriptome. Cell 146, 645–658 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Dhar, S. S., Ongwijitwat, S. & Wong-Riley, M. T. Nuclear respiratory factor 1 regulates all ten nuclear-encoded subunits of cytochrome c oxidase in neurons. J. Biol. Chem. 283, 3120–3129 (2008).
  Article CAS PubMed Google Scholar
• Virbasius, J. V. & Scarpulla, R. C. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc. Natl Acad. Sci. USA 91, 1309–1313 (1994).
  Article CAS PubMed PubMed Central Google Scholar
• Gleyzer, N., Vercauteren, K. & Scarpulla, R. C. Control of mitochondrial transcription specificity factors (TFB1M and TFB2M) by nuclear respiratory factors (NRF-1 and NRF-2) and PGC-1 family coactivators. Mol. Cell. Biol. 25, 1354–1366 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Blesa, J. R., Prieto-Ruiz, J. A., Hernandez, J. M. & Hernandez-Yago, J. NRF-2 transcription factor is required for human TOMM20 gene expression. Gene 391, 198–208 (2007).
  Article CAS PubMed Google Scholar
• Peralta, S., Wang, X. & Moraes, C. T. Mitochondrial transcription: lessons from mouse models. Biochim. Biophys. Acta 1819, 961–969 (2012).
  Article CAS PubMed Google Scholar
• Richter-Dennerlein, R., Dennerlein, S. & Rehling, P. Integrating mitochondrial translation into the cellular context. Nat. Rev. Mol. Cell Biol. 16, 586–592 (2015).
  Article PubMed Google Scholar
• Wang, Y. X. et al. Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell 113, 159–170 (2003).
  Article CAS PubMed Google Scholar
• Tanaka, T. et al. Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc. Natl Acad. Sci. USA 100, 15924–15929 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Michalik, L. et al. International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol. Rev. 58, 726–741 (2006).
  Article CAS PubMed Google Scholar
• Dufour, C. R. et al. Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRα and γ. Cell Metab. 5, 345–356 (2007).
  Article CAS PubMed Google Scholar
• Alaynick, W. A. et al. ERRγ directs and maintains the transition to oxidative metabolism in the postnatal heart. Cell Metab. 6, 13–24 (2007).
  Article CAS PubMed Google Scholar
• Mouchiroud, L., Eichner, L. J., Shaw, R. J. & Auwerx, J. Transcriptional coregulators: fine-tuning metabolism. Cell Metab. 20, 26–40 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Fernandez-Marcos, P. J. & Auwerx, J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis. Am. J. Clin. Nutr. 93, 884S–890S (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Handschin, C. & Spiegelman, B. M. Peroxisome proliferator-activated receptor γ coactivator 1 coactivators, energy homeostasis, and metabolism. Endocr. Rev. 27, 728–735 (2006).
  Article CAS PubMed Google Scholar
• Yamamoto, H. et al. NCoR1 is a conserved physiological modulator of muscle mass and oxidative function. Cell 147, 827–839 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Seth, A. et al. The transcriptional corepressor RIP140 regulates oxidative metabolism in skeletal muscle. Cell Metab. 6, 236–245 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Canto, C. et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 458, 1056–1060 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Canto, C. et al. Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle. Cell Metab. 11, 213–219 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Garcia-Roves, P. M., Osler, M. E., Holmstrom, M. H. & Zierath, J. R. Gain-of-function R225Q mutation in AMP-activated protein kinase γ3 subunit increases mitochondrial biogenesis in glycolytic skeletal muscle. J. Biol. Chem. 283, 35724–35734 (2008).
  Article CAS PubMed Google Scholar
• Wu, H. et al. Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science 296, 349–352 (2002).
  Article CAS PubMed Google Scholar
• Woods, A. et al. Ca2+/calmodulin-dependent protein kinase kinase-β acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2, 21–33 (2005). References 21–25 give examples of how different kinases signal to induce mitochondrial biogenesis.
  Article CAS PubMed Google Scholar
• Sahin, E. et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470, 359–365 (2011). A description of how telomere dysfunction can initiate reprogramming of mitochondrial regulation.
