Cardiomyocyte ATP Production, Metabolic Flexibility, and Survival Require Calcium Flux through Cardiac Ryanodine Receptors in Vivo

Bround, Michael J.; Wambolt, Richard B.; Luciani, Dan S.; Kulpa, Jerzy E.; Rodrigues, Brian; Brownsey, Roger W.; Allard, Michael F.; Johnson, James D.

doi:10.1074/jbc.m112.427062

Cited by 72 publications

(60 citation statements)

References 58 publications

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“…Calpain 10 is present in cardiac mitochondria [36]. Activation of calpain 10 increases cell injury by impairing the mitochondrial respiratory chain [35] and is also involved in the disruption of ryanodine receptormediated apoptosis [36]. Therefore, activation of the mit-CPN1 and calpain 10 each appear to contribute to cell injury during ischemia-reperfusion.…”

Section: Localization Of Calpain Within Mitochondriamentioning

confidence: 98%

“…In renal cortex mitochondria, calpain 10 is found in outer membrane, intermembrane space, inner membrane and matrix [35]. Calpain 10 is present in cardiac mitochondria [36]. Activation of calpain 10 increases cell injury by impairing the mitochondrial respiratory chain [35] and is also involved in the disruption of ryanodine receptormediated apoptosis [36].…”

Section: Localization Of Calpain Within Mitochondriamentioning

confidence: 99%

See 1 more Smart Citation

Heart mitochondria and calpain 1: Location, function, and targets

Chen¹,

Lesnefsky²

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Calpain 1 is an ubiquitous Ca(2+)-dependent cysteine protease. Although calpain 1 has been found in cardiac mitochondria, the exact location within mitochondrial compartments and its function remain unclear. The aim of the current review is to discuss the localization of calpain 1 in different mitochondrial compartments in relationship to its function, especially in pathophysiological conditions. Briefly, mitochondrial calpain 1 (mit-CPN1) is located within the intermembrane space and mitochondrial matrix. Activation of the mit-CPN1 within intermembrane space cleaves apoptosis inducing factor (AIF), whereas the activated mit-CPN1 within matrix cleaves complex I subunits and metabolic enzymes. Inhibition of the mit-CPN1 could be a potential strategy to decrease cardiac injury during ischemia-reperfusion.

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Section: Localization Of Calpain Within Mitochondriamentioning

confidence: 98%

Section: Localization Of Calpain Within Mitochondriamentioning

confidence: 99%

Heart mitochondria and calpain 1: Location, function, and targets

Chen¹,

Lesnefsky²

2015

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…A recent paper has shown that VDAC2 is coupled to RyR2 in the heart (Min et al, 2012), allowing a direct coupling of RyR-mediated Ca 2+ release to Ca 2+ uptake in the mitochondria. Moreover, RyR-mediated Ca 2+ signaling has been implicated in ATP production and metabolic flexibility in the heart (Bround et al, 2013). Other studies have implicated RyRs in the regulation of apoptosis (Kim et al, 2002) and ER-stressmediated cell death (Luciani et al, 2009;Ruiz et al, 2009) in various cell types, including neurons and pancreatic b cells.…”

Section: K17dmentioning

confidence: 99%

Bcl-2 binds to and inhibits ryanodine receptors

Vervliet¹,

Decrock²,

Molgó³

et al. 2014

Journal of Cell Science

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The anti-apoptotic B-cell lymphoma-2 (Bcl-2) protein not only counteracts apoptosis at the mitochondria by scaffolding proapoptotic Bcl-2-family members, but also acts at the endoplasmic reticulum, thereby controlling intracellular Ca 2+ dynamics. Bcl-2 inhibits Ca 2+ release by targeting the inositol 1,4,5-trisphosphate receptor (IP 3 R). Sequence analysis has revealed that the Bcl-2-binding site on the IP 3 R displays strong similarity with a conserved sequence present in all three ryanodine receptor (RyR) isoforms. We now report that Bcl-2 co-immunoprecipitated with RyRs in ectopic expression systems and in native rat hippocampi, indicating that endogenous RyR-Bcl-2 complexes exist. Purified RyR domains containing the putative Bcl-2-binding site bound fulllength Bcl-2 in pulldown experiments and interacted with the BH4 domain of Bcl-2 in surface plasmon resonance (SPR) experiments, suggesting a direct interaction. Exogenous expression of fulllength Bcl-2 or electroporation loading of the BH4 domain of Bcl-2 dampened RyR-mediated Ca 2+ release in HEK293 cell models.Finally, introducing the BH4-domain peptide into hippocampal neurons through a patch pipette decreased RyR-mediated Ca 2+ release. In conclusion, this study identifies Bcl-2 as a new inhibitor of RyR-based intracellular Ca 2+ -release channels.

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“…Recent studies have shown that genetic variation in RNF207 is associated with prolongation of the QT interval [52,53] and that RNF207 knockdown in zebrafish embryos prolonged the action potential duration (APD) [21]. It was also reported that VDAC1 is the only identified protein mediating Ca 2+ transport in the outer mitochondrial membrane [54] and that Ca 2+ dynamics is important not only for APD [55,56] but also for the regulation of cellular energetic production [57][58][59]. These findings raised the possibility that RNF207 regulates cellular Ca 2+ dynamics, especially the mitochondrial Ca concentration.…”

Section: Discussionmentioning

confidence: 99%

The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes

Mizushima

Takahashi

Watanabe

et al. 2016

Journal of Molecular and Cellular Cardiology

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A failing heart shows severe energy insufficiency, and it is presumed that this energy shortage plays a critical role in the development of cardiac dysfunction. However, little is known about the mechanisms that cause energy metabolic alterations in the failing heart. Here, we show that the novel RING-finger protein 207 (RNF207), which is specifically expressed in the heart, plays a role in cardiac energy metabolism. Depletion of RNF207 in neonatal rat cardiomyocytes (NRCs) leads to a reduced cellular concentration of adenosine triphosphate (ATP) and mitochondrial dysfunction.Consistent with this result, we observed here that the expression of RNF207 was significantly reduced in mice with common cardiac diseases including heart failure.Intriguingly, proteomic approaches revealed that RNF207 interacts with the voltage-dependent anion channel (VDAC), which is considered to be a key regulator of mitochondria function, as an RNF207-interacting protein. Our findings indicate that RNF207 is involved in ATP production by cardiomyocytes, suggesting that RNF207 plays an important role in the development of heart failure.3 Highlights l RNF207 is specifically expressed in the heart. l RNF207 enhances activity of the tricarboxylic acid cycle in cardiomyocytes.l RNF207 directly interacts with VDAC1 through its coiled-coil domain.l Heart failure significantly reduces the expression of RNF207 in mice.4

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Cardiomyocyte ATP Production, Metabolic Flexibility, and Survival Require Calcium Flux through Cardiac Ryanodine Receptors in Vivo

Cited by 72 publications

References 58 publications

Heart mitochondria and calpain 1: Location, function, and targets

Heart mitochondria and calpain 1: Location, function, and targets

Bcl-2 binds to and inhibits ryanodine receptors

The novel heart-specific RING finger protein 207 is involved in energy metabolism in cardiomyocytes

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