Mitochondrial proteostasis in the control of aging and longevity

Abstract

Mitochondria play a central role in the aging process. Studies in model organisms have started to integrate mitochondrial effects on aging with the maintenance of protein homeostasis. These findings center on the mitochondrial unfolded protein response (UPR(mt)), which has been implicated in lifespan extension in worms, flies, and mice, suggesting a conserved role in the long-term maintenance of cellular homeostasis. Here, we review current knowledge of the UPR(mt) and discuss its integration with cellular pathways known to regulate lifespan. We highlight how insight into the UPR(mt) is revolutionizing our understanding of mitochondrial lifespan extension and of the aging process.

Figure 1. UPR^mt signal transduction

Current model for UPR^mt signal transduction based on studies in worms and mammalian cells. Signaling components identified in worms are shaded blue and signaling components identified in mammalian cells are shaded green. See text for details.

Figure 2. Cellular and systemic outcomes of UPRmt activation

Cell autonomous interactions between the UPR^mt and processes ensuring cellular homeostasis, as well as non-autonomous interactions between local UPR^mt activation and peripheral cells are depicted. Individual interactions have been identified in different model systems, and detailed characterization of these interactions is needed to obtain a comprehensive model for UPR^mt responses in specific systems / tissues. See text for details.

Figure 3. Integration of the UPR^mt with processes influencing lifespan

The UPR^mt intersects with most processes influencing lifespan known to date, suggesting that interventions that preserve mitochondrial function or that trigger mitoprotective responses are promising candidates for therapies extending lifespan.