Mitochondrial Ca2+ uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity

Abstract

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 critical modulatory role for VDAC2-dependent mitochondrial Ca2+ uptake in the regulation of cardiac rhythmicity.DOI: http://dx.doi.org/10.7554/eLife.04801.001

VDAC2-specific cellular functions and the underlying structure

“…Also, VP5, a viral protein from infectious bursal disease virus, has been demonstrated to interact with VDAC2 and Rack1 (receptor of activated protein kinase C1) in host cells [76,77]. Lastly, VDAC2 was identified as a target of chemicals, Erastin [78], an anti-tumor reagent and Efsevin [79]. Several partners are promiscuous and interact with multiple VDAC isoforms but some like Bak seem to be exclusive for VDAC2 and thus, assign new isoform-specific functions to VDAC2 [65].…”

“…In addition, activation of VDAC2 through overexpression or Efsevin treatment was found to restore rhythmic contractions in Na + /Ca 2+ exchanger ( NCX ) deficient zebrafish hearts and to effectively suppress Ca 2+ overload-induced arrhythmogenic Ca 2+ events and irregular contractions in mouse and human cardiomyocytes. Potentiating VDAC2 activity by Efsevin caused enhancement of mitochondrial Ca 2+ uptake, acceleration of Ca 2+ transfer from intracellular stores into mitochondria and spatial and temporal restriction of Ca 2+ sparks in cardiomyocytes [79]. While the specific relevance of VDAC2 these results impressively come together to support that VDAC2 is required to locally couple mitochondrial Ca 2+ uptake with RyR2-mediated Ca 2+ release in the heart, providing a mechanism that protects the regular Ca 2+ cycling and contractile activity.…”

“…Mitochondrial matrix Ca 2+ and ROS are among the most effective inducers of the mPTP. VDAC2 is central to mitochondrial Ca 2+ uptake at least in the heart [68,79,94] but little is known about its isoform-specific involvement in mPTP opening. Under oxidative stress, VDAC2 was reported to mediate glycogen synthase kinase 3β (GSK3β) translocation to OMM and to promote mPTP formation to result in cell death [70].…”

“…At the level of the protein, Erastin [78], Efsevin [79] and free tubulin [88,127] have been proposed to bind and modulate VDAC2 activity mainly by interfering in the role of this protein as a gate for metabolites. Erastin is an anti-tumor agent with lethal activity on some cancer cells by perturbing metabolite transfer (e.g.NADH) across the OMM.…”

Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis

“…Recent evidence suggests that V2 is involved in Ca 2+ transport by cardiac mitochondria (6)(7)(8), and specifically interacts with several endogenous cytoplasmic and mitochondria-associated proteins, including steroidogenic acute regulatory protein (StAR) (9), glycogen synthase kinase 3 beta (GSK3β) (10), O-GlcNAc transferase (11), ryanodine receptor 2 (8), tubulin (12), viral protein 5, (13,14), and drugs [erastin (15) and esfevin (7)]. These interactions facilitate mitochondrial targeting, transport, and signaling processes, and, interestingly, they seem to have striking effects on cell survival.…”