Naked mole rats activate neuroprotective proteins during hypoxia

Abstract

Naked mole rats are a long-lived animal model that age much like humans, but that can also withstand oxidative damage, cancer, neurodegenerative diseases, and severe hypoxic conditions, which is of particular interest to this study. The conditions of their underground burrows result in competition for oxygen consumption, yet despite this oxygen deprivation they emerge unscathed. To understand the mechanisms in place to facilitate neuronal preservation during hypoxia, we investigated the protein levels of well-known cell-stress factors. We found that under hypoxic conditions, nearly half of the proteins measured increased expression in brain, while only a few decreased.Under hypoxic conditions there appeared to be a HIF1α-centered response, where HIF1α and its interactors carbonic anhydrase 9, CITED2, p21/CIP1, and NFκB1, among others, were upregulated. Concurrently, a hypoxia-induced decrease of cytochrome c was consistent with decreased mitochondrial function and protection from apoptosis. The picture that emerges is one of neuroprotection, cell-cycle arrest, and the promotion of antiapoptotic functions, all of which are consistent with conserving energy and maintaining neural integrity under low oxygen levels. These results suggest how this species may be poised to face hypoxia and contribute to its remarkable ability to deal with myriad of other damaging factors and sets the stage for future work on the neuroprotective facilitators we identified. K E Y W O R D SHeterocephalus glaber, HIF1α, NFκB, prosurvival

PPARα and PPARγ Signaling Is Enhanced in the Brain of the Naked Mole-Rat, a Mammal that Shows Intrinsic Neuroprotection from Oxygen Deprivation

“…Interestingly, SIRT2 has been reported to modulate a multitude of diverse biological processes such as aging, cell cycle control and differentiation, apoptosis, and autophagy . Further, numerous reports in the literature suggest that SIRT2 inhibition rescues neurodegenerative disease symptoms and may serve as a potential therapeutic target for neurodegenerative disease. − One study reported that increased expression of SIRT2 was observed in NMRs under hypoxic conditions, perhaps contributing to neuronal survival . Finally, we also observed an alteration in numerous transferase enzymes including glutathione S-transferase Mu 1, glutathione S-transferase Mu 3, glutathione S-transferase Mu 5, and glutathione S-transferase omega-1.…”

Hypoxic naked mole–rat brains use microRNA to coordinate hypometabolic fuels and neuroprotective defenses

“…Select central signal transduction pathways, such as TGFβ signaling were predicted to lack miRNA‐inhibition in hypoxic naked mole‐rat brains. Analysis of a panel of stress‐survival proteins performed on naked mole‐rat brains found increased protein levels of NF‐κB and HIF‐1α during hypoxia, suggesting that their involvement in cytoprotective functions (Hawkins et al, 2019). NF‐κB is considered a first molecular responder to oxidative stress—where it can rapidly modulate apoptosis, antioxidant defenses, angiogenesis, DNA damage repair, and inflammatory responses (D'Ignazio & Rocha, 2016; Hayden & Ghosh, 2012).…”

The OxymiR response to oxygen limitation: a comparative microRNA perspective

“…They live in crowded conditions in extensive underground burrows in Africa, ultimately resulting in hypoxic and hypercapnic tunnel systems (Chung et al, 2016); however, it should be mentioned that there is debate regarding the 'hypoxic' nature of their burrows (Roper et al, 2001;Holtze et al, 2018). Nonetheless, researchers have explored the unique mechanisms that allow this extraordinary long-lived mammal to survive these conditions; much focus has been on their inherent resistance to neurodegeneration and ability to withstand acute brain ischemia (Triplett et al, 2015;Hawkins et al, 2019).…”