Mitochondrial Ca(2+) uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity

Shimizu, H., Schredelseker, J., Huang, J., Lu, K., Naghdi, S., Lu, F., Franklin, S., Fiji, H.D., Wang, K., Zhu, H., Tian, C., Lin, B., Nakano, H., Ehrlich, A., Nakai, J., Stieg, A.Z., Gimzewski, J.K., Nakano, A., Goldhaber, J.I., Vondriska, T.M., Hajnóczky, G., Kwon, O., Chen, J.N.
eLIFE   4: 253-65 (Journal)
Registered Authors
Chen, Jau-Nian, Huang, Jie, Schredelseker, Johann
VDAC, arrhythmia, calcium handling, cell biology, developmental biology, fibrillation, heart, human, mitochondria, mouse, stem cells, zebrafish
MeSH Terms
  • Amino Acid Sequence
  • Animals
  • Calcium/metabolism*
  • Calcium Signaling/drug effects
  • Embryo, Mammalian/metabolism
  • Heart/physiopathology*
  • Heart Rate*/drug effects
  • Mitochondria/drug effects
  • Mitochondria/metabolism*
  • Molecular Sequence Data
  • Myocardial Contraction/drug effects
  • Myocytes, Cardiac/drug effects
  • Myocytes, Cardiac/metabolism
  • Video Recording
  • Voltage-Dependent Anion Channel 2/chemistry
  • Voltage-Dependent Anion Channel 2/metabolism*
  • Zebrafish/embryology
  • Zebrafish/physiology*
  • Zebrafish Proteins/chemistry
  • Zebrafish Proteins/metabolism*
25588501 Full text @ Elife
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.
Genes / Markers
Figure Gallery
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes