Expression of the mitochondrial calcium uniporter in cardiac myocytes improves impaired mitochondrial calcium handling and metabolism in simulated hyperglycemia.
Diabetic cardiomyopathy is associated with metabolic changes, including decreased glucose oxidation (Gox) and increased fatty acid oxidation (FAox), which result in cardiac energetic deficiency. Diabetic hyperglycemia is a pathophysiological mechanism that triggers multiple maladaptive phenomena. The mitochondrial Ca2+uniporter (MCU) is the channel responsible for Ca2+uptake in mitochondria, and free mitochondrial Ca2+concentration ([Ca2+]m) regulates mitochondrial metabolism. Experiments with cardiac myocytes (CM) exposed to simulated hyperglycemia revealed reduced [Ca2+]mand MCU protein levels. Therefore, we investigated whether returning [Ca2+]mto normal levels in CM by MCU expression could lead to normalization of Gox and FAox with no detrimental effects. Mouse neonatal CM were exposed for 72 h to normal glucose [5.5 mM glucose + 19.5 mM mannitol (NG)], high glucose [25 mM glucose (HG)], or HG + adenoviral MCU expression. Gox and FAox, [Ca2+]m, MCU levels, pyruvate dehydrogenase (PDH) activity, oxidative stress, mitochondrial membrane potential, and apoptosis were assessed. [Ca2+]mand MCU protein levels were reduced after 72 h of HG. Gox was decreased and FAox was increased in HG, PDH activity was decreased, phosphorylated PDH levels were increased, and mitochondrial membrane potential was reduced. MCU expression returned these parameters toward NG levels. Moreover, increased oxidative stress and apoptosis were reduced in HG by MCU expression. We also observed reduced MCU protein levels and [Ca2+]min hearts from type 1 diabetic mice. Thus we conclude that HG-induced metabolic alterations can be reversed by restoration of MCU levels, resulting in return of [Ca2+]mto normal levels.
Department of Medicine, University of California, San Diego, La Jolla, California; and.|Department of Pharmacology, Instituto Nacional de Cardiología Ignacio Chávez, Tlalpan, México, Mexico.
Julieta
J
Diaz-Juarez
Department of Medicine, University of California, San Diego, La Jolla, California; and.
Jorge
J
Suarez
Department of Medicine, University of California, San Diego, La Jolla, California; and.
Federico
F
Cividini
Department of Medicine, University of California, San Diego, La Jolla, California; and.
Brian T
BT
Scott
Department of Medicine, University of California, San Diego, La Jolla, California; and.
Tanja
T
Diemer
Department of Medicine, University of California, San Diego, La Jolla, California; and.
Anzhi
A
Dai
Department of Medicine, University of California, San Diego, La Jolla, California; and wdillmann@ucsd.edu.
Wolfgang H
WH
Dillmann
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006943:Hyperglycemia / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology
D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D027682:Cation Transport Proteins; C034703:mitochondrial calcium uniporter; D005947:Glucose; D002118:Calcium
O-GlcNAcylation; cardic myocytes; glucose toxicity; mitochondrial Ca2+ uniporter; mitochondrial calcium
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