ATAD3A deficiency induces oxidative eustress via the complex I reverse electron transport.

Abstract

Based on the importance of redox homeostasis, the concept of precision redox regulation has received widespread attention. As the main source of Reactive Oxygen Species (ROS) production, mitochondria play a dual role in this process: facilitating beneficial signal transmission and causing excessive oxidative damage. Numerous studies have demonstrated that this duality is not only dependent on the quantity of ROS produced but also on the different sites of production, each showing varying effects. This insight underscores the necessity and importance of accurately regulating mitochondrial redox. However, the precise regulatory system remains unclear. In our study, we discovered that specifically knocking down the atad-3 (ATAD3A) gene significantly increased the level of mitochondrial ROS in nematodes and mammalian cells. We found that ATAD3A directly interacts with the complex I subunit NDUFS8, playing an integral role in complex I assembly and activity. Knocking down atad-3 reduces complex I activity and proton leakage, increases mitochondrial membrane potential, thereby inducing reverse electron transport (RET) to produce more ROS. The induced RET-ROS may serve as a protective response to impaired mitochondrial function, activating antioxidant systems that enhance stress resistance and extend longevity in nematodes. Our findings reveal a novel function and mechanism of knocking down ATAD3A to precisely regulate mitochondrial ROS production. They provide evidence for the beneficial role of RET-ROS as a signal promoting longevity and underscore the importance of precision redox.