Description
Naked mole-rats are eusocial animals living in uncommonly hypoxic and hypercapnic environment. To counteract this adverse habitat, they have evolved unique metabolic adaptations that allow them to completely recover from prolonged oxygen deprivation, without any organ impairment – an ability that sets them apart from other terrestrial mammals, including mice. The brain, being one of the most energy-demanding tissues, typically suffers rapid and severe damage in the absence of oxygen. To elucidate the molecular mechanisms that allow the naked mole-rats to survive bouts of hypoxia without any brain injury, we developed a novel in vitro model by differentiating naked mole-rat fibroblasts into neurons (induced Neurons, iNeurons) and establishing naked mole-rat astrocyte cultures. When exposed to extreme hypoxia, both naked mole-rat iNeurons and astrocytes demonstrated greater survival than their mouse counterparts, reaffirming a remarkable hypoxia resistance at the cellular level, that was consistent with our previous in vivo observations (Park, Reznick et al., 2017). Transcriptomic and proteomic analyses will be carried out in order to identify species-specific genes and pathways involved in hypoxia resilience. Given that mitochondria, as bioenergetic organelles, are crucial for maintaining most of the brain functions and are particularly vulnerable to oxygen deprivation, we will use Trasmission Electron Microscopy (TEM) and Focused Ion Beam Scanning Electron Microscopy (FIB-SEM), to investigate mitochondrial functionality and dynamics of both naked mole-rat and mouse iNeurons under normoxic and hypoxic conditions. Our purpose is to identify neuron-specific mitochondrial features that may further explain this peculiar trait of naked mole-rats. The results obtained will contribute to novel therapeutic approaches for conditions characterized by severe oxygen deprivation, such as stroke and organ transplantations.
