Mitochondrial NAD + /NADH redox state and diabetic cardiomyopathy

Jessica M. Berthiaume, Jacob G. Kurdys, Danina M. Muntean, Mariana G. Rosca

Research output: Contribution to journalReview articlepeer-review

60 Scopus citations

Abstract

Significance: Diabetic cardiomyopathy (DCM) is a frequent complication occurring even in well-controlled asymptomatic diabetic patients, and it may advance to heart failure (HF). Recent Advances: The diabetic heart is characterized by a state of "metabolic rigidity" involving enhanced rates of fatty acid uptake and mitochondrial oxidation as the predominant energy source, and it exhibits mitochondrial electron transport chain defects. These alterations promote redox state changes evidenced by a decreased NAD + /NADH ratio associated with an increase in acetyl-CoA/CoA ratio. NAD + is a co-substrate for deacetylases, sirtuins, and a critical molecule in metabolism and redox signaling; whereas acetyl-CoA promotes protein lysine acetylation, affecting mitochondrial integrity and causing epigenetic changes. Critical Issues: DCM lacks specific therapies with treatment only in later disease stages using standard, palliative HF interventions. Traditional therapy targeting neurohormonal signaling and hemodynamics failed to improve mortality rates. Though mitochondrial redox state changes occur in the heart with obesity and diabetes, how the mitochondrial NAD + /NADH redox couple connects the remodeled energy metabolism with mitochondrial and cytosolic antioxidant defense and nuclear epigenetic changes remains to be determined. Mitochondrial therapies targeting the mitochondrial NAD + /NADH redox ratio may alleviate cardiac dysfunction. Future Directions: Specific therapies must be supported by an optimal understanding of changes in mitochondrial redox state and how it influences other cellular compartments; this field has begun to surface as a therapeutic target for the diabetic heart. We propose an approach based on an alternate mitochondrial electron transport that normalizes the mitochondrial redox state and improves cardiac function in diabetes.

Original languageEnglish
Pages (from-to)375-398
Number of pages24
JournalAntioxidants and Redox Signaling
Volume30
Issue number3
DOIs
StatePublished - Jan 20 2019

Keywords

  • NAD
  • NADH
  • cardiomyopathy
  • diabetes
  • mitochondria
  • redox balance

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