The mitochondrial unfolded protein response (UPRmt) is a conserved transcriptional response activated by multiple forms of mitochondrial dysfunction and regulated by mitochondrial-to-nuclear communication.
The UPRmt promotes cell survival and mitochondrial recovery through metabolic adaptations and a precise mitochondrial biogenesis programme.
UPRmt activation promotes lifespan extension and protects against bacterial pathogens that perturb mitochondrial function.
Prolonged UPRmt activation can lead to the propagation of deleterious mitochondrial genomes and mitochondrial damage and can contribute to age-associated organismal deterioration.
UPRmt manipulations are potential therapeutic targets for treating the vast number of diseases associated with mitochondrial dysfunction.
Mitochondrial function declines during ageing owing to the accumulation of deleterious mitochondrial genomes and damage resulting from the localized generation of reactive oxygen species, both of which are often exacerbated in diseases such as Parkinson disease. Cells have several mechanisms to assess mitochondrial function and activate a transcriptional response known as the mitochondrial unfolded protein response (UPRmt) when mitochondrial integrity and function are impaired. The UPRmt promotes cell survival and the recovery of the mitochondrial network to ensure optimal cellular function. Recent insights into the regulation, mechanisms and functions of the UPRmt have uncovered important and complex links to ageing and ageing-associated diseases. In this Review, we discuss the signal transduction mechanisms that regulate the UPRmt and the physiological consequences of its activation that affect cellular and organismal health during ageing.
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Gray, M. W., Burger, G. & Lang, B. F. The origin and early evolution of mitochondria. Genome Biol. 2, 1018.1–1018.5 (2001).
Lane, N. & Martin, W. The energetics of genome complexity. Nature 467, 929–934 (2010).
Mishra, P. & Chan, D. C. Mitochondrial dynamics and inheritance during cell division, development and disease. Nat. Rev. Mol. Cell Biol. 15, 634–646 (2014).
Schmidt, O., Pfanner, N. & Meisinger, C. Mitochondrial protein import: from proteomics to functional mechanisms. Nat. Rev. Mol. Cell Biol. 11, 655–667 (2010).
Nunnari, J. & Suomalainen, A. Mitochondria: in sickness and in health. Cell 148, 1145–1159 (2012).
Suomalainen A. & Battersby, B. J. Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat. Rev. Mol. Cell Biol. http://dx.doi.org/10.1038/nrm.2017.66 (2017).
Sun, N., Youle, R. J. & Finkel, T. The mitochondrial basis of aging. Mol. Cell 61, 654–666 (2016).
Bratic, A. & Larsson, N. G. The role of mitochondria in aging. J. Clin. Invest. 123, 951–957 (2013).
Morris, A. A. et al. Deficiency of respiratory chain complex I is a common cause of Leigh disease. Ann. Neurol. 40, 25–30 (1996).
Wallace, D. C. et al. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science 242, 1427–1430 (1988).
Peterson, C. M., Johannsen, D. L. & Ravussin, E. Skeletal muscle mitochondria and aging: a review. J. Aging Res. 2012, 194821 (2012).
Schulz, A. M. & Haynes, C. M. UPRmt-mediated cytoprotection and organismal aging. Biochim. Biophys. Acta 1847, 1448–1456 (2015).
Durieux, J., Wolff, S. & Dillin, A. The cell-non-autonomous nature of electron transport chain-mediated longevity. Cell 144, 79–91 (2011). This study reveals that mitochondrial UPRmt activation in neurons can be communicated to cells in different tissues to mediate longevity.
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).
Houtkooper, R. H. et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature 497, 451–457 (2013). This study indicates that an imbalance between nuclear-encoded and mitochondrial-encoded OXPHOS proteins induces the UPRmt and extends lifespan in mice and worms.
Liu, Y., Samuel, B. S., Breen, P. C. & Ruvkun, G. Caenorhabditis elegans pathways that surveil and defend mitochondria. Nature 508, 406–410 (2014). This study reports that mitochondrial dysfunction causes induction of detoxification and innate immune genes.