  Article CAS PubMed PubMed Central Google Scholar
• Luo, X. & Kraus, W. L. On PAR with PARP: cellular stress signaling through poly(ADP-ribose) and PARP-1. Genes Dev. 26, 417–432 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Bai, P. et al. PARP-1 inhibition increases mitochondrial metabolism through SIRT1 activation. Cell Metab. 13, 461–468 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Canto, C. et al. The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 15, 838–847 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Jazwinski, S. M. The retrograde response: when mitochondrial quality control is not enough. Biochim. Biophys. Acta 1833, 400–409 (2013).
  Article CAS PubMed Google Scholar
• Liu, Z. & Butow, R. A. Mitochondrial retrograde signaling. Annu. Rev. Genet. 40, 159–185 (2006).
  Article CAS PubMed Google Scholar
• Sekito, T., Thornton, J. & Butow, R. A. Mitochondria-to-nuclear signaling is regulated by the subcellular localization of the transcription factors Rtg1p and Rtg3p. Mol. Biol. Cell 11, 2103–2115 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Jazwinski, S. M. & Kriete, A. The yeast retrograde response as a model of intracellular signaling of mitochondrial dysfunction. Front. Physiol. 3, 139 (2012).
  Article PubMed PubMed Central Google Scholar
• Friis, R. M. et al. Rewiring AMPK and mitochondrial retrograde signaling for metabolic control of aging and histone acetylation in respiratory-defective cells. Cell Rep. 7, 565–574 (2014).
  Article CAS PubMed Google Scholar
• Heeren, G. et al. The mitochondrial ribosomal protein of the large subunit, Afo1p, determines cellular longevity through mitochondrial back-signaling via TOR1. Aging 1, 622–636 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Caballero, A. et al. Absence of mitochondrial translation control proteins extends life span by activating sirtuin-dependent silencing. Mol. Cell 42, 390–400 (2011). References 34–36 give examples of energetic retrograde signals in yeast involving the Ampk, TOR and Sir2 pathways.
  Article CAS PubMed Google Scholar
• Curtis, R., O'Connor, G. & DiStefano, P. S. Aging networks in Caenorhabditis elegans: AMP-activated protein kinase (aak-2) links multiple aging and metabolism pathways. Aging Cell 5, 119–126 (2006).
  Article CAS PubMed Google Scholar
• Apfeld, J., O'Connor, G., McDonagh, T., DiStefano, P. S. & Curtis, R. The AMP-activated protein kinase AAK-2 links energy levels and insulin-like signals to lifespan in C. elegans. Genes Dev. 18, 3004–3009 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Edwards, C. B., Copes, N., Brito, A. G., Canfield, J. & Bradshaw, P. C. Malate and fumarate extend lifespan in Caenorhabditis elegans. PLoS ONE 8, e58345 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Gallo, M., Park, D. & Riddle, D. L. Increased longevity of some C. elegans mitochondrial mutants explained by activation of an alternative energy-producing pathway. Mech. Ageing Dev. 132, 515–518 (2011).
  Article CAS PubMed Google Scholar
• Chin, R. M. et al. The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR. Nature 510, 397–401 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Egan, D. F. et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331, 456–461 (2011).
  Article CAS PubMed Google Scholar
• Lerner, C. et al. Reduced mammalian target of rapamycin activity facilitates mitochondrial retrograde signaling and increases life span in normal human fibroblasts. Aging Cell 12, 966–977 (2013).
  Article CAS PubMed Google Scholar
• Rizzuto, R., De Stefani, D., Raffaello, A. & Mammucari, C. Mitochondria as sensors and regulators of calcium signalling. Nat. Rev. Mol. Cell Biol. 13, 566–578 (2012).
  Article CAS PubMed Google Scholar
• Arnould, T. et al. CREB activation induced by mitochondrial dysfunction is a new signaling pathway that impairs cell proliferation. EMBO J. 21, 53–63 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Luo, Y., Bond, J. D. & Ingram, V. M. Compromised mitochondrial function leads to increased cytosolic calcium and to activation of MAP kinases. Proc. Natl Acad. Sci. USA 94, 9705–9710 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Amuthan, G. et al. Mitochondrial stress-induced calcium signaling, phenotypic changes and invasive behavior in human lung carcinoma A549 cells. Oncogene 21, 7839–7849 (2002).
  Article CAS PubMed Google Scholar
• Srinivasan, S. et al. Disruption of cytochrome c oxidase function induces the Warburg effect and metabolic reprogramming. Oncogene http://dx.doi.org/10.1038/onc.2015.227, (2015).
