Naked mole rat brain mitochondria electron transport system flux and H+ leak are reduced during acute hypoxia

Abstract

Mitochondrial respiration and ATP production are compromised by hypoxia. Naked mole rats (NMRs) are among the most hypoxia-tolerant mammals and reduce metabolic rate in hypoxic environments; however, little is known regarding mitochondrial function during in vivo hypoxia exposure in this species. To address this knowledge gap, we asked whether the function of NMR brain mitochondria exhibits metabolic plasticity during acute hypoxia. Respirometry was utilized to assess whole-animal oxygen consumption rates and high-resolution respirometry was utilized to assess electron transport system (ETS) function in saponin-permeabilized NMR brain. We found that NMR whole-animal oxygen consumption rate reversibly decreased by ∼85% in acute hypoxia (4 h at 3% O₂). Similarly, relative to untreated controls, permeabilized brain respiratory flux through the ETS was decreased by ∼90% in acutely hypoxic animals. Relative to carbonyl cyanide p-trifluoro-methoxyphenylhydrazone-uncoupled total ETS flux, this functional decrease was observed equally across all components of the ETS except for complex IV (cytochrome c oxidase), at which flux was further reduced, supporting a regulatory role for this enzyme during acute hypoxia. The maximum enzymatic capacities of ETS complexes I-V were not altered by acute hypoxia; however, the mitochondrial H⁺ gradient decreased in step with the decrease in ETS respiration. Taken together, our results indicate that NMR brain ETS flux and H⁺ leak are reduced in a balanced and regulated fashion during acute hypoxia. Changes in NMR mitochondrial metabolic plasticity mirror whole-animal metabolic responses to hypoxia.

Keywords: Citrate synthase; Cytochrome c oxidase; Mitochondrial membrane potential; Proton gradient.