Nidhi Kuksal - October 16

Examination of the importance of ROS release from complex I in ischemia-reperfusion injury

Recent work has suggested that complex I of the respiratory chain is the sole source of ROS during ischemia-reperfusion (IR) injury to the myocardium. Complex I is an important source of reactive oxygen species (ROS). However, mitochondria can also form ROS from 10 other potential sites. Our group and others have shown that other sources, like pyruvate dehydrogenase (PDH) and 2-oxoglutarate dehydrogenase (OGDH), can produce more ROS than complex I in liver and muscle tissue. In addition, complex III of the respiratory chain represents a major source, accounting for up to ~50% of the ROS released from liver mitochondria. Cardiac mitochondria also release high amounts of ROS from complex III and it has been demonstrated that PDH and OGDH can also form ROS in heart tissue. Here, we examined if complex I is the sole source of ROS during IR injury. Using mice deficient in complex I (NDUFS4+/-), we found that other mitochondrial sources of ROS can contribute to IR injury. It was found that the partial loss of complex I did not alter ROS release from mitochondria oxidizing pyruvate, 2-oxoglutarate, or succinate. In contrast to liver mitochondria, the respiratory chain served as the main source of ROS in cardiac mitochondria from WT and NDUFS4+/-. Indeed, complex I, II, and IV produced the bulk of the ROS in heart mitochondria whereas major sources in liver included OGDH and complex III. IR injury modeling induced a significant increase in ROS release from complex I-deficient cardiac mitochondria oxidizing pyruvate, 2-oxoglutarate, or succinate. This increase was associated with a significant increase in myocardial infarct size and limited recovery of myocardial function after the ischemic challenge. In aggregate, these results refute the recent claims that complex I is the sole source of ROS following ischemia and reperfusion. Our findings demonstrate that other sources of ROS, such as complex II and III of the respiratory chain. also contribute to IR injury. This was demonstrated with results showing that complex I deficiency augments myocardial damage due to the overproduction of ROS.

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