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Ncor2/PPARα-dependent upregulation of MCUb in the type 2 diabetic heart impacts cardiac metabolic flexibility and function

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posted on 10.12.2020, 18:19 by Ada Admin, Federico Cividini, Brian T Scott, Jorge Suarez, Darren E. Casteel, Sven Heinz, Anzhi Dai, Tanja Diemer, Jorge A Suarez, Christopher W Benner, Majid Ghassemian, Wolfgang H Dillmann
The contribution of altered mitochondrial Ca2+ handling to metabolic and functional defects in type 2 diabetic (T2D) mouse hearts is not well understood. Here, we show that the T2D heart is metabolically inflexible and almost exclusively dependent on mitochondrial fatty acid oxidation as a consequence of mitochondrial calcium uniporter complex (MCUC) inhibitory subunit MCUb overexpression. Using a recombinant endonuclease-deficient Cas9 (dCas9)-based gene promoter pull-down approach coupled with mass spectrometry we found that MCUb is upregulated in the T2D heart due to loss of glucose homeostasis regulator nuclear receptor co-repressor 2 (Ncor2) repression, and ChIP assays identified PPARα as a mediator of MCUb gene expression in T2D cardiomyocytes. Upregulation of MCUb limits mitochondrial matrix Ca2+ uptake and impairs mitochondrial energy production via glucose oxidation, by depressing Pyruvate Dehydrogenase Complex (PDC) activity. Gene therapy displacement of endogenous MCUb with a dominant-negative MCUb transgene (MCUbW246R/V251E) in vivo rescued T2D cardiomyocytes from metabolic inflexibility, and stimulated cardiac contractile function and adrenergic responsiveness by enhancing phospholamban (PLN) phosphorylation via Protein Kinase A (PKA). We conclude that MCUb represents one newly-discovered molecular effector at the interface of metabolism and cardiac function, and its repression improves the outcome of the chronically-stressed diabetic heart.

Funding

This work was supported by Merit Review Award BX003429 from the VHA Office of Research and Development (to W.H.D.); the P. Robert Majumder Charitable Foundation; the University of California Institute for Mexico and the United States (UC MEXUS)-Consejo Nacional de Ciencia y Tecnología (CONACYT) Grant CN 19-157 (to W.H.D.). Imaging studies were supported by National Institutes of Health grant NS047101 (to the University of California, San Diego Neuroscience Microscopy Imaging Core).

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