Mitochondrial fusion promoter restores mitochondrial dynamics balance and ameliorates diabetic cardiomyopathy in an optic atrophy 1‐dependent way

Abstract

Aim: Imbalanced mitochondrial dynamics including suppressed mitochondrial fusion has been observed in diabetic hearts. However, it is still unknown whether mitochondrial fusion promoter is an effective protection to diabetic hearts. This study was designed to explore the efficacy of mitochondrial fusion promoter on diabetic cardiomyopathy (DCM). Methods: Male Sprague-Dawley rats were injected with streptozotocin (STZ, 65 mg/kg/d) intraperitoneally to induce diabetes. Seven weeks after vehicle or STZ injection, control or diabetic rats were treated with the vehicle or a mitochondrial fusion promoter-M1 (2 mg/kg/d) intraperitoneally for 6 weeks. Moreover, M1 was administrated to the primary cardiomyocytes cultured in normal glucose medium (NG, 5.5 mmol/L) or high glucose (HG, 33 mnol/L). Results: Administration of M1 significantly promoted mitochondrial fusion and attenuated the reduction in optic atrophy 1 (Opa1) expression in diabetic hearts. Importantly, M1 treatment attenuated oxidative stress, improved mitochondrial function and alleviated DCM in diabetic rats. In HG-treated cardiomyocytes, M1 treatment consistently increased the expression of Opa1, promoted mitochondrial fusion, enhanced mitochondrial respiratory capacity and reduced mitochondria-derived superoxide production, all of which were blunted by Opa1 siRNA knockdown. In addition, selective upregulation of Opa1 alone can also promote mitochondrial fusion, improve mitochondrial function and inhibit mitochondria-derived superoxide production in HG-cultured cardiomyocytes. Conclusion: Our findings show for the first time that mitochondrial fusion promoter M1 effectively balances mitochondrial dynamics and protects against diabetic cardiomyopathy (DCM) via an Opa1-dependent way, suggesting that promoting mitochondrial fusion might be a potential therapeutic strategy for DCM. K E Y W O R D Sdiabetes, diabetic cardiomyopathy, mitochondrial fusion, Opa1, oxidative stress 2 of 14 | DING et al.

Harnessing the protective role of OPA1 in diabetic cardiomyopathy

“…OPA1 is recognized as an important regulator of apoptosis through cristae remodelling and cytochrome c release 4 . In agreement, Ding et al 2 report increased reactive oxygen species (ROS) production and apoptosis in the diabetic heart, which is ameliorated by M1 treatment. In their study, these effects were mediated by OPA1 and there were no changes in the levels of the other fusion and fission proteins.…”

“…Thus, its deficiency can contribute to impaired bioenergetics in the heart and the progressive loss of contractile function in heart failure. Although Ding et al 2 did not find Mitofusin 2 levels to be markedly different in hearts from diabetic mice, nor was this altered through enhanced M1‐mediated fusion, improved cardiac contractility following M1 treatment and the restoration of OPA1 supports the significance of mitochondrial morphology for cardiac function. Thus, the interplay between the SR and mitochondria in the myocardium remains a question to be addressed through future studies.…”

“…However, fragmentation also commonly occurs prior to apoptosis, or may indicate abrogated mitochondrial quality control. In their study, Ding et al 2 demonstrate that increased mitochondrial fragmentation, due to OPA1 deficiency, is an underlying cause of cardiac dysfunction in hearts of STZ‐induced diabetic rats. Following M1 treatment in diabetic rats, they also report improvements in mitochondrial dynamics and cardiac function, associated with restored levels of OPA1.…”

“…OPA1 is associated with a wide range of pathologies in which mitochondrial dysfunction occurs, including neurodegenerative and cardiac diseases, as well as primary mitochondrial diseases such as dominant optic atrophy, Behr syndrome and Leigh‐like syndrome. In this issue of Acta Physiologica , Ding et al 2 report that OPA1 plays a role in mitigating the progression of diabetic cardiomyopathy. In their study, Ding et al demonstrate that increased mitochondrial fragmentation due to OPA1 deficiency may be an underlying cause of cardiac dysfunction in hearts of streptozotocin (STZ)‐induced diabetic rats.…”

“…A hallmark of diabetic cardiomyopathy is diastolic dysfunction (left ventricular stiffness and impaired relaxation) 3 . Ding et al 2 demonstrate marked diastolic dysfunction in the STZ‐diabetic rat heart, in the absence of dilation, and likewise improvement in diastolic function following OPA1‐targeted treatment. These findings confirm the significance of impaired mitochondrial homeostasis in the progression of cardiac dysfunction, in the setting of type 1 diabetes.…”