Mitochondrial ca²⁺ uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity

Tightly regulated Ca²⁺ homeostasis is a prerequisite for proper cardiac function. To dissect the regulatory network of cardiac Ca²⁺ handling, we performed a chemical suppressor screen on zebrafish tremblor embryos, which suffer from Ca²⁺ extrusion defects. Efsevin was identified based on its potent activity to restore coordinated contractions in tremblor. We show that efsevin binds to VDAC2, potentiates mitochondrial Ca2+ uptake and accelerates the transfer of Ca²⁺ from intracellular stores into mitochondria. In cardiomyocytes, efsevin restricts the temporal and spatial boundaries of Ca²⁺ sparks and thereby inhibits Ca²⁺ overload-induced erratic Ca²⁺ waves and irregular contractions. We further show that overexpression of VDAC2 recapitulates the suppressive effect of efsevin on tremblor embryos whereas VDAC2 deficiency attenuates efsevin's rescue effect and that VDAC2 functions synergistically with MCU to suppress cardiac fibrillation in tremblor. Together, these findings demonstrate a critic l modulatory role for VDAC2-dependent mitochondrial Ca²⁺ uptake in the regulation of cardiac rhythmicity.