Divergences in the mitochondrial oxidative phosphorylation process and the role they play on reactive oxygen species production and aging

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Mitochondria provide energy through a process called oxidative phosphorylation. This process is fed by multiple pathways of electrons converging at the ubiquinone junction of the electron transfer system. By using oxygen as the final electron acceptor, oxidative phosphorylation also produces highly reactive derivatives of oxygen, i.e., reactive oxygen species. Reactive oxygen species have a dual role. At low doses, these molecules are beneficial, acting as triggers to activate cellular signal pathways and prepare the cell to defend itself against stressful events. However, at higher doses, they attack the proteins, lipids and DNA causing oxidative stress, cellular dysfunction and aging. My research indicates large variations in oxidative phosphorylation pathway utilization and regulation mechanisms among species, tissues, and sexes. To further understand the role of mitochondria in aging, we have to consider the mitochondrial diversity and its impact on reactive oxygen species production. The global objective of my research program is to investigate the consequences of heterogeneity in oxidative phosphorylation efficiency, substrates utilization and regulatory mechanisms on cellular homeostasis and aging through reactive oxygen species production. For this, we need to determine (A) how the activated pathway(s) and the regulatory mechanism(s) modulate energy production and reactive oxygen species efflux by the mitochondria, (B) how this relationship varies between species, tissues, sex and age, and (C) how it is linked with longevity. We will address these questions both at the macroevolutionary and microevolutionary scales by comparing various animal models from diverse taxa, from planarian worm to human. Our comparison will include species with similar oxidative phosphorylation regulation mechanisms, i.e., control by the phosphorylation system in the planarian worm and human heart, and species with contrasting regulation mechanisms, i.e., control by the electron transfer system in the beetle, rat and mice hearts. Furthermore, by having access to lines of beetles with large differences in longevity, we will verify, at the microevolutionary level, if the selection of oxidative phosphorylation pathways or regulatory mechanism is an efficient way to modulate aging. The results obtained through this research program will broaden our current knowledge of how variability in mitochondrial metabolism, at different time points during the course of life, affects animal cellular health and aging. Understanding these fluctuations and their impacts is crucial to pinpoint the role of mitochondria in aging, and to design strategies to protect mitochondria during the aging process.