Abstract
Calcium induced mitochondrial dysfunction is an important event that occurs during ischemia/reperfusion injury. But the details and precise mechanism of inhibition are obscure. Here we show that ADP stimulated respiration (state 3) is inhibited by calcium in a titratable manner. Isolated cardiac mitochondria from guinea pigs were exposed to varying levels of calcium while respiration was monitored using an Oroboros O2k oxygraph. The levels of calcium used are below the mitochondrial permeability transition threshold and reveal an additional component of calcium induced mitochondrial dysfunction that occurs during ischemia. Calpain I, II, and III inhibitors, as well as, calpeptin had little to no effect suggesting a mechanism other than calcium‐activated proteases leading to the decrease in state 3 respiration. In addition, unloading of mitochondrial calcium did not ameliorate the calcium‐induced state 3 dysfunction. The presence of extra‐mitochondrial ATP did protect against calcium; however, this was primarily due to calcium chelation. Higher levels of calcium to compensate for ATP complexation depressed state 3 respiration; however, a protective effect of ATP was still observed. The physiological implications for this phenomenon is significant for the ischemia/reperfusion paradigm.Support or Funding InformationThis work was supported by NIH grant R00‐HL121160.
Published Version
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