Shimizu Hirohito, Schredelseker Johann, Huang Jie, Lu Kui, Naghdi Shamim, Lu Fei, Franklin Sarah, Fiji Hannah Dg, Wang Kevin, Zhu Huanqi, Tian Cheng, Lin Billy, Nakano Haruko, Ehrlich Amy, Nakai Junichi, Stieg Adam Z, Gimzewski James K, Nakano Atsushi, Goldhaber Joshua I, Vondriska Thomas M, Hajnóczky György, Kwon Ohyun, Chen Jau-Nian
Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States.
Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States.
Elife. 2015 Jan 15;4:e04801. doi: 10.7554/eLife.04801.
Tightly regulated Ca(2+) homeostasis is a prerequisite for proper cardiac function. To dissect the regulatory network of cardiac Ca(2+) handling, we performed a chemical suppressor screen on zebrafish tremblor embryos, which suffer from Ca(2+) 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 Ca(2+) uptake and accelerates the transfer of Ca(2+) from intracellular stores into mitochondria. In cardiomyocytes, efsevin restricts the temporal and spatial boundaries of Ca(2+) sparks and thereby inhibits Ca(2+) overload-induced erratic Ca(2+) 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 Ca(2+) uptake in the regulation of cardiac rhythmicity.
严格调控的钙离子稳态是心脏正常功能的前提条件。为了剖析心脏钙离子处理的调控网络，我们对患有钙离子外排缺陷的斑马鱼震颤胚胎进行了化学抑制剂筛选。基于其恢复震颤胚胎协调收缩的强大活性，鉴定出了Efsevin。我们发现Efsevin与VDAC2结合，增强线粒体对钙离子的摄取，并加速钙离子从细胞内储存库向线粒体的转移。在心肌细胞中，Efsevin限制了钙离子火花的时间和空间边界，从而抑制了钙离子过载诱导的不稳定钙离子波和不规则收缩。我们进一步表明，VDAC2的过表达重现了Efsevin对震颤胚胎的抑制作用，而VDAC2的缺乏则减弱了Efsevin的拯救作用，并且VDAC2与MCU协同作用以抑制震颤胚胎中的心脏颤动。总之，这些发现证明了依赖VDAC2的线粒体钙离子摄取在调节心脏节律性方面具有关键的调节作用。