• Biswas, G., Anandatheerthavarada, H. K., Zaidi, M. & Avadhani, N. G. Mitochondria to nucleus stress signaling: a distinctive mechanism of NFκB/Rel activation through calcineurin-mediated inactivation of IκBβ. J. Cell Biol. 161, 507–519 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Biswas, G. et al. Retrograde Ca2+ signaling in C2C12 skeletal myocytes in response to mitochondrial genetic and metabolic stress: a novel mode of inter-organelle crosstalk. EMBO J. 18, 522–533 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Formentini, L., Sanchez-Arago, M., Sanchez-Cenizo, L. & Cuezva, J. M. The mitochondrial ATPase inhibitory factor 1 triggers a ROS-mediated retrograde prosurvival and proliferative response. Mol. Cell 45, 731–742 (2012).
  Article CAS PubMed Google Scholar
• Amuthan, G. et al. Mitochondria-to-nucleus stress signaling induces phenotypic changes, tumor progression and cell invasion. EMBO J. 20, 1910–1920 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Lim, J. H. et al. Mitochondrial dysfunction induces aberrant insulin signalling and glucose utilisation in murine C2C12 myotube cells. Diabetologia 49, 1924–1936 (2006).
  Article CAS PubMed Google Scholar
• Guha, M., Fang, J. K., Monks, R., Birnbaum, M. J. & Avadhani, N. G. Activation of Akt is essential for the propagation of mitochondrial respiratory stress signaling and activation of the transcriptional coactivator heterogeneous ribonucleoprotein A2. Mol. Biol. Cell 21, 3578–3589 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Schieber, M. & Chandel, N. S. ROS function in redox signaling and oxidative stress. Curr. Biol. 24, R453–R462 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Shadel, G. S. & Horvath, T. L. Mitochondrial ROS signaling in organismal homeostasis. Cell 163, 560–569 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Miyadera, H. et al. Altered quinone biosynthesis in the long-lived clk-1 mutants of Caenorhabditis elegans. J. Biol. Chem. 276, 7713–7716 (2001).
  Article CAS PubMed Google Scholar
• Lee, S. J., Hwang, A. B. & Kenyon, C. Inhibition of respiration extends C. elegans life span via reactive oxygen species that increase HIF-1 activity. Curr. Biol. 20, 2131–2136 (2010). Identification of a signalling mechanism involving ROS in lifespan extension following mild respiration inhibition.
  Article CAS PubMed PubMed Central Google Scholar
• Inoue, H. et al. The C. elegans p38 MAPK pathway regulates nuclear localization of the transcription factor SKN-1 in oxidative stress response. Genes Dev. 19, 2278–2283 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Zarse, K. et al. Impaired insulin/IGF1 signaling extends life span by promoting mitochondrial l-proline catabolism to induce a transient ROS signal. Cell Metab. 15, 451–465 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Schmeisser, S. et al. Mitochondrial hormesis links low-dose arsenite exposure to lifespan extension. Aging Cell 12, 508–517 (2013).
  Article CAS PubMed Google Scholar
• Monaghan, R. M. et al. A nuclear role for the respiratory enzyme CLK-1 in regulating mitochondrial stress responses and longevity. Nat. Cell Biol. 17, 782–792 (2015). Identification of a novel communication mechanism involving the nuclear translocation of an isoform of CLK-1, which regulates stress resistance and lifespan.
  Article CAS PubMed PubMed Central Google Scholar
• Owusu-Ansah, E., Yavari, A., Mandal, S. & Banerjee, U. Distinct mitochondrial retrograde signals control the G1–S cell cycle checkpoint. Nat. Genet. 40, 356–361 (2008).
  Article CAS PubMed Google Scholar
• Owusu-Ansah, E., Song, W. & Perrimon, N. Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 155, 699–712 (2013). A description of non-cell-autonomous-mediated lifespan extension through ROS, the UPR mt and insulin signalling following mitochondrial perturbation in D. melanogaster muscles.
  Article CAS PubMed Google Scholar
• Lu, W. et al. ZNF143 transcription factor mediates cell survival through upregulation of the GPX1 activity in the mitochondrial respiratory dysfunction. Cell Death Dis. 3, e422 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, X. L. & Kunsch, C. Induction of cytoprotective genes through Nrf2/antioxidant response element pathway: a new therapeutic approach for the treatment of inflammatory diseases. Curr. Pharm. Des. 10, 879–891 (2004).
