Mitochondrial dysfunction, aging, and the mitochondrial unfolded protein response in Caenorhabditis elegans.

We review the findings that establish that perturbations of various aspects of mitochondrial function, including oxidative phosphorylation, can promote lifespan extension, with different types of perturbations acting sometimes independently and additively on extending lifespan. We also review the great variety of processes and mechanisms that together form the mitochondrial unfolded protein response. We then explore the relationships between different types of mitochondrial dysfunction-dependent lifespan extension and the mitochondrial unfolded protein response. We conclude that, although several ways that induce extended lifespan through mitochondrial dysfunction require a functional mitochondrial unfolded protein response, there is no clear indication that activation of the mitochondrial unfolded protein response is sufficient to extend lifespan, despite the fact that the mitochondrial unfolded protein response impacts almost every aspect of mitochondrial function. In fact, in some contexts, mitochondrial unfolded protein response activation is deleterious. To explain this pattern, we hypothesize that, although triggered by mitochondrial dysfunction, the lifespan extension observed might not be the result of a change in mitochondrial function.