Rescue of myocardial energetic dysfunction in diabetes through the correction of mitochondrial hyperacetylation by honokiol

Kerr, M; Miller, JJ; Thapa, D; Stiewe, S; Timm, KN; Aparicio, CNM; Scott, I; Tyler, DJ; Heather, LC

Journal article

Rescue of myocardial energetic dysfunction in diabetes through the correction of mitochondrial hyperacetylation by honokiol

Abstract:: Cardiac energetic dysfunction has been reported in patients with type 2 diabetes (T2D) and is an independent predictor of mortality. Identification of the mechanisms driving mitochondrial dysfunction, and therapeutic strategies to rescue these modifications, will improve myocardial energetics in T2D. We demonstrate using 31P-magnetic resonance spectroscopy (31P-MRS) that decreased cardiac ATP and phosphocreatine (PCr) concentrations occurred before contractile dysfunction or a reduction in PCr/ATP ratio in T2D. Real-time mitochondrial ATP synthesis rates and state 3 respiration rates were similarly depressed in T2D, implicating dysfunctional mitochondrial energy production. Driving this energetic dysfunction in T2D was an increase in mitochondrial protein acetylation, and increased ex vivo acetylation was shown to proportionally decrease mitochondrial respiration rates. Treating T2D rats in vivo with the mitochondrial deacetylase SIRT3 activator honokiol reversed the hyperacetylation of mitochondrial proteins and restored mitochondrial respiration rates to control levels. Using 13C-hyperpolarized MRS, respiration with different substrates, and enzyme assays, we localized this improvement to increased glutamate dehydrogenase activity. Finally, honokiol treatment increased ATP and PCr concentrations and increased total ATP synthesis flux in the T2D heart. In conclusion, hyperacetylation drives energetic dysfunction in T2D, and reversing acetylation with the SIRT3 activator honokiol rescued myocardial and mitochondrial energetics in T2D.

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Kerr, M., Miller, J. J., Thapa, D., Stiewe, S., Timm, K. N., Aparicio, C. N. M., Scott, I., Tyler, D. J., & Heather, L. C. (2020). Rescue of myocardial energetic dysfunction in diabetes through the correction of mitochondrial hyperacetylation by honokiol. JCI Insight, 5(17).

MLA Style

Kerr, M., et al. “Rescue of Myocardial Energetic Dysfunction in Diabetes through the Correction of Mitochondrial Hyperacetylation by Honokiol.” JCI Insight, vol. 5, no. 17, Journal of Clinical Investigation, 2020.

Chicago Style

Kerr, M, JJ Miller, D Thapa, S Stiewe, KN Timm, CNM Aparicio, I Scott, DJ Tyler, and LC Heather. 2020. “Rescue of Myocardial Energetic Dysfunction in Diabetes through the Correction of Mitochondrial Hyperacetylation by Honokiol.” JCI Insight 5 (17).
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