Rationale: Mitochondrial Ca2+loading augments oxidative metabolism to match functional demands during times of increased work or injury. However, mitochondrial Ca2+overload also directly causes mitochondrial rupture and cardiomyocyte death during ischemia-reperfusion injury by inducing mitochondrial permeability transition pore opening. The MCU (mitochondrial Ca2+uniporter) mediates mitochondrial Ca2+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 Ca2+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 Ca2+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 Ca2+uptake. Furthermore, hindlimb remote ischemic preconditioning induced MCUb expression in the heart, which was associated with decreased mitochondrial Ca2+uptake, collectively suggesting that induction of MCUb protein in the heart is protective. Similarly, mouse embryonic fibroblasts from Mcub-/-mice were more sensitive to Ca2+overload. Conclusions: Our studies suggest that Mcub is a protective cardiac inducible gene that reduces mitochondrial Ca2+influx and permeability transition pore opening after ischemic injury to reduce ongoing pathological remodeling.
- reperfusion injury
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine