Metabolic Adaptations to High-altitude Hypoxia in Two Ethiopian Populations

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Abstract Rationale: Chronic exposure to high-altitude hypoxia may elicit mitochondrial and metabolic responses to reduce the oxygen cost of energy production and decrease reactive oxygen species production. Two East African high-altitude populations have adapted physiologically to high altitude differently, the Amhara through increased nitric oxide/blood flow and the Oromo through increased carrying capacity for oxygen. We hypothesize that mitochondria and metabolism also differ between the two groups. Methods: We compare high-altitude Ethiopian Amhara and Oromo (112 high-altitude Amhara at 3700 m; 105 high-altitude Oromo at 4000 m) to their respective low-altitude counterparts (53 low-altitude Amhara at 1200 m; 47 low-altitude Oromo at 1700 m). We estimated oxygen delivery from heart rate, pulse pressure, and arterial oxygen content and measured mitochondrial DNA copies relative to nuclear DNA (mtDNA-CN). We also measured TCA metabolites in plasma in a subset of high-altitude participants (67 high-altitude Amhara, 43 high-altitude Oromo) and calculated metabolite ratios to estimate tricarboxylic acid (TCA) cycle activity. Results: High-altitude populations have similar estimated oxygen delivery as their low-altitude counterparts (median (IQR) (mlO2/min): Amhara, high-altitude, 1206 (1004-1468); low-altitude, 1249 (1063-1442); p=0.8; Oromo, high-altitude, 1137 (960-1483); low-altitude, 1158 (931-1355); p=0.6) and comparable to each other (p=0.4). Despite similar oxygen delivery, mtDNA-CN and metabolic responses differ between the two high-altitude populations. High-altitude Amhara have 21% higher median mtDNA-CN than low-altitude Amhara (high-altitude, 363.0 (280.5-427.7); low-altitude, 299.7 (246.6-333.2); p<.0001), while high-altitude Oromo have 17% lower mtDNA-CN than low-altitude Oromo (high-altitude, 236.7 (165.2-315.6); low-altitude, 283.7 (216.9-335.6); p=0.01). High-altitude Amhara have significantly higher median mtDNA-CN than high-altitude Oromo (p<.0001). Among high-altitude natives, Oromo had higher lactate/pyruvate ratio than Amhara (Amhara, 14.4 (11.8-21.4); Oromo, 26.7 (21.7-33.4); p<.0001), suggesting greater reductive metabolism. In contrast, Amhara had higher α-ketoglutarate/citrate (Amhara, 0.24 (0.19-0.32); Oromo, 0.18 (0.12-0.24); p=.0003) and fumarate/succinate (Amhara, 0.72 (0.63-0.91); Oromo, 0.55 (0.43-0.68); p<.0001) ratios, suggesting greater oxidative metabolism in the Amhara. Conclusions: High-altitude Amhara and Oromo maintain adequate oxygen delivery to tissues, yet these metabolic responses suggest differences in cellular oxygen availability. The Amhara may have a higher cellular concentration of oxygen available for aerobic respiration and energy production. These findings require validation and expansion to address the interplay between physiologic and metabolic adaptations to chronic hypoxia.

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