  Article CAS PubMed Google Scholar
• Kops, G. J. et al. Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419, 316–321 (2002).
  Article CAS PubMed Google Scholar
• Tan, W. Q., Wang, K., Lv, D. Y. & Li, P. F. Foxo3a inhibits cardiomyocyte hypertrophy through transactivating catalase. J. Biol. Chem. 283, 29730–29739 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Nguyen, T., Nioi, P. & Pickett, C. B. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J. Biol. Chem. 284, 13291–13295 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Chae, S. et al. A systems approach for decoding mitochondrial retrograde signaling pathways. Sci. Signal. 6, rs4 (2013).
  Article CAS PubMed Google Scholar
• Acin-Perez, R. et al. ROS-triggered phosphorylation of complex II by Fgr kinase regulates cellular adaptation to fuel use. Cell Metab. 19, 1020–1033 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Shi, S. Y. et al. DJ-1 links muscle ROS production with metabolic reprogramming and systemic energy homeostasis in mice. Nat. Commun. 6, 7415 (2015).
  Article PubMed Google Scholar
• Quiros, P. M., Langer, T. & Lopez-Otin, C. New roles for mitochondrial proteases in health, ageing and disease. Nat. Rev. Mol. Cell Biol. 16, 345–359 (2015).
  Article CAS PubMed Google Scholar
• Jovaisaite, V., Mouchiroud, L. & Auwerx, J. The mitochondrial unfolded protein response, a conserved stress response pathway with implications in health and disease. J. Exp. Biol. 217, 137–143 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Houtkooper, R. H. et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497, 451–457 (2013). Establishment of the concept of mitonuclear imbalance to explain the identification of Mrps5 as a mouse longevity gene and the pro-longevity effect of mitochondrial translation inhibition.
  Article CAS PubMed PubMed Central Google Scholar
• Durieux, J., Wolff, S. & Dillin, A. The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 144, 79–91 (2011). The first description of non-cell-autonomous-mediated longevity following mitochondrial stress.
  Article CAS PubMed PubMed Central Google Scholar
• Mouchiroud, L. et al. The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430–441 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Pirinen, E. et al. Pharmacological inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle. Cell Metab. 19, 1034–1041 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Gariani, K. et al. Eliciting the mitochondrial unfolded protein response via NAD repletion reverses fatty liver disease. Hepatology http://dx.doi.org/10.1002/hep.28245, (2015). References 21, 22, 28–29 and 77–79 describe mechanisms of mitochondrial regulation involving NAD+ and SIRT1.
• Haynes, C. M., Yang, Y., Blais, S. P., Neubert, T. A. & Ron, D. The matrix peptide exporter HAF-1 signals a mitochondrial UPR by activating the transcription factor ZC376.7 in C. elegans. Mol. Cell 37, 529–540 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Nargund, A. M., Pellegrino, M. W., Fiorese, C. J., Baker, B. M. & Haynes, C. M. Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 337, 587–590 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Benedetti, C., Haynes, C. M., Yang, Y., Harding, H. P. & Ron, D. Ubiquitin-like protein 5 positively regulates chaperone gene expression in the mitochondrial unfolded protein response. Genetics 174, 229–239 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Haynes, C. M., Petrova, K., Benedetti, C., Yang, Y. & Ron, D. ClpP mediates activation of a mitochondrial unfolded protein response in C. elegans. Dev. Cell 13, 467–480 (2007).
  Article CAS PubMed Google Scholar
• Nargund, A. M., Fiorese, C. J., Pellegrino, M. W., Deng, P. & Haynes, C. M. Mitochondrial and nuclear accumulation of the transcription factor ATFS-1 promotes OXPHOS recovery during the UPRmt. Mol. Cell 58, 123–133 (2015). References 80–84 unravel the molecular mechanisms of UPR mt regulation in worms.
  Article CAS PubMed PubMed Central Google Scholar
• Pimenta de Castro, I. et al. Genetic analysis of mitochondrial protein misfolding in Drosophila melanogaster. Cell Death Differ. 19, 1308–1316 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Horibe, T. & Hoogenraad, N. J. The chop gene contains an element for the positive regulation of the mitochondrial unfolded protein response. PLoS ONE 2, e835 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Zhao, Q. et al. A mitochondrial specific stress response in mammalian cells. EMBO J. 21, 4411–4419 (2002). The first description of the UPR mt.
