Honokiol regulates mitochondrial substrate utilization and cellular fatty acid metabolism in diabetic mice heart.

Type 2 diabetes mellitus is strongly associated with cardiac mitochondrial dysfunction, which is one of the main reasons for cardiovascular diseases. Among the mitochondrial metabolic changes, fatty acid metabolism is of great importance as cardiac tissues depend primarily on fatty acids. Honokiol, a constituent of Magnolia tree bark extract, is reported to strongly influence cardiac mitochondrial functions, via various mechanisms. The current study showed that honokiol decreased fatty acid-mediated complex I respiration and increased carbohydrate-mediated complex I and II respiration in diabetic C57BL/6 mice cardiac mitochondria. It was also found that honokiol treatment decreased expression of Cluster of Differentiation 36, AMP-activated kinases and nuclear transcription factors like, Peroxisome proliferator-activated receptor γ co-activator 1α/ß and Peroxisome proliferator-activated receptor α, surrogating the evidence of decreased fatty acid-mediated complex I respiration. Honokiol treatment also reduced the levels of mitochondrial acetylated proteins, suggesting the possible action of honokiol via acetylation/deacetylation mechanism of regulation of protein functions in diabetic mitochondria. The antioxidant effect of honokiol is evidenced by the augmented expression of Manganese super oxide dismutase. In conclusion, honokiol imparts beneficial effect on diabetic cardiac mitochondria by decreasing the oxidant burden via regulating mitochondrial fatty acid respiration and expression of oxidant response factors.

Impaired substrate-mediated cardiac mitochondrial complex I respiration with unaltered regulation of fatty acid metabolism and oxidative stress status in type 2 diabetic Asian Indians.

BACKGROUND: The cardiovascular complications associated with type 2 diabetes mellitus could be attributed to changes in myocardial mitochondrial metabolism. Though it is a known fact that permeabilized cardiac muscle fibers and isolated mitochondria are metabolically compromised in the Caucasian population, studies of Asian Indian myocardial mitochondrial function are lacking. Thus, the objective of the present study is to analyze if there is altered cardiac mitochondrial substrate utilization in diabetic Asian Indians. METHODS: Mitochondrial substrate utilization was measured using high-resolution respirometry in isolated mitochondria prepared from right atrial appendage tissues of diabetic and nondiabetic subjects undergoing coronary artery bypass graft surgery. Western blotting and densitometric analysis were also done to compare the levels of proteins involved in fatty acid metabolism and regulation. RESULTS: The mitochondrial oxygen consumption rate for fatty acid substrate was shown to be decreased in diabetic subjects compared to nondiabetic subjects along with an unvaried mitochondrial DNA copy number and uniform levels of electron transport chain complex proteins and proteins involved in fatty acid metabolism and regulation. Decreased glutamate but unchanged pyruvate-mediated state 3 respiration were also observed in diabetic subjects. CONCLUSION: The current study reports deranged cardiac mitochondrial fatty acid-mediated complex I respiration in type 2 diabetic Asian Indians with comparable levels of regulators of fatty acid oxidation to that of nondiabetic myocardium. Altered glutamate-mediated mitochondrial respiration also points toward possible alterations in mitochondrial complex I activity. When compared with previous reports on other ethnic populations, the current study suggests that Asian Indian population too have altered cardiac mitochondrial substrate utilization.