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Abstract 882: The Valosin-containing Protein Resists Pathological Cardiac Calcium Overload via Inhibiting Mitochondrial Calcium Uptake


 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.
