Mitochondrial uncoupling, ROS generation and cardioprotection

Biochim Biophys Acta Bioenerg. 2018 Sep;1859(9):940-950. doi: 10.1016/j.bbabio.2018.05.019. Epub 2018 May 31.


Mitochondrial oxidative phosphorylation is incompletely coupled, since protons translocated to the intermembrane space by specific respiratory complexes of the electron transport chain can return to the mitochondrial matrix independently of the ATP synthase -a process known as proton leak- generating heat instead of ATP. Proton leak across the inner mitochondrial membrane increases the respiration rate and decreases the electrochemical proton gradient (Δp), and is an important mechanism for energy dissipation that accounts for up to 25% of the basal metabolic rate. It is well established that mitochondrial superoxide production is steeply dependent on Δp in isolated mitochondria and, correspondingly, mitochondrial uncoupling has been identified as a cytoprotective strategy under conditions of oxidative stress, including diabetes, drug-resistance in tumor cells, ischemia-reperfusion (IR) injury or aging. Mitochondrial uncoupling proteins (UCPs) are able to lower the efficiency of oxidative phosphorylation and are involved in the control of mitochondrial reactive oxygen species (ROS) production. There is strong evidence that UCP2 and UCP3, the UCP1 homologues expressed in the heart, protect against mitochondrial oxidative damage by reducing the production of ROS. This review first analyzes the relationship between mitochondrial proton leak and ROS generation, and then focuses on the cardioprotective role of chemical uncoupling and uncoupling mediated by UCPs. This includes their protective effects against cardiac IR, a condition known to increase ROS production, and their roles in modulating cardiovascular risk factors such as obesity, diabetes and atherosclerosis.

Keywords: Cardioprotection; Ischemia-reperfusion; Mitochondrial uncoupling; Proton leak; Reactive oxygen species (ROS); Uncoupling proteins (UCPs).

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Cardiovascular Diseases / prevention & control*
  • Humans
  • Membrane Potential, Mitochondrial / drug effects*
  • Mitochondria / drug effects
  • Mitochondria / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Uncoupling Agents / pharmacology*


  • Reactive Oxygen Species
  • Uncoupling Agents