Abstract

Prolonged exposure to high altitude (HA) results in a range of systemic changes, some of which, specifically for the heart, particularly cardiac changes, remain difficult to reverse after returning to low altitude. Cardiac de-acclimatization after HA exposure and its underlying mechanisms remain unclear. In this study, mice were subjected to a decompression chamber to simulate a 6000-m altitude exposure for 10 days, followed by the other 10-day de-acclimatization period at a lower altitude of 400 m. The cardiac dysfunction induced by HA exposure persisted throughout the de-acclimatization, accompanied with sustained mitochondrial dysfunction and the short peptide mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c) deficiency. Exogenous supplementation of MOTS-c during de-acclimatization effectively alleviated the cardiac dysfunction post HA exposure. Mechanistically, MOTS-c activated the PTEN-induced putative kinase 1 (Pink1) / Parkin pathway, promoting mitophagy and improving mitochondrial quality. Silencing Pink1 abolished the protective effects of MOTS-c during de-acclimatization. Additionally, reduced circulating MOTS-c levels were observed in patients with high altitude heart disease and acute coronary syndrome. These results suggest that HA exposure leaves a memory of cardiac dysfunction upon return to lower altitude. This is attributed to a sustained deficiency in MOTS-c. MOTS-c maintains mitochondrial quality through promoting mitophagy, highlighting its therapeutic potential for treating HA-induced cardiac dysfunction during de-acclimatization.