Martinus, R. D. et al. Selective induction of mitochondrial chaperones in response to loss of the mitochondrial genome. Eur. J. Biochem. 240, 98–103 (1996).
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). This study suggests how mitochondrial dysfunction is sensed and communicated to the nucleus to induce a broad transcriptional response.
Yoneda, T. et al. Compartment-specific perturbation of protein handling activates genes encoding mitochondrial chaperones. J. Cell Sci. 117, 4055–4066 (2004).
Zhao, Q. et al. A mitochondrial specific stress response in mammalian cells. EMBO J. 21, 4411–4419 (2002).
Chan, D. C. Fusion and fission: interlinked processes critical for mitochondrial health. Annu. Rev. Genet. 46, 265–287 (2012).
Lewis, S. C., Uchiyama, L. F. & Nunnari, J. ER-mitochondria contacts couple mtDNA synthesis with mitochondrial division in human cells. Science 353, aaf5549 (2016).
Lin, Y. F. & Haynes, C. M. Metabolism and the UPRmt. Mol. Cell 61, 677–682 (2016).
Pellegrino, M. W. et al. Mitochondrial UPR-regulated innate immunity provides resistance to pathogen infection. Nature 516, 414–417 (2014). This study shows that the UPRmt can serve as a means to detect pathogens that perturb mitochondria and provide an antibacterial response.
Gitschlag, B. L. et al. Homeostatic responses regulate selfish mitochondrial genome dynamics in C. elegans. Cell Metab. 24, 91–103 (2016).
Lin, Y. F. et al. Maintenance and propagation of a deleterious mitochondrial genome by the mitochondrial unfolded protein response. Nature 533, 416–419 (2016). References 25 and 26 report that UPRmt activation preferentially maintains a ΔmtDNA in C. elegans.
Merkwirth, C. et al. Two conserved histone demethylases regulate mitochondrial stress-induced longevity. Cell 165, 1209–1223 (2016). This study reveals a role for two histone demethylases and chromatin remodelling in the UPRmt.
Tian, Y. et al. Mitochondrial stress induces chromatin reorganization to promote longevity and UPRmt. Cell 165, 1197–1208 (2016). This study shows that mitochondrial stress results in nuclear compaction with concomitant opening up of UPRmt chromatin regions.
Berendzen, K. M. et al. Neuroendocrine coordination of mitochondrial stress signaling and proteostasis. Cell 166, 1553–1563.e10 (2016).
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).
Shao, L. W., Niu, R. & Liu, Y. Neuropeptide signals cell non-autonomous mitochondrial unfolded protein response. Cell Res. 26, 1182–1196 (2016).
Dillin, A. et al. Rates of behavior and aging specified by mitochondrial function during development. Science 298, 2398–2401 (2002).
Rea, S. L., Ventura, N. & Johnson, T. E. Relationship between mitochondrial electron transport chain dysfunction, development, and life extension in Caenorhabditis elegans. PLoS Biol. 5, e259 (2007).
Walter, P. & Ron, D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 334, 1081–1086 (2011).
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).
Bennett, C. F. et al. Activation of the mitochondrial unfolded protein response does not predict longevity in Caenorhabditis elegans. Nat. Commun. 5, 3483 (2014).
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).
Runkel, E. D., Liu, S., Baumeister, R. & Schulze, E. Surveillance-activated defenses block the ROS-induced mitochondrial unfolded protein response. PLoS Genet. 9, e1003346 (2013).
Rauthan, M., Ranji, P., Aguilera Pradenas, N., Pitot, C. & Pilon, M. The mitochondrial unfolded protein response activator ATFS-1 protects cells from inhibition of the mevalonate pathway. Proc. Natl Acad. Sci. USA 110, 5981–5986 (2013).
