The Valosin-Containing Protein Protects the Heart against Pathological Ca²⁺ Overload by Modulating Ca²⁺ Uptake Proteins

Stress-induced mitochondrial calcium (Ca²⁺) overload is a key cellular toxic effectors and a trigger of cardiomyocyte death during cardiac ischemic injury through the opening of mitochondrial permeability transition pore (mPTP). 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 acts as a novel regulator of mitochondrial Ca²⁺ uptake proteins and resists cardiac mitochondrial Ca²⁺ overload by modulating mitochondrial Ca²⁺ homeostasis. By using a cardiac-specific transgenic (TG) mouse model in which VCP is overexpressed by 3.5 folds in the heart compared to the wild type (WT) mouse, we found that, under the pathological extra-mitochondrial Ca²⁺ overload, Ca²⁺ entry into cardiac mitochondria was reduced in VCP TG mice compared to their little-matched WT mice, subsequently preventing mPTP opening and ATP depletion under the Ca²⁺ challenge. Mechanistically, overexpression of VCP in the heart resulted in post-translational protein degradation of the mitochondrial Ca²⁺ uptake protein 1, an activator of the mitochondria Ca²⁺ uniporter that is responsible for mitochondrial calcium uptake. Together, our results reveal a new regulatory role of VCP in cardiac mitochondrial Ca²⁺ homeostasis and unlock the potential mechanism by which VCP confers its cardioprotection.