A mitochondrial ROS signal activates mitochondrial turnover and represses TOR during stress

Abstract

Ageing and age-related diseases are multidimensional processes characterised by the accumulation of damaged mitochondria and a reduced capacity to respond to stress. While mitochondria play a central role in cellular signalling and stress adaptation, how damaged mitochondria accumulate and whether this affects healthy lifespan and onset of age-related diseases is unclear. In the following chapters, I demonstrate how mitochondrial turnover is involved in the process of stress adaptation, mediated by mitochondrial reactive oxygen species (mtROS), using the power of Drosophila genetics. I focus on the role of mitochondria, specifically on how Reactive oxygen species (ROS) are involved in the process of temperature adaptation. Additionally, I establish that ROS acts as a signalling molecule in communicating with different downstream processes. Combining different approaches to measure ROS, I have dissected the nature of this signal. I show that an increase in mtROS associated with thermal stress is produced as a consequence of over-reduction of the electron transport chain and identify the molecular intermediate as H2O2. Moreover, I study in detail the downstream targets and demonstrate that the levels of mtROS regulate levels of Pink1. Furthermore, I provide evidence that mitochondrial H2O2 (mtH2O2) act as a mitochondrial signal to activate mitophagy, and to repress Target of rapamycin (TOR). When this signal is supressed, mitochondrial respiration is markedly diminished, canonical Pink1-Parkin mediated mitophagy is obstructed and TOR signalling is hyper-activated. This in turn causes the accumulation of damaged proteins and organelles and a drastic reduction in fly lifespan. I show that restoring mitophagy in a low mtH2O2 background restores mitochondrial respiration, TOR signalling and rescues lifespan. In the following chapters, I describe in detail a novel mitochondrial H2O2-Pink1/Parkin-TOR signalling axis that regulates cellular quality control and how it can be modulated by pharmacological and genetic interventions. My results also reveal the existence of a novel ROS signalling pathway that regulates mitochondrial density, which in turn determines the activation of TOR signalling and lifespan.