Mitochondria play a critical role in the regulation of myocardial metabolism and function. Diminished insulin-activated Akt translocation into mitochondria matrix contributed to the development of diabetic cardiomyopathy. However, its mechanisms of actions are not fully understood. Using an inducible heart specific transgenic mice harboring a mitochondria-targeting dominant Akt (CAMDAKT), we have observed 50% attenuation of pyruvate dehydrogenase activity in mitochondria. Proteomic study revealed insulin injection promoted formation of pyruvate dehydrogenase supercomplex in the control mice, however, insulin-stimulated formation of pyruvate dehydrogenase supercomplex was inhibited in the CAMDAKT mice. We next used a novel small molecular inhibitor (SMI) to disrupt binding of Akt to the E3 subunit of pyruvate dehydrogenase to dissect how active Akt interacted and modulated pyruvate dehydrogenase complex (PDC). Insulin stimulation of PDC activity and complex formation were inhibited by the SMI. Acetyl-CoA, which bridges PDC to the TCA cycle, was significantly reduced by 40% in the cardiac mitochondria of CAMDAKT mice. Interestingly, this was accompanied by reduced NAD+ and NADH levels (40-50% reduction) and NAD+/NADH ratio (30-40% reduction). Therefore the redox state was compromised. In CAMDAKT mice, cardiac mitochondria underwent adaptive changes once mitochondrial Akt became inhibited, with biphasic alteration of mitochondria abundance (up and down). The expression of PPARγ and PGC1α, showed a similar pattern of changes, suggesting compensatory mitochondria biogenesis.

In summary, mitochondrial Akt action in the heart is at least partially mediated through its direct interaction with the E3 subunit of PDC, and inhibition of this pathway led to metabolic remodeling and compensatory mitochondria biogenesis. These data shed new light into the mechanism of mitochondrial Akt actions and how it modulated cardiac metabolism.


Y. Chen: None. Y. Chen: None. A. Ta: None. H. Lee: None. H. Lin: None. P.H. Wang: None.

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