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The mitochondrial unfolded protein response in mammalian physiology

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Abstract

Mitochondria, the main site of cellular energy harvesting, are derived from proteobacteria that evolved within our cells in endosymbiosis. Mitochondria retained vestiges of their proteobacterial genome, the circular mitochondrial DNA, which encodes 13 subunits of the oxidative phosphorylation multiprotein complexes in the electron transport chain (ETC), while the remaining ~80 ETC components are encoded in the nuclear DNA (nDNA). A further ~1,400 proteins, which are essential for mitochondrial function are also encoded in nDNA. Thus, a majority of mitochondrial proteins are translated in the cytoplasm, then imported, processed, and assembled in the mitochondria. An intricate protein quality control (PQC) network, constituted of chaperones and proteases that refold or degrade defective proteins, maintains mitochondrial proteostasis and ensures the cell and organism health. The mitochondrial unfolded protein response is a relatively recently discovered PQC pathway, which senses the proteostatic disturbances specifically in the mitochondria and resolves the stress by retrograde signaling to the nucleus and consequent transcriptional activation of protective genes. This PQC system does not only transiently resolve the local stress but also can have long-lasting effects on whole body metabolism, fitness, and longevity. A delicate tuning of its activation levels might constitute a treatment of various diseases, such as metabolic diseases, cancer, and neurodegenerative disorders.

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Acknowledgments

JA is the Nestlé Chair in Energy Metabolism. Work in the laboratory is supported by the Ecole Polytechnique Fédérale de Lausanne, the National Institutes of Health (R01AG043930), the Swiss National Science Foundation (31003A-124713), and Systems X (51RTP0-151019).

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  1. Laboratory for Integrative and Systems Physiology, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    Adrienne Mottis, Virginija Jovaisaite & Johan Auwerx

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  1. Adrienne Mottis
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  2. Virginija Jovaisaite
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  3. Johan Auwerx
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Correspondence to Johan Auwerx.

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Mottis, A., Jovaisaite, V. & Auwerx, J. The mitochondrial unfolded protein response in mammalian physiology. Mamm Genome 25, 424–433 (2014). https://doi.org/10.1007/s00335-014-9525-z

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