Mitochondrial fusion promoter restores mitochondrial dynamics balance and ameliorates diabetic cardiomyopathy in an optic atrophy 1-dependent way
Mitochondrial fusion promoter restores mitochondrial dynamics balance and ameliorates diabetic cardiomyopathy in an optic atrophy 1-dependent way
复制标题
线粒体融合启动子以视神经萎缩1依赖性方式恢复线粒体动力学平衡并改善糖尿病心肌病
DOI：
10.1111/apha.13428
复制
发表时间：
2020-01-22
影响因子：
6.3
通讯作者：
Mi, Mantian
中科院分区：
文献类型：
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作者：
Ding, Mingge;Liu, Chaoyang;Mi, Mantian
目的糖尿病心肌线粒体动力学失衡，包括线粒体融合抑制。然而，线粒体融合启动子是否对糖尿病心脏有保护作用尚不清楚。本研究旨在探讨线粒体融合促进剂对糖尿病心肌病（DCM）的治疗作用。方法雄性SD大鼠腹腔注射链脲佐菌素（STZ，65 mg/kg/d）诱导糖尿病模型。在媒介物或STZ注射后7周，对照或糖尿病大鼠用媒介物或线粒体融合促进剂-M1（2 mg/kg/d）腹膜内处理6周。此外，将M1给予在正常葡萄糖培养基（NG，5.5mmol/L）或高糖培养基（HG，33 mmol/L）中培养的原代心肌细胞。结果给予M1可显著促进糖尿病心肌线粒体融合，减轻视神经萎缩1（Opa 1）表达的减少。重要的是，M1治疗减轻了糖尿病大鼠的氧化应激，改善了线粒体功能并缓解了DCM。在HG处理的心肌细胞中，M1处理持续增加Opa 1的表达，促进线粒体融合，增强线粒体呼吸能力，减少线粒体源性超氧化物的产生，所有这些都被Opa 1 siRNA敲低所减弱。此外，单独选择性上调Opa 1也可以促进线粒体融合，改善线粒体功能，并抑制HG培养的心肌细胞中线粒体衍生的超氧化物的产生。结论线粒体融合启动子M1可有效平衡线粒体动力学，并通过依赖Opa 1的方式对糖尿病心肌病（DCM）起保护作用，提示促进线粒体融合可能是DCM的潜在治疗策略。
Aim Imbalanced mitochondrial dynamic 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 inhibited 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.