Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans

Abstract

Chronic mountain sickness (CMS) is a disease that potentially threatens a large segment of high-altitude populations during extended living at altitudes above 2,500 m. Patients with CMS suffer from severe hypoxemia, excessive erythrocytosis and neurologic deficits. The cellular mechanisms underlying CMS neuropathology remain unknown. We previously showed that iPSC-derived CMS neurons have altered mitochondrial dynamics and increased susceptibility to hypoxia-induced cell death. Genome analysis from the same population identified many ER stress-related genes that play an important role in hypoxia adaptation or lack thereof. In the current study, we showed that iPSC-derived CMS neurons have increased expression of ER stress markers Grp78 and XBP1s under normoxia and hyperphosphorylation of PERK under hypoxia, alleviating ER stress does not rescue the hypoxia-induced CMS neuronal cell death. Akt is a cytosolic regulator of ER stress with PERK as a direct target of Akt. CMS neurons exhibited lack of Akt activation and lack of increased Parkin expression as compared to non-CMS neurons under hypoxia. By enhancing Akt activation and Parkin overexpression, hypoxia-induced CMS neuronal cell death was reduced. Taken together, we propose that increased Akt activation protects non-CMS from hypoxia-induced cell death. In contrast, impaired adaptive mechanisms including failure to activate Akt and increase Parkin expression render CMS neurons more susceptible to hypoxia-induced cell death.

mTORC2 Is Activated under Hypoxia and Could Support Chronic Myeloid Leukemia Stem Cells

“…In the present study, we observed that mTORC2 appears to be active and phosphorylates Akt kinase under hypoxic conditions. Overall, our observations are consistent with previously published studies [ 48 , 49 ]. One interesting study suggests that mTORC2 may mediate several processes associated with migration, invasion and survival through PLD activation due to stress-dependent serum withdrawal.…”

The Brain at High Altitude: From Molecular Signaling to Cognitive Performance

“…It is proposed that increased Akt activation protects against hypoxia-induced cell death. Therefore, it is suggested that impaired adaptive mechanisms, including lack of Akt activation and increased Parkin expression, render neurons from chronic mountain sickness subjects more susceptible to hypoxia-induced cell death [ 99 ].…”

Ferroptosis-related genes are considered as potential targets for CPAP treatment of obstructive sleep apnea

“…Recent studies have found that serum ferritin levels tend to rise with increasing OSA severity ( 13 ). Chronic intermittent hypoxia is the signature manifestation of OSA, and intermittent hypoxia in the brain will lead to excessive accumulation of reactive oxygen species (ROS) in neurons, which may cause permanent death of neurons ( 14 ). Recent studies have shown that hypoxia can increase the iron content in the brain of animals leading to neurodegeneration, and disorder the metabolism of nerve cells by affecting the ferroptosis-related to genes, resulting in excess oxygen free radicals ( 15 , 16 ).…”