Ncor2/PPARα-Dependent Upregulation of MCUb in the Type 2 Diabetic Heart Impacts Cardiac Metabolic Flexibility and Function

Autor: Wolfgang H. Dillmann, Anzhi Dai, Jorge Suarez, Federico Cividini, Christopher Benner, Jorge A. Suarez, Darren E. Casteel, Tanja Diemer, Majid Ghassemian, Sven Heinz, Brian T. Scott
Rok vydání: 2020
Předmět:
0301 basic medicine
Endocrinology
Diabetes and Metabolism
Transgene
030209 endocrinology & metabolism
Inbred C57BL
Cardiovascular
Medical and Health Sciences
Mitochondrial Proteins
Endocrinology & Metabolism
Mice
03 medical and health sciences
0302 clinical medicine
Downregulation and upregulation
Tandem Mass Spectrometry
Diabetes Mellitus
Genetics
Internal Medicine
2.1 Biological and endogenous factors
Animals
Glucose homeostasis
Myocytes
Cardiac
Nuclear Receptor Co-Repressor 2
PPAR alpha
Aetiology
Protein kinase A
Metabolic and endocrine
Nutrition
Myocytes
Chemistry
Myocardium
Diabetes
Membrane Proteins
Pyruvate dehydrogenase complex
Mitochondria
Cell biology
Phospholamban
Mice
Inbred C57BL
Heart Disease
Metabolism
030104 developmental biology
Diabetes Mellitus
Type 2
Mitochondrial matrix
Phosphorylation
Calcium
Cardiac
Oxidation-Reduction
Type 2
Zdroj: Diabetes
Diabetes, vol 70, iss 3
ISSN: 1939-327X
0012-1797
Popis: The contribution of altered mitochondrial Ca2+ handling to metabolic and functional defects in type 2 diabetic (T2D) mouse hearts is not well understood. In this study, 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-based gene promoter pulldown approach coupled with mass spectrometry, we found that MCUb is upregulated in the T2D heart due to loss of glucose homeostasis regulator nuclear receptor corepressor 2 repression, and chromatin immunoprecipitation assays identified peroxisome proliferator–activated receptor α 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 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 phosphorylation via protein kinase A. 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.
Databáze: OpenAIRE
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