Intermittent hypoxia, the hallmark of sleep apnea, induces HIF-1-dependent mitochondrial dysfunction

Chronic intermittent hypoxia (IH) is the major detrimental factor of obstructive sleep apnea (OSA), leading to myocardial alterations (myocardial infarction occurrence and worse recovery). Mitochondrial metabolism is highly sensitive to oxygen fluctuations. Moreover, the oxygen-regulated transcription factor, hypoxia inducible factor-1 (HIF-1), is activated by IH in rodents and in OSA patients with high cardiovascular risk. Thus, we aimed to assess the impact of IH and consecutive HIF-1 activation on myocardial mitochondrial function, dynamic and turnover. Wild type and HIF-1α+/- mice were exposed to 21 days of IH (21-5% FiO2, 60s-cycles, 8h/day), or normoxia (N). After isolation of cardiac mitochondria, oxygen consumption, ROS production, membrane potential and calcium retention capacity (CRC) were measured using a Clark electrode and spectrofluorimetry. Mitochondrial dynamic and turnover were assessed by Western blot. Compared to N, IH decreased mitochondrial respiration by 30%, ROS production by 50%, CRC by 25% and increased time to membrane repolarization by 30%. Although mitochondrial biogenesis and fission were not modified, IH decreased fusion protein and increased autophagy and mitophagy markers. All these IH-induced modifications were abolished in mice with partial HIF-1α deletion. These results demonstrate that HIF-1 is involved in IH-induced myocardial mitochondrial dysfunction, prone to explain deleterious myocardial consequences of IH. Further studies are needed to determine specifically how mitochondria could be considered as a potential therapeutic target in OSA patients with high cardiovascular risk.