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

Abstract

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.

The Physiological and Pathological Roles of Mitochondrial Calcium Uptake in Heart

“…In addition, a recent study has shown that an ATPase protein named valosin-containing protein (VCP) is involved in the regulation of mitochondrial Ca 2+ uptake [ 13 ]. VCP belongs to an ATPase associated family with four structural domains [ 87 ]: an N-terminal substrate-binding domain, two ATPase domains, and a C terminal domain.…”

“…Recently, VCP has been found to play an essential role in mitochondrial function, including mitochondrial respiration, ATP production and mPTP opening. Overexpression of the VCP protects cardiomyocyte against stimulated death and reduces the I/R induced infarct size in the heart [ 13 , 90 , 91 , 92 ]. Notably, the most recent study found that VCP protects the heart from the stress by preventing excessive Ca 2+ overload through inhibiting Ca 2+ uptake [ 13 ].…”

“…Overexpression of the VCP protects cardiomyocyte against stimulated death and reduces the I/R induced infarct size in the heart [ 13 , 90 , 91 , 92 ]. Notably, the most recent study found that VCP protects the heart from the stress by preventing excessive Ca 2+ overload through inhibiting Ca 2+ uptake [ 13 ]. The study also showed that the VCP-mediated inhibition in Ca 2+ uptake attenuates the stress-induced reduction of ATP production and the mPTP opening [ 13 ].…”

“…Notably, the most recent study found that VCP protects the heart from the stress by preventing excessive Ca 2+ overload through inhibiting Ca 2+ uptake [ 13 ]. The study also showed that the VCP-mediated inhibition in Ca 2+ uptake attenuates the stress-induced reduction of ATP production and the mPTP opening [ 13 ]. The mechanism of this protective effect was linked to the VCP-mediated selective degradation of MICU1, which subsequently reduced the uptake of Ca 2+ under stress [ 13 ].…”

“…The uptake of mitochondrial Ca 2+ may affect the initiation and activation of the releasing system, particularly mPTP opening under the stress conditions [ 10 , 11 , 12 ]. In addition to the conventional regulatory apparatus, more new regulators are being discovered to be involved in regulating mitochondrial Ca 2+ homeostasis and participate in the cardiac mitochondrial function, such as valosin-containing protein (VCP), a new identified ATPase, which was found to be involved in both mitochondrial calcium uptake and mPTP opening [ 13 ]. A better understanding of the underlying mechanism would bring new insights into the molecular mechanism underlying human heart disease and lead to the discovery of new targets for the development of therapeutic strategies.…”