UPRmt and mitophagy, key processes to understand lifespan regulation by mitochondrial stress

Abstract

Aging is a biological process characterized by a progressive decline of body homeostasis. Among the cellular pathways affected by aging, mitochondrial signalling is essential for the maintenance of proper energy metabolism and cellular health. In that sense, mitochondrial dysfunction triggers the activation of quality control mechanisms, such as the mitochondrial unfolded protein response (UPRmt) and mitophagy, which restore mitochondrial homeostasis under stress conditions and degrade damaged mitochondria, respectively. Although both responses have been implicated in the regulation of aging, the underlying molecular mechanisms and their regulation remain largely elusive. We have previously demonstrated that depletion of prohibitin (PHB), a multimeric complex sitting in the inner mitochondrial membrane, shortens lifespan and induces a strong UPRmt in wild type worms. However, in Serum- and Glucocorticoid-induced Kinase 1 (SGK-1) loss of function mutants, PHB depletion increases lifespan and show reduced UPRmt induction. SGK-1 acts both, through the mechanistinc Target of Rapamycin Complex 2 (mTORC2) and the Insulin/IGF-1 signalling pathway to regulate longevity and UPRmt. Moreover, SGK1 inhibits autophagy in mammals, leading to accelerated aging and neurodegenerative diseases. Here, we show that SGK-1 is down regulated throughout aging in C. elegans. Furthermore, severe mitochondrial stress reduces the expression levels of SGK-1 triggering autophagy, while inhibition of the UPRmt or mitophagy increase SGK-1 levels. In this intricate scenario, the enhancement of longevity of sgk-1 mutants upon PHB depletion depends on the activation of the UPRmt, while mitophagy inhibition has a beneficial effect in the same background. These data constitute, to our knowledge, the first evidence of SGK-1 regulating the autophagy pathway in C. elegans and underpin the role of SGK-1 in the regulation of the mitochondrial quality control mechanisms, UPRmt and mitophagy, hence affecting lifespan.