The Dynamic Genome at Altitude: Mitochondrial DNA Copy Numbers in Acute and Chronic Hypoxia

Abstract

Mitochondria contain a tiny circular DNA (mtDNA) that encodes components of the electron transport chain, including Complex IV, where over 95% of oxygen is consumed in the process of generating energy. Each mitochondrion contains tens to hundreds of copies of mtDNA, which decrease with aging and disease, but little is known regarding how mtDNA levels change in response to hypoxia. Here we compare samples with different durations and magnitudes of exposure to high-altitude hypoxia: Ethiopian Amhara with >5000 years exposure and the potential for evolved adaptations, Ethiopian Oromo with ~500 years of generations of lifelong acclimatization, and acutely exposed European trekkers with 15 days of abrupt individual acclimatization followed by descent to baseline. Lowland natives of the same ethnicities provide unstressed reference samples. Our previous studies found that Amhara adapted to hypoxia through increased blood flow due to nitric oxide-mediated vasodilation, while Oromo have increased carrying capacity through elevated hemoglobin concentration. We measured mtDNA copy numbers relative to nuclear DNA (mtDNA-CN) in 326 healthy adults: 52 low-altitude Amhara at 1200 m, 113 high-altitude Amhara at 3700 m; 47 low-altitude Oromo at 1700 m, and 105 high-altitude Oromo at 4000 m; and 9 European lowlanders at a baseline of 1300 m, after ascent to 5050 m, and upon return to 1300 m. High-altitude Amhara had 21% higher median mtDNA-CN than their low-altitude counterparts (median (IQR): high-altitude, 363.0 (281.0–427.0); low-altitude, 299.0 (246.1–333.2); p<0.0001), while high-altitude Oromo had 17% lower mtDNA-CN than their low-altitude counterparts (high-altitude, 236.7 (165.2–315.6); low-altitude, 283.7 (216.9–335.6); p=0.01). High-altitude Amhara had significantly higher median mtDNA-CN than high-altitude Oromo (p<.0001). European lowlanders had 44% lower mtDNA-CN after an 13-day ascent to 5050 m (1300 m, 322.5 (262.8–356.4); 5050 m 180.9 (145.1–230.5); p=0.002) that returned to baseline (319.5 (247.3–267.6); p=0.5) after a 6-day descent to 1300 m. These findings further confirm variation in acute and chronic responses to hypoxia, within and across populations. These findings require validation and expansion to address the mechanisms connecting expression of mtDNA copy numbers to oxygen-requiring bioenergetics. This work is supported by the National Heart, Lung, and Blood Institute HL060917 and National Science Foundation BCS-0452326. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.