Insulin Stimulates Mitochondrial Fusion and Function in Cardiomyocytes via the Akt-mTOR-NFκB-Opa-1 Signaling Pathway

Abstract

Insulin regulates heart metabolism through the regulation of insulin-stimulated glucose uptake. Studies have indicated that insulin can also regulate mitochondrial function. Relevant to this idea, mitochondrial function is impaired in diabetic individuals. Furthermore, the expression of Opa-1 and mitofusins, proteins of the mitochondrial fusion machinery, is dramatically altered in obese and insulin-resistant patients. Given the role of insulin in the control of cardiac energetics, the goal of this study was to investigate whether insulin affects mitochondrial dynamics in cardiomyocytes. Confocal microscopy and the mitochondrial dye MitoTracker Green were used to obtain three-dimensional images of the mitochondrial network in cardiomyocytes and L6 skeletal muscle cells in culture. Three hours of insulin treatment increased Opa-1 protein levels, promoted mitochondrial fusion, increased mitochondrial membrane potential, and elevated both intracellular ATP levels and oxygen consumption in cardiomyocytes in vitro and in vivo. Consequently, the silencing of Opa-1 or Mfn2 prevented all the metabolic effects triggered by insulin. We also provide evidence indicating that insulin increases mitochondrial function in cardiomyocytes through the Akt-mTOR-NFκB signaling pathway. These data demonstrate for the first time in our knowledge that insulin acutely regulates mitochondrial metabolism in cardiomyocytes through a mechanism that depends on increased mitochondrial fusion, Opa-1, and the Akt-mTOR-NFκB pathway.

Mitochondrial fission is required for cardiomyocyte hypertrophy via a Ca2+-calcineurin signalling pathway

“…Three-dimensional images were obtained by confocal microscopy and then the Z-stacks of the thresholded images were volume-reconstituted as previously described (Parra et al, 2008;Parra et al, 2014). Our results showed that after 24 h, norepinephrine-treated cells presented a less connected mitochondrial network consistent with increased mitochondrial fission (Fig.…”

OPA1 in Cardiovascular Health and Disease

“…The effect of OPA1 on mitochondrial function was shown to be mediated by the activation of the Akt-mTOR-NFκB pathway in a manner which was shown to be dependent on OPA1 (66). The physiological significance of this effect of insulin on mitochondrial morphology and metabolism is unclear and remains to be investigated.…”

“…Parra et al (66) have reported in neonatal rat cardiomyocytes that treatment with insulin increased OPA1 protein levels, induced mitochondrial fusion, increased mitochondrial membrane potential, and augmented both intracellular ATP levels and oxygen consumption. The effect of OPA1 on mitochondrial function was shown to be mediated by the activation of the Akt-mTOR-NFκB pathway in a manner which was shown to be dependent on OPA1 (66).…”

Regulation of Mitochondrial Dynamics and Cell Fate

“…Consistent with defective insulin signaling in diabetic individuals is concomitant impairment of mitochondrial function and expression of mitochondria fusion proteins Opa-1 and Mfn1/ Mfn2. 58 Further, insulin treatment of cardiomyocytes and skeletal muscle cells increased the expression of Opa-1, and mitochondrial fusion. Notably, the ability of insulin to influence metabolism was impaired in cells deficient for Mfn2 or Opa-1.…”