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Mitochondria govern a variety of cellular processes including bioenergetics, metabolism, reactive oxygen species production, cell survival, and Ca 2+ homeostasis. Collectively, our findings demonstrate a critical role for the evolutionary conserved E73 in determining the anti-arrhythmic effect of VDAC isoforms through modulating Ca 2+ cross-talk between the SR and mitochondria in cardiomyocytes.

In HL-1 cardiomyocytes, VDAC2 knockdown diminished the transfer of Ca 2+ from the SR into mitochondria and overexpression of VDAC2 or VDAC3 Q73E restored SR-mitochondrial Ca 2+ transfer in VDAC2 deficient HL-1 cells, whereas this rescue effect was absent for VDAC3 and drastically compromised for VDAC2 E73Q. Interestingly, VDAC2 E73Q failed to restore rhythmic cardiac contractions in ncx1 deficient hearts, while the Q73E conversion induced a gain of function in VDAC3. To investigate whether E73/Q73 determines VDAC isoform-specific anti-arrhythmic effect, we mutated E73 to Q in VDAC2 (VDAC2 E73Q) and Q73 to E in VDAC3 (VDAC3 Q73E). Phylogenetic analysis further revealed that a glutamate at position 73, which was previously described to be an important regulator of VDAC function, is sevolutionarily conserved in VDAC1 and VDAC2, whereas a glutamine occupies position 73 (Q73) of VDAC3. A chimeric approach showed that moieties in the N-terminal half of VDAC are responsible for their divergent functions in cardiac biology.

We found that overexpression of VDAC1 or VDAC2, but not VDAC3, suppresses the fibrillation-like phenotype in zebrafish tremblor/ncx1h mutants. Here, we used the zebrafish tremblor/ncx1h mutant to dissect the isoform-specific roles of VDAC proteins in Ca 2+ handling. Vertebrates express three highly homologous VDAC isoforms. However, molecular mechanisms by which VDAC2 controls mitochondrial Ca 2+ transport and thereby influences cardiac rhythmicity remain elusive. In cardiomyocytes, genetic or pharmacological activation of isoform 2 of VDAC (VDAC2) effectively potentiates mitochondrial Ca 2+ uptake and suppresses Ca 2+ overload-induced arrhythmogenic events. The voltage-dependent anion channel (VDAC) functions as a passageway for the exchange of ions, including Ca 2+, across the outer mitochondrial membrane. Mitochondria critically regulate a range of cellular processes including bioenergetics, cellular metabolism, apoptosis, and cellular Ca 2+ signaling.

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