Elevated MCU Expression by CaMKIIδB Limits Pathological Cardiac Remodeling

Abstract

Background: Calcium (Ca 2+ ) is a key regulator of energy metabolism. Impaired Ca 2+ homeostasis damages mitochondria, causing cardiomyocyte death, pathological hypertrophy, and heart failure. This study investigates the regulation and the role of the mitochondrial Ca 2+ uniporter (MCU) in chronic stress-induced pathological cardiac remodeling. Methods: MCU knockout or transgenic mice were infused with isoproterenol (ISO, 10 mg/kg/day, 4 weeks). Cardiac hypertrophy and remodeling were evaluated by echocardiography and histology. Primary cultured rodent adult cardiomyocytes were treated with ISO (1 nM, 48 hr). Intracellular Ca 2+ handling and cell death pathways were monitored. Adenovirus-mediated gene manipulations were used in vitro . Results: Chronic administration of the β-adrenergic receptor (β-AR) agonist ISO increased the levels of the MCU and the MCU complex in cardiac mitochondria, raising mitochondrial Ca 2+ concentrations, in vivo and in vitro . ISO also upregulated MCU without affecting its regulatory proteins in adult cardiomyocytes. Interestingly, ISO-induced cardiac hypertrophy, fibrosis, contractile dysfunction, and cardiomyocyte death were exacerbated in global MCU knockout (KO) mice. Cardiomyocytes from KO mice or mice overexpressing a dominant negative MCU exhibited defective intracellular Ca 2+ handling and activation of multiple cell death pathways. Conversely, cardiac-specific overexpression of MCU maintained intracellular Ca 2+ homeostasis and contractility, suppressed cell death, and prevented ISO-induced heart hypertrophy. ISO upregulated MCU expression through activation of Ca 2+ /calmodulin kinase II δB (CaMKIIδB) and promotion of its nuclear translocation via calcineurin-mediated dephosphorylation at serine 332. Nuclear CaMKIIδB phosphorylated cAMP-response element binding protein (CREB), which bound the MCU promotor to enhance MCU gene transcription. Conclusions: The β-AR/CaMKIIδB/CREB pathway upregulates MCU gene expression in the heart. MCU upregulation is a compensatory mechanism that counteracts stress-induced pathological cardiac remodeling by preserving Ca 2+ homeostasis and cardiomyocyte viability.

IGF-1 boosts mitochondrial function by a Ca2+ uptake-dependent mechanism in cultured human and rat cardiomyocytes

“…Ca 2+ allows the real-time adaptation of mitochondrial function to meet energy demands during increased cardiomyocyte workload ( Wescott et al, 2019 ). This occurs even under pathological cardiac remodeling where MCU upregulation sustains mitochondrial and cardiac function and its downregulation exacerbates the pathological phenotype ( Wang et al, 2022 ). This is possible because part of the released Ca 2+ during contraction is absorbed by mitochondria, directly stimulating the activity of the isocitrate and α-ketoglutarate dehydrogenases, and indirectly, the PDH activity, which together will increase ATP synthesis ( Glancy and Balaban, 2012 ).…”

Long non-coding RNA KCND1 protects hearts from hypertrophy by targeting YBX1

“…It is widely accepted that mitochondria provide energy to cells that require a high-energy supply, such as cardiomyocytes. Mitochondrial dysfunction induces cardiomyocyte death, pathological hypertrophy, and heart failure [24] . Thus, targeting mitochondrial function is a new strategy for treating cardiac hypertrophy.…”

The interplay between cardiac dyads and mitochondria regulated the calcium handling in cardiomyocytes

“…Joiner et al (2012) found exogenous expression of a membrane-targeted CaMKII inhibitor in mice was able to mitigate cardiac ischemia-reperfusion injury by inhibiting IMCU. A recent study found cardiac-specific overexpression of MCU maintained intracellular Ca2+ homeostasis and contractility, which is a compensatory mechanism that counteracts stress-induced pathological cardiac remodeling by preserving Ca2+ homeostasis and cardiomyocyte viability (Wang et al, 2022). Metformin can stabilize the structure of MAMs, reduce the expression of MICU1, and lower the amount of mitochondrial Ca2+, which enhances the function of respiration chain complex I in dilated cardiomyopathy (Angebault et al, 2020).…”