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 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% O). Similarly, relative to untreated controls, permeabilized brain respiratory flux through the ETS was decreased by ∼90% in acutely hypoxic animals. Relative to carbonyl cyanide -trifluoro-methoxyphenylhydrazone-uncoupled total ETS flux, this functional decrease was observed equally across all components of the ETS except for complex IV (cytochrome 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.

Naked mole rats activate neuroprotective proteins during hypoxia

“…While most of the examined proteins either increased or showed no statistical difference, three were found to significantly decrease in hypoxic brains (Figure a), with CYC displaying the greatest reduction in protein level (Figure b). CYC is a necessary component of the mitochondrial electron transport chain (ETC), and its reduction is consistent with the reduced flux through the ETC in hypoxic NMR brains (Pamenter et al, ). Moreover, CYC also serves a role in signaling apoptosis when released from the mitochondria into the cytosol (Cai et al, ); therefore, besides matching lowered oxidative phosphorylation capacity, the reduction of CYC may also reduce the apoptotic potential of NMR brain cells during hypoxia.…”

“…Naked mole rats (NMRs) are remarkably long‐lived mammals and have evolved a suite of adaptations that have led to their cancer resistance, resistance to neurodegeneration, and survival of prolonged oxygen deprivation (Edrey et al, ; Liang, Mele, Wu, Buffenstein, & Hornsby, ; Pamenter, Lau, Richards, & Milsom, ; Park et al, ). Native to East Africa where they live in underground tunnel systems, NMRs are one of two eusocial mammalian species and studies have shown to fluctuate body temperature with ambient temperatures (Buffenstein & Yahav, ; Ilacqua, Kirby, & Pamenter, ; Kirby, Fairman, & Pamenter, ).…”

“…It is possible that a combination of their heterothermic capacity, along with other molecular adaptations such as their enhanced hemoglobin oxygen binding (Johansen, Lykkeboe, Weber, & Maloiy, ) and their ability to switch to fructose‐driven metabolism allow them to endure periods of reduced oxygen availability (Park et al, ). The nature of their tunnel colonies make this mammal no stranger to hypoxia such that they can survive for days to weeks at 8% O 2 levels, for hours at 3%, and up to 18 min of complete anoxia (Chung, Dzal, Seow, Milsom, & Pamenter, ; Pamenter et al, ; Park et al, ), although how often the animals are exposed to hypoxia in their colonies is controversial (Holtze et al, ).…”

Temperature sensitivity differs between heart and red muscle mitochondria in mahi-mahi (Coryphaena hippurus)

“…Although this was not explicitly investigated in this present study, this could be due to tissue specific differences in not only the ETS complexes themselves. Previous studies have shown tissue and species specificity in temperature sensitivity of individual mitochondrial complexes assayed in vitro 21,22 . Additionally, enzymes and pathways upstream of the ETS can also influence temperature sensitivity of ETS flux pathway.…”

Induced pluripotent stem cells as a tool for comparative physiology: lessons from the thirteen-lined ground squirrel

“…Deep-diving marine mammals such as seals have attracted research interest based on their specialized inflammatory responses and tolerance of hypoxia and ischemia-reperfusion stresses associated with their diving behavior (Bagchi et al, 2018;Meir et al, 2009;Vázquez-Medina et al, 2012). The naked mole rat is known for its extreme tolerance of hypoxia (Pamenter et al, 2018;Park et al, 2017), as well as its longevity and robust cancer resistance (Buffenstein, 2005;Liang et al, 2010;Tian et al, 2013). Lastly, and most germane to this Commentary, hibernating mammals, such as some ground squirrels and bears, can actively lower their metabolic rates and body temperature (Carey et al, 2003;Geiser, 2004;Staples, 2016;Toien et al, 2011;Treat et al, 2018) and tolerate hypoxia and ischemia (Dave et al, 2006;Drew et al, 2016).…”