  Article CAS PubMed PubMed Central Google Scholar
• Aldridge, J. E., Horibe, T. & Hoogenraad, N. J. Discovery of genes activated by the mitochondrial unfolded protein response (mtUPR) and cognate promoter elements. PLoS ONE 2, e874 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Kohler, F., Muller-Rischart, A. K., Conradt, B. & Rolland, S. G. The loss of LRPPRC function induces the mitochondrial unfolded protein response. Aging 7, 701–717 (2015).
  Article PubMed PubMed Central Google Scholar
• Papa, L. & Germain, D. SirT3 regulates the mitochondrial unfolded protein response. Mol. Cell. Biol. 34, 699–710 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Al-Furoukh, N. et al. ClpX stimulates the mitochondrial unfolded protein response (UPRmt) in mammalian cells. Biochim. Biophys. Acta 1853, 2580–2591 (2015).
  Article CAS PubMed Google Scholar
• Siegelin, M. D. et al. Exploiting the mitochondrial unfolded protein response for cancer therapy in mice and human cells. J. Clin. Invest. 121, 1349–1360 (2011).
  Article PubMed PubMed Central Google Scholar
• Jin, S. M. & Youle, R. J. The accumulation of misfolded proteins in the mitochondrial matrix is sensed by PINK1 to induce PARK2/Parkin-mediated mitophagy of polarized mitochondria. Autophagy 9, 1750–1757 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Dogan, S. A. et al. Tissue-specific loss of DARS2 activates stress responses independently of respiratory chain deficiency in the heart. Cell Metab. 19, 458–469 (2014).
  Article CAS PubMed Google Scholar
• Song, M., Mihara, K., Chen, Y., Scorrano, L. & Dorn, G. W. 2nd. Mitochondrial fission and fusion factors reciprocally orchestrate mitophagic culling in mouse hearts and cultured fibroblasts. Cell Metab. 21, 273–285 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Khan, N. A. et al. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3 . EMBO Mol. Med. 6, 721–731 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Ryu, D. et al. A SIRT7-dependent acetylation switch of GABPβ1 controls mitochondrial function. Cell Metab. 20, 856–869 (2014).
  Article CAS PubMed Google Scholar
• Mohrin, M. et al. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 347, 1374–1377 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Wu, Y. et al. Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population. Cell 158, 1415–1430 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Papa, L. & Germain, D. Estrogen receptor mediates a distinct mitochondrial unfolded protein response. J. Cell Sci. 124, 1396–1402 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Bahat, A. et al. Transcriptional activation of LON gene by a new form of mitochondrial stress: a role for the nuclear respiratory factor 2 in StAR overload response (SOR). Mol. Cell Endocrinol. 408, 62–72 (2015).
  Article CAS PubMed Google Scholar
• Bahat, A. et al. StAR enhances transcription of genes encoding the mitochondrial proteases involved in its own degradation. Mol. Endocrinol. 28, 208–224 (2014).
  Article CAS PubMed Google Scholar
• Akerfelt, M., Morimoto, R. I. & Sistonen, L. Heat shock factors: integrators of cell stress, development and lifespan. Nat. Rev. Mol. Cell Biol. 11, 545–555 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Tan, K. et al. Mitochondrial SSBP1 protects cells from proteotoxic stresses by potentiating stress-induced HSF1 transcriptional activity. Nat. Commun. 6, 6580 (2015).
  Article CAS PubMed Google Scholar
• Harding, H. P. et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell 6, 1099–1108 (2000).
  Article CAS PubMed Google Scholar
• Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, 619–633 (2003).
  Article CAS PubMed Google Scholar
• Donnelly, N., Gorman, A. M., Gupta, S. & Samali, A. The eIF2α kinases: their structures and functions. Cell. Mol. Life Sci. 70, 3493–3511 (2013).
