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Characterizing the function of MCUb as an inducible activator of mitochondrial oxidative phosphorylation

ABSTRACT: Influx of Ca2+ across the inner mitochondrial membrane via the mitochondrial Ca2+ uniporter (MCU) enhances the activity of several electron transport chain dehydrogenases and the F1F0 ATP synthase. In this study, we investigated the role of MCUb, an MCU complex gene product that is a direct inhibitor of MCU mediated Ca2+ influx. We find MCUb expression to be induced by caloric restriction in heart, skeletal muscle, liver and kidney where it functions as a metabolic activator of mitochondrial fatty acid utilization. Mice selectively deficient for Mcub in skeletal muscle showed a metabolic signature of deficient fatty acid utilization in muscle, associated with progressive age-related obesity, glucose intolerance and metabolic syndrome. To define transcriptional changes underlying, and potentially contributing to this regulation of Ca2+-dependent mitochondrial fatty acid utilization, microarray analyses of tibialis anterior (TA) muscle from control and knockout mice was carried out. We used microarrays to elucidate effects of MCU and MCUb ablation on transcriptional profiles of TA muscle

ORGANISM(S): Mus musculus

PROVIDER: GSE205193 | GEO | 2023/11/07

REPOSITORIES: GEO

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Project description:Chronic low-grade inflammation is a hallmark of aging, but its etiology is not well understood. Mitochondrial dysfunction has been linked to both cellular senescence and age-related inflammation or inflammaging but fundamental mechanisms underlying these links are unclear. We analyzed age-related gene expression in different human tissues and discovered that in blood, the mRNA expression of Mitochondrial Calcium Uniporter (MCU) and its regulatory subunit MICU1 correlated inversely with age. MCU is the pore-forming subunit of a Ca2+-selective ion channel complex residing in the mitochondrial inner membrane and is the main conduit for Ca2+-influx into the mitochondrial matrix. Based on these findings we tested the simple hypothesis that mitochondrial Ca2+ uptake capacity of macrophages decreases with age. We found a significant reduction in the mitochondrial Ca2+-uptake capacity of macrophages derived from aged (80-90 weeks) mice. Notably, these macrophages display amplified cytosolic Ca2+ elevations and increased inflammatory output. To test the salience of mitochondrial calcium uptake in regulating macrophage inflammatory output, we deleted Mcu selectively in macrophages. The Mcu-/- macrophages of young mice (<25 weeks) express more inflammatory genes at baseline and show a hyper-inflammatory response when stimulated. We show that reduced mitochondrial Ca2+ amplifies cytosolic Ca2+ oscillations and potentiates downstream NFkB activation, which is central to inflammation. The regulation of inflammatory response by mitochondrial Ca2+ uptake is also seen readily in human macrophages. The siRNA-mediated knockdown of MCU in human blood derived macrophages recapitulates the phenomenon – the mitochondrial Ca2+-uptake is greatly reduced, cytosolic Ca2+ elevations are more pronounced, and the macrophages are hyper-inflammatory. Our findings pinpoint the MCU complex as a keystone molecular apparatus that links age-related changes in mitochondrial physiology to macrophage-mediated inflammation. Resident macrophages are intrinsic to every organ system and the steady erosion of their mitochondrial Ca2+-uptake capacity may play a germinal or exacerbating role in many age-related neurodegenerative, cardiometabolic, renal and musculoskeletal diseases that afflict us.

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Characterizing the function of MCUb as an inducible activator of mitochondrial oxidative phosphorylation

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