Williams, C. C., Jan, C. H. & Weissman, J. S. Targeting and plasticity of mitochondrial proteins revealed by proximity-specific ribosome profiling. Science 346, 748–751 (2014).
Harbauer, A. B., Zahedi, R. P., Sickmann, A., Pfanner, N. & Meisinger, C. The protein import machinery of mitochondria-a regulatory hub in metabolism, stress, and disease. Cell Metab. 19, 357–372 (2014).
Wright, G., Terada, K., Yano, M., Sergeev, I. & Mori, M. Oxidative stress inhibits the mitochondrial import of preproteins and leads to their degradation. Exp. Cell Res. 263, 107–117 (2001).
Kang, P. J. et al. Requirement for hsp70 in the mitochondrial matrix for translocation and folding of precursor proteins. Nature 348, 137–143 (1990).
Neupert, W. & Brunner, M. The protein import motor of mitochondria. Nat. Rev. Mol. Cell Biol. 3, 555–565 (2002).
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).
Stiburek, L. et al. YME1L controls the accumulation of respiratory chain subunits and is required for apoptotic resistance, cristae morphogenesis, and cell proliferation. Mol. Biol. Cell 23, 1010–1023 (2012).
Martinelli, P. & Rugarli, E. I. Emerging roles of mitochondrial proteases in neurodegeneration. Biochim. Biophys. Acta 1797, 1–10 (2010).
Wrobel, L. et al. Mistargeted mitochondrial proteins activate a proteostatic response in the cytosol. Nature 524, 485–488 (2015).
Wang, X. & Chen, X. J. A cytosolic network suppressing mitochondria-mediated proteostatic stress and cell death. Nature 524, 481–484 (2015).
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). This is one of the first in vivo mammalian studies demonstrating that mitochondrial dysfunction in the heart leads to the activation of the ISR.
Chung, H. K. et al. Growth differentiation factor 15 is a myomitokine governing systemic energy homeostasis. J. Cell Biol. 216, 149–165 (2017).
Munch, C. & Harper, J. W. Mitochondrial unfolded protein response controls matrix pre-RNA processing and translation. Nature 534, 710–713 (2016).
Harding, H. P. et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol. Cell 11, 619–633 (2003).
Teske, B. F. et al. CHOP induces activating transcription factor 5 (ATF5) to trigger apoptosis in response to perturbations in protein homeostasis. Mol. Biol. Cell 24, 2477–2490 (2013).
Pakos-Zebrucka, K. et al. The integrated stress response. EMBO Rep. 17, 1374–1395 (2016).
Dey, S. et al. Both transcriptional regulation and translational control of ATF4 are central to the integrated stress response. J. Biol. Chem. 285, 33165–33174 (2010).
Zhang, P. et al. The GCN2 eIF2α kinase is required for adaptation to amino acid deprivation in mice. Mol. Cell. Biol. 22, 6681–6688 (2002).
Yan, W. et al. Control of PERK eIF2α kinase activity by the endoplasmic reticulum stress-induced molecular chaperone P58IPK. Proc. Natl Acad. Sci. USA 99, 15920–15925 (2002).
Hori, O. et al. Transmission of cell stress from endoplasmic reticulum to mitochondria: enhanced expression of Lon protease. J. Cell Biol. 157, 1151–1160 (2002).
Harding, H. P. et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol. Cell 6, 1099–1108 (2000).
Zhou, D. et al. Phosphorylation of eIF2 directs ATF5 translational control in response to diverse stress conditions. J. Biol. Chem. 283, 7064–7073 (2008).
Jousse, C. et al. Inhibition of CHOP translation by a peptide encoded by an open reading frame localized in the chop 5'UTR. Nucleic Acids Res. 29, 4341–4351 (2001).
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).
Fiorese, C. J. et al. The transcription factor ATF5 mediates a mammalian mitochondrial UPR. Curr. Biol. 26, 2037–2043 (2016).
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).