  Article CAS PubMed Google Scholar
• Palam, L. R., Baird, T. D. & Wek, R. C. Phosphorylation of eIF2 facilitates ribosomal bypass of an inhibitory upstream ORF to enhance CHOP translation. J. Biol. Chem. 286, 10939–10949 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Novoa, I., Zeng, H., Harding, H. P. & Ron, D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2α. J. Cell Biol. 153, 1011–1022 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Ohoka, N., Yoshii, S., Hattori, T., Onozaki, K. & Hayashi, H. TRB3, a novel ER stress-inducible gene, is induced via ATF4–CHOP pathway and is involved in cell death. EMBO J. 24, 1243–1255 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Baker, B. M., Nargund, A. M., Sun, T. & Haynes, C. M. Protective coupling of mitochondrial function and protein synthesis via the eIF2α kinase GCN-2. PLoS Genet. 8, e1002760 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Rainbolt, T. K., Atanassova, N., Genereux, J. C. & Wiseman, R. L. Stress-regulated translational attenuation adapts mitochondrial protein import through Tim17A degradation. Cell Metab. 18, 908–919 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Michel, S., Canonne, M., Arnould, T. & Renard, P. Inhibition of mitochondrial genome expression triggers the activation of CHOP-10 by a cell signaling dependent on the integrated stress response but not the mitochondrial unfolded protein response. Mitochondrion 21, 58–68 (2015).
  Article CAS PubMed Google Scholar
• Moullan, N. et al. Tetracyclines disturb mitochondrial function across eukaryotic models: a call for caution in biomedical research. Cell Rep. 10, 1681–1691 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Bruning, A., Brem, G. J., Vogel, M. & Mylonas, I. Tetracyclines cause cell stress-dependent ATF4 activation and mTOR inhibition. Exp. Cell Res. 320, 281–289 (2014).
  Article CAS PubMed Google Scholar
• Moisoi, N. et al. Mitochondrial dysfunction triggered by loss of HtrA2 results in the activation of a brain-specific transcriptional stress response. Cell Death Differ. 16, 449–464 (2009).
  Article CAS PubMed Google Scholar
• Evstafieva, A. G. et al. A sustained deficiency of mitochondrial respiratory complex III induces an apoptotic cell death through the p53-mediated inhibition of pro-survival activities of the activating transcription factor 4. Cell Death Dis. 5, e1511 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Martinez-Reyes, I., Sanchez-Arago, M. & Cuezva, J. M. AMPK and GCN2–ATF4 signal the repression of mitochondria in colon cancer cells. Biochem. J. 444, 249–259 (2012).
  Article CAS PubMed Google Scholar
• Silva, J. M., Wong, A., Carelli, V. & Cortopassi, G. A. Inhibition of mitochondrial function induces an integrated stress response in oligodendroglia. Neurobiol. Dis. 34, 357–365 (2009).
  Article CAS PubMed Google Scholar
• Viader, A. et al. Aberrant Schwann cell lipid metabolism linked to mitochondrial deficits leads to axon degeneration and neuropathy. Neuron 77, 886–898 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, X. & Chen, X. J. A cytosolic network suppressing mitochondria-mediated proteostatic stress and cell death. Nature 524, 481–484 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Wrobel, L. et al. Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. Nature 524, 485–488 (2015). References 121 and 122 identify a cytosolic stress response activated by mitochondrial stress.
  Article CAS PubMed Google Scholar
• Copeland, J. M. et al. Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Curr. Biol. 19, 1591–1598 (2009).
  Article CAS PubMed Google Scholar
• Lee, C. et al. The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance. Cell Metab. 21, 443–454 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Lee, C., Yen, K. & Cohen, P. Humanin: a harbinger of mitochondrial-derived peptides? Trends Endocrinol. Metab. 24, 222–228 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Hashimoto, Y. et al. 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, 6336–6341 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Chau, M. D., Gao, J., Yang, Q., Wu, Z. & Gromada, J. Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK–SIRT1–PGC-1α pathway. Proc. Natl Acad. Sci. USA 107, 12553–12558 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Tyynismaa, H. et al. Mitochondrial myopathy induces a starvation-like response. Hum. Mol. Genet. 19, 3948–3958 (2010).
  Article CAS PubMed Google Scholar
• Suomalainen, A. et al. FGF-21 as a biomarker for muscle-manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol. 10, 806–818 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Kim, K. H. et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat. Med. 19, 83–92 (2013). References 124 and 128–130 report examples of non-cell-autonomous signalling of mitochondrial stress in mammals.
