Ischemia-reperfusion injury (IRI) often stems from an imbalance between mitochondrial dynamics and autophagy. Melatonin mitigates IRI by regulating mitochondrial dynamics. However, the precise molecular mechanism underlying the role of melatonin in reducing IRI through modulating mitochondrial dynamics remains elusive. The objective of this study was to investigate whether pre-treatment with melatonin before IRI confers protective effects by modulating mitochondrial dynamics and mitophagy. Melatonin pre-treatment was administered to HK-2 cells and live rats before subjecting them to hypoxia-reoxygenation (HR) or IRI, respectively. Cells and rat kindey models were evaluated for markers of oxidative stress, autophagy, mitochondrial dynamics, and the expression of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) and phospho-AMPKα (P-AMPK). Following renal IRI, increased mitochondrial fission and autophagy were observed, accompanied by exacerbated cellular oxidative stress injury and aggravated mitochondrial dysfunction. Nevertheless, melatonin pre-treatment inhibited mitochondrial fission, promoted mitochondrial fusion, and attenuated autophagy levels. This intervention was correlated with a notable reduction in oxidative stress injury and remarkable restoration of mitochondrial functionality. IRI led to a decline in P-AMPK levels, whereas melatonin pre-treatment increased the level of P-AMPK levels. Silencing AMPK with small interfering RNA exacerbated mitochondrial damage, and in this context, melatonin pre-treatment did not alleviate mitochondrial fission or autophagy levels but resulted in sustained oxidative stress damage. Collectively, these findings indicate that melatonin pre-treatment shields the kidneys from IRI by mitigating excessive mitochondrial fission, moderating autophagy levels, and preserving appropriate mitochondrial fission, all in an AMPK-dependent manner.
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