PINK1/Parkin-Mediated Mitophagy Participates in High-Altitude Hypoxia Adaptation in Yaks via Energy Metabolism Remodeling.

Yaks are an ideal model for investigating mammalian adaptation to high-altitude hypoxia; however, the underlying adaptive mechanisms remain unclear. Therefore, this study aimed to investigate the mechanisms underlying yak adaptation to high altitudes, focusing on the role of the PINK1/Parkin pathway. In particular, we established normoxic and hypoxic models of yak skeletal muscle satellite cells (SMSCs). In addition, we examined the relationship between PINK1/Parkin-mediated mitophagy and the activities of key enzymes involved in mitochondrial energy metabolism. At the tissue level, an increase in altitude significantly decreased p62 expression and upregulated LC3B-II expression. Notably, mitophagy levels and the expression of PINK1 and Parkin in the skeletal muscle, lungs, and myocardial tissues increased with altitude. At the cellular level, hypoxia markedly elevated the expression of PINK1 and Parkin proteins in SMSCs, induced the conversion of LC3-I to LC3-II, decreased p62 accumulation, significantly increased the number of autolysosomes, and enhanced autophagic flux. Hypoxia altered mitochondrial electron transport chain function, resulting in compensatory elevation of key enzyme activities in the mitochondrial respiratory chain. However, 3-methyladenine (3-MA) treatment reversed these hypoxia-induced changes. In conclusion, yak SMSCs sustain mitochondrial functional homeostasis under hypoxia via PINK1/Parkin-mediated mitophagy, effectively managing hypoxic stress.