  Article CAS PubMed Google Scholar
• Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Nunnari, J. & Suomalainen, A. Mitochondria: in sickness and in health. Cell 148, 1145–1159 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Feng, J., Bussiere, F. & Hekimi, S. Mitochondrial electron transport is a key determinant of life span in Caenorhabditis elegans. Dev. Cell 1, 633–644 (2001).
  Article CAS PubMed Google Scholar
• Wong, A., Boutis, P. & Hekimi, S. Mutations in the clk-1 gene of Caenorhabditis elegans affect developmental and behavioral timing. Genetics 139, 1247–1259 (1995).
  CAS PubMed PubMed Central Google Scholar
• Yang, W. & Hekimi, S. A mitochondrial superoxide signal triggers increased longevity in Caenorhabditis elegans. PLoS Biol. 8, e1000556 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• Kirchman, P. A., Kim, S., Lai, C. Y. & Jazwinski, S. M. Interorganelle signaling is a determinant of longevity in Saccharomyces cerevisiae. Genetics 152, 179–190 (1999).
  CAS PubMed PubMed Central Google Scholar
• Kaeberlein, M. et al. Regulation of yeast replicative life span by TOR and Sch9 in response to nutrients. Science 310, 1193–1196 (2005).
  Article CAS PubMed Google Scholar
• Hwang, A. B. et al. Feedback regulation via AMPK and HIF-1 mediates ROS-dependent longevity in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 111, E4458–E4467 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Baruah, A. et al. CEP-1, the Caenorhabditis elegans p53 homolog, mediates opposing longevity outcomes in mitochondrial electron transport chain mutants. PLoS Genet. 10, e1004097 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Walter, L., Baruah, A., Chang, H. W., Pace, H. M. & Lee, S. S. The homeobox protein CEH-23 mediates prolonged longevity in response to impaired mitochondrial electron transport chain in C. elegans. PLoS Biol. 9, e1001084 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Palikaras, K., Lionaki, E. & Tavernarakis, N. Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans. Nature 521, 525–528 (2015). A description of how mitochondrial biogenesis and mitophagy are coordinately regulated to determine lifespan in C. elegans.
  Article CAS PubMed Google Scholar
• Ristow, M. Unraveling the truth about antioxidants: mitohormesis explains ROS-induced health benefits. Nat. Med. 20, 709–711 (2014).
  Article CAS PubMed Google Scholar
• Zhang, Y., Shao, Z., Zhai, Z., Shen, C. & Powell-Coffman, J. A. The HIF-1 hypoxia-inducible factor modulates lifespan in C. elegans. PLoS ONE 4, e6348 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Heidler, T., Hartwig, K., Daniel, H. & Wenzel, U. Caenorhabditis elegans lifespan extension caused by treatment with an orally active ROS-generator is dependent on DAF-16 and SIR-2.1. Biogerontology 11, 183–195 (2010).
  Article CAS PubMed Google Scholar
• Lee, H. et al. The Caenorhabditis elegans AMP-activated protein kinase AAK-2 is phosphorylated by LKB1 and is required for resistance to oxidative stress and for normal motility and foraging behavior. J. Biol. Chem. 283, 14988–14993 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Schaar, C. E. et al. Mitochondrial and cytoplasmic ROS have opposing effects on lifespan. PLoS Genet. 11, e1004972 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, X. et al. Evolutionary conservation of the _clk-1_-dependent mechanism of longevity: loss of mclk1 increases cellular fitness and lifespan in mice. Genes Dev. 19, 2424–2434 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Lapointe, J. & Hekimi, S. Early mitochondrial dysfunction in long-lived Mclk1+/− mice. J. Biol. Chem. 283, 26217–26227 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Dell'agnello, C. et al. Increased longevity and refractoriness to Ca2+-dependent neurodegeneration in Surf1 knockout mice. Hum. Mol. Genet. 16, 431–444 (2007).
  Article CAS PubMed Google Scholar
• Zordan, M. A. et al. Post-transcriptional silencing and functional characterization of the Drosophila melanogaster homolog of human Surf1. Genetics 172, 229–241 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Pulliam, D. A. et al. Complex IV-deficient Surf1−/− mice initiate mitochondrial stress responses. Biochem. J. 462, 359–371 (2014).
  Article CAS PubMed Google Scholar
• Caldeira da Silva, C. C., Cerqueira, F. M., Barbosa, L. F., Medeiros, M. H. & Kowaltowski, A. J. Mild mitochondrial uncoupling in mice affects energy metabolism, redox balance and longevity. Aging Cell 7, 552–560 (2008). References 147–152 give some examples of mitochondrial stress affecting health and lifespan in mammals.
