Key result
Pharmacological Mcu inhibition ameliorates post-infarction cardiac and mitochondrial dysfunction in preclinical models.
Why the study?
The function and upstream regulatory mechanism of mitochondrial calcium uniporter (Mcu) in myocardial infarction (MI) were unclear, prompting investigation into the pathway controlling post-MI Mcu expression and its potential as a therapeutic target.
Does targeting the Fto-Ythdf2-Mcu regulatory axis or inhibiting Mcu with DS16570511 reduce mitochondrial oxidative stress, cardiomyocyte injury, and post-infarction cardiac dysfunction in myocardial infarction models?
Does targeting the Fto-Ythdf2-Mcu regulatory axis or inhibiting Mcu with DS16570511 reduce mitochondrial oxidative stress, cardiomyocyte injury, and post-infarction cardiac dysfunction in myocardial infarction models?
Answers are grounded in this paper and cite their sources.
Identifies an m6A-dependent Fto-Ythdf2-Mcu regulatory axis in myocardial infarction and demonstrates that pharmacological Mcu inhibition with DS16570511 ameliorates post-infarction cardiac dysfunction in mice.
Mitochondrial calcium uniporter (Mcu) is essential for mitochondrial calcium homeostasis, yet its function and upstream regulatory mechanism in myocardial infarction (MI) remain unclear. This study was designed to define the pivotal regulatory pathway controlling Mcu expression post-MI and verify whether Mcu can act as a therapeutic target for MI. Mendelian randomization was used to verify the genetic link between Mcu and MI. In vitro gain- and loss-of-function assays together with m6A-seq, MeRIP-qPCR, RIP-qPCR and dual-luciferase assays were applied to explore the m6A-dependent regulatory mechanism of Fto/Ythdf2 on Mcu, and the biological effects of this axis on mitochondrial homeostasis and cardiomyocyte injury were validated via cell-based gene interventions. In vivo MI mouse models with cardiomyocyte-specific Fto/Mcu overexpression or DS16570511-mediated pharmacological Mcu inhibition were constructed to detect cardiac function, infarct size, myocardial fibrosis and mitochondrial injury. Our results demonstrated that elevated Mcu is positively associated with MI risk; excess Mcu triggers mitochondrial calcium overload, ROS buildup, mitochondrial membrane potential loss and respiratory chain damage to facilitate cardiomyocyte damage, whereas Mcu knockdown alleviates these pathological alterations. Mechanistically, ischemic injury downregulates Fto to increase m6A modification of Mcu mRNA. Meanwhile, ischemia-suppressed Ythdf2 expression impairs its binding to Mcu mRNA, which enhances Mcu mRNA stability and translation efficiency and leads to Mcu upregulation. Both Fto and Ythdf2 overexpression counteract Mcu-induced mitochondrial dysfunction and cardiomyocyte damage. In vivo experiments further confirmed that specific Mcu overexpression partially offsets Fto-mediated cardioprotection, and the Mcu inhibitor DS16570511 significantly ameliorates post-infarction cardiac dysfunction. In conclusion, Mcu aggravates ischemic myocardial damage by disturbing mitochondrial calcium balance, and we newly identify an Fto-Ythdf2-Mcu regulatory axis, providing a promising therapeutic target for MI.
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Chen et al. (2026) studied Myocardial infarction (MI). Cardiomyocyte-specific Fto/Mcu overexpression, Mcu knockdown, or DS16570511-mediated pharmacological Mcu inhibition was evaluated on Cardiac function, infarct size, myocardial fibrosis, and mitochondrial homeostasis/injury. Pharmacological Mcu inhibition with DS16570511 and Fto/Ythdf2 overexpression ameliorated post-infarction cardiac and mitochondrial dysfunction in mouse and cell models.
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