Basal mitophagy as an anti-ageing programme

Abstract

Cellular senescence is a stress response implicated in ageing and age-related diseases, resulting in irreparable damage and a permanent cell cycle arrest. Cellular senescence has now emerged as an important element of organismal ageing. However, the mechanisms leading to senescence acquisition are complex and the key drivers that activate the senescence programme remain unclear. Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. Perturbation of mitophagy may contribute to the development of age-related diseases. Furthermore, like senescence, the molecular mechanisms, and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. In this thesis, I discovered that primary human skin fibroblasts in cell culture maintain highly active basal mitophagy driven by mitochondrial ROS signalling. Mitophagy was found to be mediated by PINK1/Parkin-dependent pathway involving p62 as a selective autophagy receptor. Importantly, this pathway was disturbed upon the induction of cellular senescence leading to a robust shutdown of mitophagy. Suppression of mitophagy was sufficient to trigger the senescence programme, whilst re-activation of mitophagy was necessary for anti-senescence effects of NAD precursors or rapamycin. Furthermore, I show that activation of mitophagy by a p62- targeting small molecule suppressed markers of senescence establishing mitochondrial quality control as a promising target for the development of novel antiageing interventions. In summary, I have demonstrated that in human skin fibroblasts, basal mitophagy dysfunction is an early event in senescence acquisition. This mitophagy is initiated by the recruitment of oligomerised p62 to ROS enriched mitochondria. Therefore, by targeting p62 and inducing ROS-dependent oligomerisation we can prevent mitophagy dysfunction, reduce senescence acquisition and reduce markers of cellular ageing.