Mitochondria are dynamic organelles that undergo continual fusion and fission to maintain their morphology and functions, but the mechanism involved is still not clear. Here, we investigated the effect of mitochondrial oxidative stress triggered by high‐fluence low‐power laser irradiation (HF‐LPLI) on mitochondrial dynamics in human lung adenocarcinoma cells (ASTC‐a‐1) and African green monkey SV40‐transformed kidney fibroblast cells (COS‐7). Upon HF‐LPLI‐triggered oxidative stress, mitochondria displayed a fragmented structure, which was abolished by exposure to dehydroascorbic acid, a reactive oxygen species scavenger, indicating that oxidative stress can induce mitochondrial fragmentation. Further study revealed that HF‐LPLI caused mitochondrial fragmentation by inhibiting fusion and enhancing fission. Mitochondrial translocation of the profission protein dynamin‐related protein 1 (Drp1) was observed following HF‐LPLI, demonstrating apoptosis‐related activation of Drp1. Notably, overexpression of Drp1 increased mitochondrial fragmentation and promoted HF‐LPLI‐induced apoptosis through promoting cytochrome c release and caspase‐9 activation, whereas overexpression of mitofusin 2 (Mfn2), a profusion protein, caused the opposite effects. Also, neither Drp1 overexpression nor Mfn2 overexpression affected mitochondrial reactive oxygen species generation, mitochondrial depolarization, or Bax activation. We conclude that mitochondrial oxidative stress mediated through Drp1 and Mfn2 causes an imbalance in mitochondrial fission–fusion, resulting in mitochondrial fragmentation, which contributes to mitochondrial and cell dysfunction.

Metformin is a widely used antidiabetic drug that exerts cardiovascular protective effects in patients with diabetes. How metformin protects against diabetes-related cardiovascular diseases remains poorly understood. Here, we show that metformin abated the progression of diabetes-accelerated atherosclerosis by inhibiting mitochondrial fission in endothelial cells. Metformin treatments markedly reduced mitochondrial fragmentation, mitigated mitochondrial-derived superoxide release, improved endothelial-dependent vasodilation, inhibited vascular inflammation, and suppressed atherosclerotic lesions in streptozotocin (STZ)-induced diabetic ApoE−/− mice. In high glucose–exposed endothelial cells, metformin treatment and adenoviral overexpression of constitutively active AMPK downregulated mitochondrial superoxide, lowered levels of dynamin-related protein (Drp1) and its translocation into mitochondria, and prevented mitochondrial fragmentation. In contrast, AMPK-α2 deficiency abolished the effects of metformin on Drp1 expression, oxidative stress, and atherosclerosis in diabetic ApoE−/−/AMPK-α2−/− mice, indicating that metformin exerts an antiatherosclerotic action in vivo via the AMPK-mediated blockage of Drp1-mediated mitochondrial fission. Consistently, mitochondrial division inhibitor 1, a potent and selective Drp1 inhibitor, reduced mitochondrial fragmentation, attenuated oxidative stress, ameliorated endothelial dysfunction, inhibited inflammation, and suppressed atherosclerosis in diabetic mice. These findings show that metformin attenuated the development of atherosclerosis by reducing Drp1-mediated mitochondrial fission in an AMPK-dependent manner. Suppression of mitochondrial fission may be a therapeutic approach for treating macrovascular complications in patients with diabetes.

Background FUN14 domain containing 1 (FUNDC1) is a highly conserved outer mitochondrial membrane protein. The aim of this study is to examine if FUNDC1 modulates the mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs), mitochondrial morphology, and function in cardiomyocytes and in intact hearts. Methods The impacts of FUNDC1 on MAMs formation and cardiac functions were studied in mouse neonatal cardiomyocytes, in mice with cardiomyocyte-specific Fundc1 gene knockout (Fundc1f/Y/CreαMyHC+/−), and in the cardiac tissues of the patients with heart failure. Results In mouse neonatal cardiomyocytes and intact hearts, FUNDC1 was localized in MAMs by binding to ER-resided inositol 1,4,5-trisphosphate type 2 receptor (IP3R2). Fundc1 ablation disrupted MAMs, reduced the levels of IP3R2 and Ca2+ in both mitochondria and cytosol whereas overexpression of Fundc1 increased the levels of IP3R2 and Ca2+ in both mitochondria and cytosol. Consistently, Fundc1 ablation increased Ca2+ levels in ER whereas Fundc1 overexpression lowered ER Ca2+ levels. Further, Fundc1 ablation in cardiomyocytes elongated mitochondria, and compromised mitochondrial functions. Mechanistically, we found that Fundc1 ablation-induced reduction of intracellular Ca2+ levels suppressed mitochondrial fission 1 protein (Fis1) expression and mitochondrial fission by reducing the binding of the cAMP response element binding protein (CREB) in the Fis1 promoter. Fundc1f/Y/CreαMyHC+/− mice but not their littermate control mice (Fundc1wt/Y/CreαMyHC+/−) exhibited cardiac dysfunction. The ligation of the left ventricle artery of Fundc1f/Y/CreαMyHC+/− mice caused more severe cardiac dysfunction than those in sham-treated Fundc1f/Y/CreαMyHC+/− mice. Finally, we found that the FUNDC1/MAMs/CREB/Fis1 signaling axis was significantly suppressed in the patients with heart failure. Conclusions We conclude that FUNDC1 binds to IP3R2 to modulate ER Ca2+ release into mitochondria and cytosol and that a disruption of FUNDC1 and IP3R2 interaction lowers the levels of Ca2+ in mitochondria and cytosol, both of which instigate aberrant mitochondrial fission, mitochondrial dysfunction, cardiac dysfunction, and heart failure.