The Interplay Between Respiratory Supercomplexes and ROS in Aging

Significance: The molecular mechanism of aging is still vigorously debated, although a general consensus exists that mitochondria are significantly involved in this process. However, the previously postulated role of mitochondrial-derived reactive oxygen species (ROS) as the damaging agents inducing functional loss in aging has fallen out of favor in the recent past. In this review, we critically examine the role of ROS in aging in the light of recent advances on the relationship between mitochondrial structure and function. Recent Advances: The functional mitochondrial respiratory chain is now recognized as a reflection of the dynamic association of respiratory complexes in the form of supercomplexes (SCs). Besides providing kinetic advantage (channeling), SCs control ROS generation by the respiratory chain, thus providing a means to regulate ROS levels in the cell. Depending on their concentration, these ROS are either physiological signals essential for the life of the cell or toxic species that damage cell structure and functions. Critical Issues: We propose that under physiological conditions the dynamic nature of SCs reversibly controls the generation of ROS as signals involved in mitochondrial-nuclear communication. During aging, there is a progressive loss of control of ROS generation so that their production is irreversibly enhanced, inducing a vicious circle in which signaling is altered and structural damage takes place. Future Directions: A better understanding on the forces affecting SC association would allow the manipulation of ROS generation, directing these species to their physiological signaling role. Antioxid. Redox Signal. 23, 208-238.