Modulation of the oxidative stress associated with respiratory chain dysfunction and mPTP opening

Abstract

The mitochondrion is deeply involved in ROS production through electron leak that occur in the respiratory chain. Measurement of mitochondrial ROS is useful to evaluate the consequences of MRC inhibition, electron leak, complex I dysfunction and stimulation of some oxidative pathways induced by chemicals or natural products. These parameters measured on isolated mitochondria allow identification of direct mitochondrial impairment with subsequent toxicity on skin, blood or organs. On the other hand, the mitochondrion is itself a target of ROS (vicious circle or cellular ROS) which may lead to irreversible damage of mtDNA or mitochondrial membrane lipids and proteins, resulting in mitochondrial dysfunction. For example, permeability transition pore (mPTP) susceptibility to oxidative stress is observed in various pathological cases (aging, neuronal injury, cardiac reperfusion injury...). Such damages can be reproduced on isolated mitochondria to identify mitochondrial protective molecules against oxidative stress induced-mPTP opening. In conclusion, simultaneous assessment of mitochondrial integrity, function and ROS production is a valuable toolbox to identify the risk of compound-induced liability in human, in particular regarding organ toxicity. Such approach can also be used to identify antioxidant properties of compounds in order to preserve mitochondrial integrity and cell life.