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The mitochondrial UPR: mechanisms, physiological functions and implications in ageing

Key Points

  • 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.

Abstract

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.

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Figure 1: Perturbations that impair mitochondrial protein import activate the mitochondrial unfolded protein response.
Figure 2: Signalling the mammalian mitochondrial unfolded protein response.
Figure 3: Chromatin remodelling during mitochondrial stress.
Figure 4: Mitochondrial unfolded protein response in cell–cell communication and innate immunity.
Figure 5: Mitochondrial unfolded protein response activation promotes the preferential maintenance and propagation of deleterious mitochondrial genome heteroplasmy.

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Acknowledgements

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.

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T.S. and C.M.H. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the manuscript before submission.

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Correspondence to Cole M. Haynes.

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Glossary

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.

β-Oxidation

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.

Heteroplasmy

The presence of more than one type of mitochondrial DNA within a cell or individual.

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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

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