LAUSR

Stress-induced mitochondrial calcium (Ca 2+ ) overload is a trigger of cardiomyocyte death though the opening of mitochondrial permeability transition pore (mPTP) during cardiac ischemic injury. We previously found that the valosin-containing protein (VCP), an ATPase-associated protein, protects cardiomyocytes against stress-induced death and also inhibits mPTP opening in vitro. However, the underlying molecular mechanisms are not fully understood. Here, we tested our hypothesis that VCP protects cardiomyocytes against stress-induced mPTP opening through resisting excessive mitochondrial Ca 2+ uptake. By using a cardiac-specific transgenic (TG) mouse model in which VCP is overexpressed by 3.5 folds in the hearts, we found that, under the pathological extra-mitochondrial Ca 2+ overload (10-70μM), Ca 2+ entered into cardiac mitochondriawas much lessin VCP TG mice compared to little-matched WT mice, subsequently preventing mPTP opening and ATP depletion under the Ca 2+ challenge. Mechanistically, overexpression of VCP in the heart results in post-translational protein degradation of the mitochondrial Ca 2+ uptake protein 1 (MICU1), an activator of the mitochondria Ca 2+ uniporter (MCU) which is responsible for mitochondrial calcium uptake. Together, our results reveal a new regulatory role of VCP in cardiac mitochondrial Ca 2+ homeostasis and unlocks the potential mechanism by which VCP confers its cardioprotection.