Quiros, P. M. et al. Multi-omics analysis identifies ATF4 as a key regulator of the mitochondrial stress response in mammals. J. Cell Biol. 216, 2027–2045 (2017).
Fawcett, T. W., Martindale, J. L., Guyton, K. Z., Hai, T. & Holbrook, N. J. Complexes containing activating transcription factor (ATF)/cAMP-responsive-element-binding protein (CREB) interact with the CCAAT/enhancer-binding protein (C/EBP)-ATF composite site to regulate Gadd153 expression during the stress response. Biochem. J. 339, 135–141 (1999).
Wang, X. Z. et al. Signals from the stressed endoplasmic reticulum induce C/EBP-homologous protein (CHOP/GADD153). Mol. Cell. Biol. 16, 4273–4280 (1996).
Fraser, J. E., Wang, C., Chan, K. W., Vasudevan, S. G. & Jans, D. A. Novel dengue virus inhibitor 4-HPR activates ATF4 independent of Protein Kinase R-like Endoplasmic Reticulum Kinase and elevates levels of eIF2α phosphorylation in virus infected cells. Antiviral Res. 130, 1–6 (2016).
Watatani, Y. et al. Stress-induced translation of ATF5 mRNA is regulated by the 5′-untranslated region. J. Biol. Chem. 283, 2543–2553 (2008).
Lee, Y. Y., Cevallos, R. C. & Jan, E. An upstream open reading frame regulates translation of GADD34 during cellular stresses that induce eIF2α phosphorylation. J. Biol. Chem. 284, 6661–6673 (2009).
Bao, X. R. et al. Mitochondrial dysfunction remodels one-carbon metabolism in human cells. eLife 5, e10575 (2016).
Fusakio, M. E. et al. Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver. Mol. Biol. Cell 27, 1536–1551 (2016).
Marciniak, S. J. et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev. 18, 3066–3077 (2004).
Radke, S. et al. Mitochondrial protein quality control by the proteasome involves ubiquitination and the protease Omi. J. Biol. Chem. 283, 12681–12685 (2008).
Papa, L. & Germain, D. Estrogen receptor mediates a distinct mitochondrial unfolded protein response. J. Cell Sci. 124, 1396–1402 (2011).
Riar, A. K. et al. Sex specific activation of the ERα axis of the mitochondrial UPR (UPRmt) in the G93A-SOD1 mouse model of familial ALS. Hum. Mol. Genet. 26, 1318–1327 (2017).
Towbin, B. D. et al. Step-wise methylation of histone H3K9 positions heterochromatin at the nuclear periphery. Cell 150, 934–947 (2012).
Hoffmann, I. et al. The role of histone demethylases in cancer therapy. Mol. Oncol. 6, 683–703 (2012).
Kim, K. H. et al. Metformin-induced inhibition of the mitochondrial respiratory chain increases FGF21 expression via ATF4 activation. Biochem. Biophys. Res. Commun. 440, 76–81 (2013).
Keipert, S. et al. Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine. Am. J. Physiol. Endocrinol. Metab. 306, E469–E482 (2014).
Kim, K. H. & Lee, M. S. FGF21 as a stress hormone: the roles of FGF21 in stress adaptation and the treatment of metabolic diseases. Diabetes Metab. J. 38, 245–251 (2014).
Gleyzer, N. & Scarpulla, R. C. PGC-1-related coactivator (PRC), a sensor of metabolic stress, orchestrates a redox-sensitive program of inflammatory gene expression. J. Biol. Chem. 286, 39715–39725 (2011).
Lehtonen, J. M. et al. FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders. Neurology 87, 2290–2299 (2016).
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).
Fujita, Y. et al. GDF15 is a novel biomarker to evaluate efficacy of pyruvate therapy for mitochondrial diseases. Mitochondrion 20, 34–42 (2015).
Wu, Y. et al. Multilayered genetic and omics dissection of mitochondrial activity in a mouse reference population. Cell 158, 1415–1430 (2014).
