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- W3016938385 abstract "Rationale: Mitochondrial Ca 2+ loading augments oxidative metabolism to match functional demands during times of increased work or injury. However, mitochondrial Ca 2+ overload also directly causes mitochondrial rupture and cardiomyocyte death during ischemia-reperfusion injury by inducing mitochondrial permeability transition pore opening. The MCU (mitochondrial Ca 2+ uniporter) mediates mitochondrial Ca 2+ influx, and its activity is modulated by partner proteins in its molecular complex, including the MCUb subunit. Objective: Here, we sought to examine the function of the MCUb subunit of the MCU-complex in regulating mitochondria Ca 2+ influx dynamics, acute cardiac injury, and long-term adaptation after ischemic injury. Methods and Results: Cardiomyocyte-specific MCUb overexpressing transgenic mice and Mcub gene-deleted ( Mcub − /− ) mice were generated to dissect the molecular function of this protein in the heart. We observed that MCUb protein is undetectable in the adult mouse heart at baseline, but mRNA and protein are induced after ischemia-reperfusion injury. MCUb overexpressing mice demonstrated inhibited mitochondrial Ca 2+ uptake in cardiomyocytes and partial protection from ischemia-reperfusion injury by reducing mitochondrial permeability transition pore opening. Antithetically, deletion of the Mcub gene exacerbated pathological cardiac remodeling and infarct expansion after ischemic injury in association with greater mitochondrial Ca 2+ uptake. Furthermore, hindlimb remote ischemic preconditioning induced MCUb expression in the heart, which was associated with decreased mitochondrial Ca 2+ uptake, collectively suggesting that induction of MCUb protein in the heart is protective. Similarly, mouse embryonic fibroblasts from Mcub −/− mice were more sensitive to Ca 2+ overload. Conclusions: Our studies suggest that Mcub is a protective cardiac inducible gene that reduces mitochondrial Ca 2+ influx and permeability transition pore opening after ischemic injury to reduce ongoing pathological remodeling." @default.
- W3016938385 created "2020-04-24" @default.
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- W3016938385 date "2020-07-17" @default.
- W3016938385 modified "2023-10-15" @default.
- W3016938385 title "MCUb Induction Protects the Heart From Postischemic Remodeling" @default.
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- W3016938385 doi "https://doi.org/10.1161/circresaha.119.316369" @default.
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