  Article CAS PubMed Google Scholar
• Kim, H. J., Morrow, G., Westwood, J. T., Michaud, S. & Tanguay, R. M. Gene expression profiling implicates OXPHOS complexes in lifespan extension of flies over-expressing a small mitochondrial chaperone, Hsp22. Exp. Gerontol. 45, 611–620 (2010).
  Article CAS PubMed Google Scholar
• Andreux, P. A., Houtkooper, R. H. & Auwerx, J. Pharmacological approaches to restore mitochondrial function. Nat. Rev. Drug Discov. 12, 465–483 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Williams, E. G. & Auwerx, J. The convergence of systems and reductionist approaches in complex trait analysis. Cell 162, 23–32 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• Yun, J. & Finkel, T. Mitohormesis. Cell Metab. 19, 757–766 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Dietrich, A., Wallet, C., Iqbal, R. K., Gualberto, J. M. & Lotfi, F. Organellar non-coding RNAs: emerging regulation mechanisms. Biochimie 117, 48–62 (2015).
  Article CAS PubMed Google Scholar
• Sugiura, A., McLelland, G. L., Fon, E. A. & McBride, H. M. A new pathway for mitochondrial quality control: mitochondrial-derived vesicles. EMBO J. 33, 2142–2156 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Arnoult, D., Soares, F., Tattoli, I. & Girardin, S. E. Mitochondria in innate immunity. EMBO Rep. 12, 901–910 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Liu, Y., Samuel, B. S., Breen, P. C. & Ruvkun, G. Caenorhabditis elegans pathways that surveil and defend mitochondria. Nature 508, 406–410 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• Pellegrino, M. W. et al. Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection. Nature 516, 414–417 (2014).
  Article CAS PubMed PubMed Central Google Scholar
• West, A. P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553–557 (2015).
  Article CAS PubMed PubMed Central Google Scholar
• West, A. P. et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 472, 476–480 (2011).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, D., Malo, D. & Hekimi, S. Elevated mitochondrial reactive oxygen species generation affects the immune response via hypoxia-inducible factor-1α in long-lived Mclk1+/− mouse mutants. J. Immunol. 184, 582–590 (2010).
  Article CAS PubMed Google Scholar
• Wang, D. et al. An enhanced immune response of Mclk1+/− mutant mice is associated with partial protection from fibrosis, cancer and the development of biomarkers of aging. PLoS ONE 7, e49606 (2012).
  Article CAS PubMed PubMed Central Google Scholar
• Manzanillo, P. S. et al. The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature 501, 512–516 (2013).
  Article CAS PubMed PubMed Central Google Scholar
• Baixauli, F. et al. Mitochondrial respiration controls lysosomal function during inflammatory T cell responses. Cell Metab. 22, 485–498 (2015). References 160–167 report several examples of crosstalk between mitochondrial stress signalling and immunity.
  Article CAS PubMed PubMed Central Google Scholar
• Williams, D. S., Cash, A., Hamadani, L. & Diemer, T. Oxaloacetate supplementation increases lifespan in Caenorhabditis elegans through an AMPK/FOXO-dependent pathway. Aging Cell 8, 765–768 (2009).
  Article CAS PubMed Google Scholar
• Dillin, A. et al. Rates of behavior and aging specified by mitochondrial function during development. Science 298, 2398–2401 (2002). A description of the longevity phenotypes of C. elegans ETC mutants.
  Article CAS PubMed Google Scholar
• Yang, W. & Hekimi, S. Two modes of mitochondrial dysfunction lead independently to lifespan extension in Caenorhabditis elegans. Aging Cell 9, 433–447 (2010).
  Article CAS PubMed Google Scholar
• Liu, J. et al. Drosophila sbo regulates lifespan through its function in the synthesis of coenzyme Q in vivo. J. Genet. Genom. 38, 225–234 (2011).
  Article CAS Google Scholar
• Lemire, B. D., Behrendt, M., DeCorby, A. & Gaskova, D. C. elegans longevity pathways converge to decrease mitochondrial membrane potential. Mech. Ageing Dev. 130, 461–465 (2009).
  Article CAS PubMed Google Scholar