Mitochondrial Ca(2+) 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 D. G. 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 +22 more
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TLDR
A critical modulatory role for VDAC2-dependent mitochondrial Ca2+ uptake in the regulation of cardiac rhythmicity is demonstrated and efsevin is identified based on its potent activity to restore coordinated contractions in tremblor.Abstract:
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.read more
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The machineries, regulation and cellular functions of mitochondrial calcium.
TL;DR: Expanding the understanding of the mechanisms of mitochondrial Ca2+ regulation and function in different cell types is an important task in biomedical research, which offers the possibility of targeting mitochondrial Ca 2+ machinery for the treatment of several disorders.
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Endoplasmic Reticulum–Mitochondrial Contactology: Structure and Signaling Functions
TL;DR: The structure of the ER-mito contacts, methods for studying them, and the roles of contacts in Ca2+ and reactive oxygen species (ROS) signaling are reviewed.
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Mitochondrial Function, Biology, and Role in Disease A Scientific Statement From the American Heart Association
Elizabeth Murphy,Hossein Ardehali,Robert S. Balaban,Fabio DiLisa,Gerald W. Dorn,Richard N. Kitsis,Kinya Otsu,Peipei Ping,Rosario Rizzuto,Michael N. Sack,Douglas C. Wallace,Richard J. Youle +11 more
TL;DR: This statement will define the key roles that mitochondria play in cardiovascular physiology and disease and provide insight into how mitochondrial defects can contribute to cardiovascular disease; it will also discuss potential biomarkers of mitochondrial disease and suggest potential novel therapeutic approaches.
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Little Fish, Big Data: Zebrafish as a Model for Cardiovascular and Metabolic Disease
Philipp Gut,Philipp Gut,Sven Reischauer,Sven Reischauer,Didier Y.R. Stainier,Didier Y.R. Stainier,Rima Arnaout,Rima Arnaout +7 more
TL;DR: A comprehensive guide on applications of zebrafish to investigate cardiovascular and metabolic diseases and an impressive regenerative capacity scientists hope to unlock in humans are provided.
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Intracellular Ca(2+) signaling and Ca(2+) microdomains in the control of cell survival, apoptosis and autophagy.
TL;DR: The most recent insights in the emerging role of Ca(2+) signaling in cellular survival by controlling basal mitochondrial bioenergetics and by regulating apoptosis, a mitochondrial process, and autophagy, a lysosomal process, in response to cell damage and cell stress are discussed.
References
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Cardiac excitation–contraction coupling
TL;DR: Of the ions involved in the intricate workings of the heart, calcium is considered perhaps the most important and spatial microdomains within the cell are important in localizing the molecular players that orchestrate cardiac function.
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TL;DR: The Tol2kit greatly facilitates zebrafish transgenesis, simplifies the sharing of clones, and enables large‐scale projects testing the functions of libraries of regulatory or coding sequences.
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Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter
Joshua M. Baughman,Fabiana Perocchi,Fabiana Perocchi,Hany S. Girgis,Hany S. Girgis,Molly Plovanich,Molly Plovanich,Casey A. Belcher-Timme,Casey A. Belcher-Timme,Yasemin Sancak,Yasemin Sancak,X. Robert Bao,X. Robert Bao,Laura Strittmatter,Laura Strittmatter,Olga Goldberger,Olga Goldberger,Roman L. Bogorad,Victor Koteliansky,Vamsi K. Mootha,Vamsi K. Mootha +20 more
TL;DR: Genome phylogenetic profiling, genome-wide RNA co-expression analysis and organelle-wide protein coexpression analysis are used to predict proteins functionally related to MICU1, establishing MCU as an essential component of the mitochondrial Ca2+ uniporter.
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A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter
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Association of the APC gene product with beta-catenin
Bonnee Rubinfeld,Brian Souza,Iris Albert,Oliver Müller,Scott H. Chamberlain,Frank R. Masiarz,Susan Munemitsu,Paul G. Polakis +7 more
TL;DR: Results suggest that APC is involved in cell adhesion, and an antibody specific to beta-catenin also recognized the 95-kilodalton protein in the immunoprecipitates.
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