Junnan Xu

Optic atrophy 1 (OPA1)-related mitochondrial fusion and mitophagy are vital to sustain mitochondrial homeostasis under stress conditions. However, no study has confirmed whether OPA1-related mitochondrial fusion/mitophagy is activated by melatonin and, consequently, attenuates cardiomyocyte death and mitochondrial stress in the setting of cardiac ischemia-reperfusion (I/R) injury. Our results indicated that OPA1, mitochondrial fusion, and mitophagy were significantly repressed by I/R injury, accompanied by infarction area expansion, heart dysfunction, myocardial inflammation, and cardiomyocyte oxidative stress. However, melatonin treatment maintained myocardial function and cardiomyocyte viability, and these effects were highly dependent on OPA1-related mitochondrial fusion/mitophagy. At the molecular level, OPA1-related mitochondrial fusion/mitophagy, which was normalized by melatonin, substantially rectified the excessive mitochondrial fission, promoted mitochondria energy metabolism, sustained mitochondrial function, and blocked cardiomyocyte caspase-9-involved mitochondrial apoptosis. However, genetic approaches with a cardiac-specific knockout of OPA1 abolished the beneficial effects of melatonin on cardiomyocyte survival and mitochondrial homeostasis in vivo and in vitro. Furthermore, we demonstrated that melatonin affected OPA1 stabilization via the AMPK signaling pathway and that blockade of AMPK repressed OPA1 expression and compromised the cardioprotective action of melatonin. Overall, our results confirm that OPA1-related mitochondrial fusion/mitophagy is actually modulated by melatonin in the setting of cardiac I/R injury. Moreover, manipulation of the AMPK-OPA1-mitochondrial fusion/mitophagy axis via melatonin may be a novel therapeutic approach to reduce cardiac I/R injury.

Mitochondrial fusion is linked to heart and liver ischemia-reperfusion (IR) insult. Unfortunately, there is no report to elucidate the detailed influence of mitochondrial fusion in renal IR injury. This study principally investigated the mechanism by which mitochondrial fusion protected kidney against IR injury. Our results indicated that sirtuin 3 (Sirt3) was inhibited after renal IR injury in vivo and in vitro. Overexpression of Sirt3 improved kidney function, modulated oxidative injury, repressed inflammatory damage, and reduced tubular epithelial cell apoptosis. The molecular investigation found that Sirt3 overexpression attenuated IR-induced mitochondrial damage in renal tubular epithelial cells, as evidenced by decreased reactive oxygen species production, increased antioxidants sustained mitochondrial membrane potential, and inactivated mitochondria-initiated death signaling. In addition, our information also illuminated that Sirt3 maintained mitochondrial homeostasis against IR injury by enhancing optic atrophy 1 (OPA1)-triggered fusion of mitochondrion. Inhibition of OPA1-induced fusion repressed Sirt3 overexpression-induced kidney protection, leading to mitochondrial dysfunction. Further, our study illustrated that OPA1-induced fusion could be affected through ERK; inhibition of ERK abolished the regulatory impacts of Sirt3 on OPA1 expression and mitochondrial fusion, leading to mitochondrial damage and tubular epithelial cell apoptosis. Altogether, our results suggest that renal IR injury is closely associated with Sirt3 downregulation and mitochondrial fusion inhibition. Regaining Sirt3 and/or activating mitochondrial fission by modifying the ERK-OPA1 cascade may represent new therapeutic modalities for renal IR injury.

Dysregulated activation of the cyclin-dependent kinases (CDKs) 4/6, leading to uncontrolled cell division, is hallmark of cancers. Further study of the cell cycle will advance the cancer treatment. As powerful and effective drugs, inhibitors of CDK 4/6 have been widely used in clinical practice for several malignancies, particularly against breast cancers driven by the estrogen receptor (ER). Three CDK4/6 inhibitors, including palbociclib (PD0332991), ribociclib (LEE011) and abemaciclib (LY2835219), have been approved by the US Food and Drug Administration (FDA) for the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer. However, CDK4/6 inhibitors act downstream of many mitogenic signaling pathways, and this has implications for resistance. It is worth to note that the mechanisms of resistance are not very clear. Up to now, a small number of preclinical and clinical studies have explored potential mechanisms of CDK4/6 inhibitors resistance in breast cancer. On this basis, rational and effective combination therapy is under development. Here we review the current knowledge about the mechanisms and efficacy of CDK4/6 inhibitors, and summarize data on resistance mechanisms to make future combination therapies more accurate and reasonable.