Mitochondrial calcium ([Ca
2+
]
m
) is essential for cardiomyocyte viability, and aberration of [Ca
2+
]
m
is known to elicit multiple cardiac stress conditions associated with ATP depletion, reactive oxygen species, and mitochondrial permeability transition pore opening, all of which can lead to metabolic stress and the loss of dysfunctional mitochondria by aberrant autophagy. Elucidating the regulatory role of
m
itochondrial
c
alcium
u
niporter (MCU)-mediated [Ca
2+
]
m
in modulating cardiac mitochondrial bioenergetics and autophagy has high significance and clinical impact for many pathophysiological processes. [Ca
2+
]
m
is exquisitely controlled by the inner mitochondrial membrane uniporter, transporters, regulators and exchangers including MCU, MCUR1, EMRE, MICU1, MICU2 and LETM1. Our recently published findings revealed that Mitochondrial Ca
2+
Uniporter Regulator 1 (MCUR1) serves as a scaffold factor for uniporter complex assembly. We found that deletion of MCUR1 impaired [Ca
2+
]
m
uptake, mitochondrial Ca
2+
current (
I
MCU
) and mitochondrial bioenergetics and is associated with increased autophagy. Our new findings indicate that the impairment of [Ca
2+
]
m
uptake exacerbated autophagy following ischemia-reperfusion (I/R) injury. In support of our mouse model, human failing hearts show that MCUR1 protein levels are markedly decreased and autophagy markers are increased, demonstrating a crucial link between [Ca
2+
]
m
uptake and autophagy during heart failure. Additionally, our results reveal that either oxidation or disruption of human MCU Cys-97 (in mouse Cys-96; gain-of-function MCU
C96A
mutant) produces a conformational change within the N terminal β-grasp fold of MCU which promotes higher-order MCU complex assembly and increased
I
MCU
activity and mitochondrial ROS levels. The results of our studies using a novel cardiac-specific MCUR1-KO model and a constitutively active global MCU
C96A
KI mouse model (CRISPR-Cas9 genome edited) elucidate the regulatory role of [Ca
2+
]
m
in cardiac bioenergetics and autophagy during oxidative stress and myocardial infarction. Thus, targeting assembly and the activity of MCU complex will offer a new potential therapeutic target in the treatment of cardiomyopathy and heart failure.
Pathophysiological role of oxidative stress in systolic and diastolic heart failure and its therapeutic implications
