eLife (Jan 2015)
Mitochondrial Ca2+ uptake by the voltage-dependent anion channel 2 regulates cardiac rhythmicity
- Hirohito Shimizu,
- Johann Schredelseker,
- Jie Huang,
- Kui Lu,
- Shamim Naghdi,
- Fei Lu,
- Sarah Franklin,
- Hannah DG Fiji,
- Kevin Wang,
- Huanqi Zhu,
- Cheng Tian,
- Billy Lin,
- Haruko Nakano,
- Amy Ehrlich,
- Junichi Nakai,
- Adam Z Stieg,
- James K Gimzewski,
- Atsushi Nakano,
- Joshua I Goldhaber,
- Thomas M Vondriska,
- György Hajnóczky,
- Ohyun Kwon,
- Jau-Nian Chen
Affiliations
- Hirohito Shimizu
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
- Johann Schredelseker
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
- Jie Huang
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
- Kui Lu
- Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States
- Shamim Naghdi
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, United States
- Fei Lu
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
- Sarah Franklin
- Department of Anesthesiology, University of California, Los Angeles, Los Angeles, United States
- Hannah DG Fiji
- Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States
- Kevin Wang
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
- Huanqi Zhu
- Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States
- Cheng Tian
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
- Billy Lin
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
- Haruko Nakano
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States; Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, United States
- Amy Ehrlich
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, United States
- Junichi Nakai
- Brain Science Institute, Saitama University, Saitama, Japan
- Adam Z Stieg
- ORCiD
- California NanoSystems Institute, University of California, Los Angeles, Los Angeles, United States; WPI Center for Materials Nanoarchitectonics, National Institute for Materials Science, Tsukuba, Japan
- James K Gimzewski
- Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States; California NanoSystems Institute, University of California, Los Angeles, Los Angeles, United States; WPI Center for Materials Nanoarchitectonics, National Institute for Materials Science, Tsukuba, Japan; School of Physics, Centre for Nanoscience and Quantum Information, University of Bristol, Bristol, UK
- Atsushi Nakano
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States; Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, United States
- Joshua I Goldhaber
- Cedars-Sinai Heart Institute, Los Angeles, United States
- Thomas M Vondriska
- Department of Anesthesiology, University of California, Los Angeles, Los Angeles, United States
- György Hajnóczky
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, United States
- Ohyun Kwon
- Department of Chemistry and Biochemistry, University of California, Los Angeles, Los Angeles, United States
- Jau-Nian Chen
- Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, United States
- DOI
- https://doi.org/10.7554/eLife.04801
- Journal volume & issue
-
Vol. 4
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.
Keywords
