In contrast, other studies have shown that truncated-Bid (BH3-interacting domain death agonist) induced MOM permeabilization and cell death in wild-type (WT) but not in VDAC2 knock-out (KO) mouse embryonic fibroblasts 8.Ĭalcium flux into the mitochondrial matrix takes place primarily through the mitochondrial calcium uniporter (MCU), present in the mitochondrial inner membrane (MIM). Studies show that VDAC2–BAK complex was absent during death stimulus and deletion of VDAC2 promotes apoptosis 7. While VDAC2–BAK (Bcl2-antagonist/killer protein) interaction is reported to be highly important to control cellular apoptosis, it is still controversial if this interaction promotes or inhibits apoptosis. VDAC2 is known to interact with pro-apoptotic proteins such as Bcl2 family proteins. The voltage-dependent anion channel 2 (VDAC2) is a 32 kDa porin present on the mitochondrial outer membrane (MOM) and contributes to apoptosis, steroidogenesis, metabolite flux, and calcium homeostasis 6. The mitochondria also appear to play a role in calcium uptake during this process and its importance is under investigation 4, 5. Part of the calcium is pumped back into the SR through sarcoplasmic endoplasmic reticulum calcium ATPase 2a (SERCA2a) and the rest of the calcium is extruded out of the cell via the sodium–calcium exchanger (NCX1) and the sarcolemma calcium pump. The excess cytosolic calcium is pumped out of the cytoplasm through three main processes. This release results in an overall increase in the cytosolic calcium which binds to troponin thereby facilitating cellular contraction. During systole, electrical excitation of the membrane causes L-type calcium channels (LTCC) to open and a small amount of calcium enters the cell which binds to ryanodine receptor 2 (RyR2) and triggers the sarcoplasmic reticulum (SR) to release some of its calcium reserve. Calcium plays a crucial role in ECC and influences cardiac rhythmicity and cellular contraction. The impaired myocardial function has been partly attributed to alterations in the function of contractile proteins and excitation–contraction coupling (ECC) 3. DCM is a condition in which the cardiac ventricular chambers enlarge and have impaired systolic and diastolic function. Non-ischemic dilated cardiomyopathy (DCM) is one of the most common causes that lead to the syndrome of chronic heart failure (HF) which is currently a growing global epidemic 1, 2. Through this unique role in cellular calcium dynamics and excitation-contraction coupling VDAC2 emerges as a plausible therapeutic target for heart failure. In conclusion, our findings demonstrate that VDAC2 plays a crucial role in cardiac function by influencing cellular calcium signaling. Activation of VDAC2 by efsevin increased cardiac contractile force in a mouse model of pressure-overload induced heart failure. Reintroduction of VDAC2 in 6-week-old knock-out mice partially rescued the cardiomyopathy phenotype. We also observed adverse cardiac remodeling which progressed to severe cardiomyopathy and death. Our results indicate that loss of VDAC2 in the myocardium causes severe impairment in excitation-contraction coupling by altering both intracellular and mitochondrial calcium signaling. To elucidate the role of VDAC2 in calcium homeostasis, we generated a cardiac ventricular myocyte-specific developmental deletion of Vdac2 in mice. However, the specific role of VDAC2 in intracellular calcium dynamics and cardiac function is not well understood. Abnormalities in calcium homeostasis often leads to electrical and contractile dysfunction and can cause dilated cardiomyopathy and heart failure. Voltage dependent anion channel 2 (VDAC2) is an outer mitochondrial membrane porin known to play a significant role in apoptosis and calcium signaling. Nature Communications volume 12, Article number: 4583 ( 2021) Cardiac-specific deletion of voltage dependent anion channel 2 leads to dilated cardiomyopathy by altering calcium homeostasis
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |