2015 Articles

Mitochondrial calcium overload is a key determinant in heart failure

Santulli, Gaetano; Xie, Wenjun; Reiken, Steven R.; Marks, Andrew R.

We demonstrate that intracellular Ca2+ leak causes mitochondrial Ca2+ overload and dysfunction in postischemic heart failure (HF). In particular, sarcoplasmic reticulum (SR) Ca2+ leak via type 2 ryanodine receptor (RyR2)—but not type 2 inositol 1,4,5-trisphosphate receptor (IP3R2)—channels plays a fundamental role in the pathophysiology of mitochondrial Ca2+ overload and dysfunction in HF. We present here a previously undisclosed molecular mechanism in HF with crucial implications in cardiac physiology. Indeed, our data establish a feedback loop between SR and mitochondria in which SR Ca2+ leak triggers mitochondrial dysfunction and increases the production of free radicals, which in turn lead to posttranslational modifications of RyR2 and enhance intracellular Ca2+ leak, thereby contributing to impaired cardiac function after myocardial infarction.