Munkacsy, E. et al. DLK-1, SEK-3 and PMK-3 are required for the life extension induced by mitochondrial bioenergetic disruption in C. elegans. PLoS Genet. 12, e1006133 (2016).
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).
Wang, X. et al. Joint mouse-human phenome-wide association to test gene function and disease risk. Nat. Commun. 7, 10464 (2016).
Celardo, I., Lehmann, S., Costa, A. C., Loh, S. H. & Miguel Martins, L. dATF4 regulation of mitochondrial folate-mediated one-carbon metabolism is neuroprotective. Cell Death Differ. 24, 638–648 (2017).
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).
Kim, H. E. et al. Lipid biosynthesis coordinates a mitochondrial-to-cytosolic stress response. Cell 166, 1539–1552.e16 (2016).
Georgakopoulos, N. D., Wells, G. & Campanella, M. The pharmacological regulation of cellular mitophagy. Nat. Chem. Biol. 13, 136–146 (2017).
Narendra, D. P. et al. PINK1 is selectively stabilized on impaired mitochondria to activate Parkin. PLoS Biol. 8, e1000298 (2010).
Pickrell, A. M. et al. Endogenous Parkin preserves dopaminergic substantia nigral neurons following mitochondrial DNA mutagenic stress. Neuron 87, 371–381 (2015).
Suen, D. F., Narendra, D. P., Tanaka, A., Manfredi, G. & Youle, R. J. Parkin overexpression selects against a deleterious mtDNA mutation in heteroplasmic cybrid cells. Proc. Natl Acad. Sci. USA 107, 11835–11840 (2010).
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).
Youle, R. J. & Narendra, D. P. Mechanisms of mitophagy. Nat. Rev. Mol. Cell Biol. 12, 9–14 (2011).
Burbulla, L. F. et al. Mitochondrial proteolytic stress induced by loss of mortalin function is rescued by Parkin and PINK1. Cell Death Dis. 5, e1180 (2014).
Geisler, S. et al. PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1. Nat. Cell Biol. 12, 119–131 (2010).
Vives-Bauza, C. et al. PINK1-dependent recruitment of Parkin to mitochondria in mitophagy. Proc. Natl Acad. Sci. USA 107, 378–383 (2010).
Kim, Y. et al. PINK1 controls mitochondrial localization of Parkin through direct phosphorylation. Biochem. Biophys. Res. Commun. 377, 975–980 (2008).
Felkai, S. et al. CLK-1 controls respiration, behavior and aging in the nematode Caenorhabditis elegans. EMBO J. 18, 1783–1792 (1999).
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).
Lee, S. S. et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nat. Genet. 33, 40–48 (2003).
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).
Lakowski, B. & Hekimi, S. Determination of life-span in Caenorhabditis elegans by four clock genes. Science 272, 1010–1013 (1996).
Copeland, J. M. et al. Extension of Drosophila life span by RNAi of the mitochondrial respiratory chain. Curr. Biol. 19, 1591–1598 (2009).
Owusu-Ansah, E., Song, W. & Perrimon, N. Muscle mitohormesis promotes longevity via systemic repression of insulin signaling. Cell 155, 699–712 (2013).
Delaney, J. R. et al. Stress profiling of longevity mutants identifies Afg3 as a mitochondrial determinant of cytoplasmic mRNA translation and aging. Aging Cell 12, 156–166 (2013).
Yee, C., Yang, W. & Hekimi, S. The intrinsic apoptosis pathway mediates the pro-longevity response to mitochondrial ROS in C. elegans. Cell 157, 897–909 (2014).
Labbadia, J. & Morimoto, R. I. Repression of the heat shock response is a programmed event at the onset of reproduction. Mol. Cell 59, 639–650 (2015).
Dell'agnello, C. et al. Increased longevity and refractoriness to Ca2+-dependent neurodegeneration in Surf1 knockout mice. Hum. Mol. Genet. 16, 431–444 (2007).
