The Role of Respiratory Complex IV in Lifespan Length and Quality

Abstract

Mitochondria play a pivotal role in lifespan regulation, though the underlying mechanisms remain elusive. As ageing progresses, damaged mitochondria with reduced ATP production and increased Reactive Oxygen Species (ROS) generation accumulate, yet mitochondrial depletion extends the lifespan of various animal models. Our previous research demonstrated that complex I (CI) activity during development but not adulthood is crucial for determining the lifespan of Drosophila melanogaster. Still, CI-deficient mitochondria do not generate excessive ROS, failing to recapitulate mitochondrial ageing. In this study, we focus on complex IV (CIV), whose depletion leads to the accumulation of "old-mitochondria", i.e. producing less ATP and more ROS. We reveal that CIV's role in longevity is more intricate than CI's, shaping lifespan through two "windows of opportunity". The first window, shared by CI and CIV, occurs during development. Small perturbations in CIV during development lead to the emergence of short-lived flies. These flies exhibit an adult phenotype reminiscent of mitochondrial associated diseases, primarily characterised by their inability to store fat efficiently. Accordingly, partial complementation of CIV function using an alternative oxidase (AOX) restores molecular and physiological phenotypes. The second window emerges during fly senescence, where CIV deficiency curtails lifespan without hastening ageing, i.e. flies die earlier but not more rapidly. Notably, only the developmental phenotype is associated with TOR dysregulation and altered autophagy, emphasising that developmental dysfunction uniquely interferes with nutrient sensing and the main cellular recycling pathway. This study sheds light on the multifaceted role of mitochondrial complex IV in modulating lifespan, providing potential targets for interventions to foster healthy ageing.