Melatonin activates Parkin translocation and rescues the impaired mitophagy activity of diabetic cardiomyopathy through Mst1 inhibition

Abstract

Mitophagy eliminates dysfunctional mitochondria and thus plays a cardinal role in diabetic cardiomyopathy (DCM). We observed the favourable effects of melatonin on cardiomyocyte mitophagy in mice with DCM and elucidated their underlying mechanisms. Electron microscopy and flow cytometric analysis revealed that melatonin reduced the number of impaired mitochondria in the diabetic heart. Other than decreasing mitochondrial biogenesis, melatonin increased the clearance of dysfunctional mitochondria in mice with DCM. Melatonin increased LC3 II expression as well as the colocalization of mitochondria and lysosomes in HG‐treated cardiomyocytes and the number of typical autophagosomes engulfing mitochondria in the DCM heart. These results indicated that melatonin promoted mitophagy. When probing the mechanism, increased Parkin translocation to the mitochondria may be responsible for the up‐regulated mitophagy exerted by melatonin. Parkin knockout counteracted the beneficial effects of melatonin on the cardiac mitochondrial morphology and bioenergetic disorders, thus abolishing the substantial effects of melatonin on cardiac remodelling with DCM. Furthermore, melatonin inhibited Mammalian sterile 20‐like kinase 1 (Mst1) phosphorylation, thus enhancing Parkin‐mediated mitophagy, which contributed to mitochondrial quality control. In summary, this study confirms that melatonin rescues the impaired mitophagy activity of DCM. The underlying mechanism may be attributed to activation of Parkin translocation via inhibition of Mst1.

Melatonin attenuates doxorubicin‐induced cardiotoxicity through preservation of YAP expression

“…Furthermore, there is evidence suggesting that Mel is able to reduce the infarct area, sustain myocardial function and suppress cardiomyocyte death during cardiac ischaemia‐reperfusion injury . Mel also abrogates diabetic cardiomyopathy, by reducing ROS level and rescuing impaired mitophagy activity . Additional studies also showed Mel being involved in alleviating mitochondrial oxidative damage and apoptosis caused by Dox in cardiomyocytes .…”

“…12,13 Mel also abrogates diabetic cardiomyopathy, by reducing ROS level and rescuing impaired mitophagy activity. 14,15 Additional studies also showed Mel being involved in alleviating mitochondrial oxidative damage and apoptosis caused by Dox in cardiomyocytes. 2,16 However, the exact mechanism mediating this protective effect of Mel on Dox-induced cardiotoxicity remains unclear.…”

Mitophagy in Cardiovascular Diseases

“…[62] Parkin-deficient mice are more sensitive to MI, developing larger infarcts and exhibiting reduced survival. [63] An increase in BNIP3 expression is detected in adult rat hearts with chronic HF.…”

“…In a recent investigation, Wang S. et al reported that mitophagy could be a target of melatonin treatment. Indeed, melatonin inhibits Mst1 phosphorylation, increases LC3-II levels and enhances Parkin-mediated mitochondrial removal to counteract the negative effects of CM [63]. In line with these observations, chronic treatment with metformin (classified as an antidiabetic and a potent inducer of autophagy), heme oxygenase-1 (HO-1) or mitochondrial aldehyde dehydrogenase (ALDH2) prevents CM by activating AMPK, normalizing cardiac autophagic activity, and inhibiting cardiomyocyte apoptosis through stimulation of Mitogen-Activated Protein Kinase 8 (JNK)-Bcl-2 signaling, thereby promoting the disruption of the Bcl-2-Beclin1 complex in diabetic heart tissue [123,134,135].…”

Melatonin: new insights on its therapeutic properties in diabetic complications

“…Melatonin also regulates the activity of mammalian Ste20-like kinase 1 (Mst1)/Sirt3 signaling pathway. Suppression of Mst1 by melatonin contributes to the upregulation of autophagy/Parkin-mediated mitophagy, inhibition of apoptosis and modulation of mitochondrial integrity and biogenesis leading to the alleviation of cardiac remodeling and dysfunction in diabetic mice [86,87]. Table 1 summarizes studies indicating the protective effects of melatonin on diabetic cardiomyopathy.…”