Munkacsy, E. & Rea, S. L. The paradox of mitochondrial dysfunction and extended longevity. Exp. Gerontol. 56, 221–233 (2014).
Ren, Y. et al. The activation of protein homeostasis protective mechanisms perhaps is not responsible for lifespan extension caused by deficiencies of mitochondrial proteins in C. elegans. Exp. Gerontol. 65, 53–57 (2015).
Schieber, M. & Chandel, N. S. TOR signaling couples oxygen sensing to lifespan in C. elegans. Cell Rep. 9, 9–15 (2014).
Bennett, C. F. et al. Transaldolase inhibition impairs mitochondrial respiration and induces a starvation-like longevity response in Caenorhabditis elegans. PLoS Genet. 13, e1006695 (2017).
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).
Yun, J. & Finkel, T. Mitohormesis. Cell Metab. 19, 757–766 (2014).
Beck, J. S., Mufson, E. J. & Counts, S. E. Evidence for mitochondrial UPR gene activation in familial and sporadic Alzheimer's disease. Curr. Alzheimer Res. 13, 610–614 (2016).
Kambe, Y. & Miyata, A. Potential involvement of the mitochondrial unfolded protein response in depressive-like symptoms in mice. Neurosci. Lett. 588, 166–171 (2015).
Angelastro, J. M. Targeting ATF5 in Cancer. Trends Cancer 3, 471–474 (2017).
Mouchiroud, L. et al. The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling. Cell 154, 430–441 (2013).
Zhang, H. et al. NAD+ repletion improves mitochondrial and stem cell function and enhances life span in mice. Science 352, 1436–1443 (2016).
Gariani, K. et al. Eliciting the mitochondrial unfolded protein response by nicotinamide adenine dinucleotide repletion reverses fatty liver disease in mice. Hepatology 63, 1190–1204 (2016).
Tanaka, T. et al. Targeted disruption of ATF4 discloses its essential role in the formation of eye lens fibres. Genes Cells 3, 801–810 (1998).
Dalton, R. P., Lyons, D. B. & Lomvardas, S. Co-opting the unfolded protein response to elicit olfactory receptor feedback. Cell 155, 321–332 (2013).
Wang, S. Z., Ou, J., Zhu, L. J. & Green, M. R. Transcription factor ATF5 is required for terminal differentiation and survival of olfactory sensory neurons. Proc. Natl Acad. Sci. USA 109, 18589–18594 (2012).
West, A. P., Shadel, G. S. & Ghosh, S. Mitochondria in innate immune responses. Nat. Rev. Immunol. 11, 389–402 (2011).
Montecino-Rodriguez, E., Berent-Maoz, B. & Dorshkind, K. Causes, consequences, and reversal of immune system aging. J. Clin. Invest. 123, 958–965 (2013).
Rudel, T., Kepp, O. & Kozjak-Pavlovic, V. Interactions between bacterial pathogens and mitochondrial cell death pathways. Nat. Rev. Microbiol. 8, 693–705 (2010).
West, A. P. & Shadel, G. S. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat. Rev. Immunol. 17, 363–375 (2017).
Galmiche, A. & Rassow, J. Targeting of Helicobacter pylori VacA to mitochondria. Gut Microbes 1, 392–395 (2010).
Bos, L. D., Sterk, P. J. & Schultz, M. J. Volatile metabolites of pathogens: a systematic review. PLoS Pathog. 9, e1003311 (2013).
Melo, J. A. & Ruvkun, G. Inactivation of conserved C. elegans genes engages pathogen- and xenobiotic-associated defenses. Cell 149, 452–466 (2012).
Reddy, K. C., Dunbar, T. L., Nargund, A. M., Haynes, C. M. & Troemel, E. R. The C. elegans CCAAT-enhancer-binding protein gamma is required for surveillance immunity. Cell Rep. 14, 1581–1589 (2016).
