Mitochondrial dysfunction as a driver of cellular senescence

Abstract

Ph. D. ThesisCellular senescence is a stress response implicated in ageing and age-related diseases (Baker et al., 2016; von Zglinicki, 2002). Senescent cells are characterised by mitochondrial dysfunction (Dalle Pezze et al., 2014; Korolchuk et al., 2017; Passos et al., 2007). Importantly, mitochondria were shown to regulate the senescence-associated secretory phenotype (SASP) (Correia-Melo et al., 2016). However, the exact mechanisms via which mitochondria contribute to the SASP as well as its conservation between the main studied models of senescence, remains to be elucidated. In this thesis, I discovered that senescent cells are characterized by a sub-lethal mitochondrial apoptotic stress, consisting of the activation of pro-apoptotic factor, BAX and the release of cytochrome c and mtDNA into the cytosol. BAK and BAX are required for the SASP in damage-induced senescence (DIS), however, their genetic depletion in oncogeneinduced senescence (OIS), increases it. A pharmacological inhibition of BAX after the establishment of cell cycle arrest, ameliorates SASP in OIS. Cells in DIS secrete higher levels of mtDNA than proliferating cells. However, the level of circulating mtDNA is not a strong biomarker of senescence burden in mice and humans. Next, I demonstrate OIS and DIS are characterised by a different degree of mitochondrial apoptotic stress as well as oxidative phosphorylation (OXPHOS) dysfunction. Mitochondrial network was confirmed to be hyperfused in DIS (Dalle Pezze et al., 2014), however, it was found to be fragmented in OIS. Interfering with mitochondrial dynamics by inducing mitochondrial fusion exacerbates the SASP in both models of senescence. In contrast, a shift to mitochondrial fragmentation reduces the SASP in the model of DIS and exacerbates it in OIS. Finally, I found myxovirus resistance protein B (MxB) plays an important function in maintaining the integrity of mitochondrial network and mitochondrial bioenergetics, as MxB depletion induces mitochondrial apoptotic stress and activates mitochondrial biogenesis. In DIS, MxB is highly up-regulated and translocates from mitochondria to the nucleus. MxB was found to be a key factor required for the SASP development.Medical Research Council and Mayo Clini