Rehacek, Z., Ramankutty, M. & Kozova, J. Respiratory chain of antimycin A-producing Streptomyces antibioticus. Appl. Microbiol. 16, 29–32 (1968).
Smith, R. M., Peterson, W. H. & McCoy, E. Oligomycin, a new antifungal antibiotic. Antibiot. Chemother. 4, 962–970 (1954).
Denver, D. R., Morris, K., Lynch, M., Vassilieva, L. L. & Thomas, W. K. High direct estimate of the mutation rate in the mitochondrial genome of Caenorhabditis elegans. Science 289, 2342–2344 (2000).
Stewart, J. B. & Chinnery, P. F. The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat. Rev. Genet. 16, 530–542 (2015).
Payne, B. A. et al. Universal heteroplasmy of human mitochondrial DNA. Hum. Mol. Genet. 22, 384–390 (2013).
Kauppila, T. E., Kauppila, J. H. & Larsson, N. G. Mammalian mitochondria and aging: an update. Cell Metab. 25, 57–71 (2017).
Tsang, W. Y. & Lemire, B. D. Stable heteroplasmy but differential inheritance of a large mitochondrial DNA deletion in nematodes. Biochem. Cell Biol. 80, 645–654 (2002).
Pulliam, D. A. et al. Complex IV-deficient Surf1(−/−) mice initiate mitochondrial stress responses. Biochem. J. 462, 359–371 (2014).
Khan, N. A. et al. Effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin B3 . EMBO Mol. Med. 6, 721–731 (2014).
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).
This work was supported by an EMBO long-term fellowship (ALTF 715–2015) to T.S., the Mallinckrodt Foundation, HHMI and NIH grants R01AG040061, R01AG047182 and R01HL127891 to C.M.H.
The authors declare no competing financial interests.
- Oxidative phosphorylation
(OXPHOS). The mitochondrial pathway that metabolizes nutrients and generates ATP, which requires the respiratory chain and ATP synthase complexes.
- Translocase of the outer membrane complex
(TOM complex). A protein complex localized in the mitochondrial outer membrane required for nuclear-encoded proteins synthesized on cytosolic ribosomes to cross the mitochondrial outer membrane.
- Translocase of the inner membrane 23 complex
(TIM23 complex). A protein complex localized in the mitochondrial inner membrane that facilitates the translocation of proteins from the intermembrane space to the mitochondrial matrix or to the mitochondrial inner membrane.
- Integrated stress response
(ISR). A stress response initiated by kinases responsive to endoplasmic reticulum stress, amino acid depletion, haem depletion or viral infection that leads to phosphorylation of eukaryotic translation initiation factor 2 subunit 1 (eIF2α), ultimately resulting in reduced protein synthesis and increased translation of mRNAs harbouring upstream open reading frames.
The catabolic process that occurs within mitochondria by which the breakdown of fatty acids yields acetyl-CoA, NADH and FADH2.
- Adipose tissue browning
The development of beige adipocytes in white adipose tissue, which involves the accumulation of mitochondria within white adipocytes.
- Hypoxia-inducible factor 1
(HIF-1). A transcription factor activated during hypoxia that promotes cell growth and survival by affecting a variety of processes, including metabolic adaptations.
The presence of more than one type of mitochondrial DNA within a cell or individual.
About this article
Cite this article
Shpilka, T., Haynes, C. The mitochondrial UPR: mechanisms, physiological functions and implications in ageing. Nat Rev Mol Cell Biol 19, 109–120 (2018). https://doi.org/10.1038/nrm.2017.110
Journal of Experimental & Clinical Cancer Research (2021)
Nature Metabolism (2021)
Nature Reviews Molecular Cell Biology (2021)
Endoplasmic reticulum−mitochondria coupling increases during doxycycline-induced mitochondrial stress in HeLa cells
Cell Death & Disease (2021)
Nature Aging (2021)