Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans

Reading between the lines, if Akt activation can reduce neuron death in chronic mountain sickness, then we should immediately start up research to see if it can do the same for stroke. BUT SINCE WE HAVE NO STROKE LEADERS OR STRATEGY. Nothing will occur, you're screwed, your children and grandchildren will be screwed when they have strokes. 

Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans

Helen Zhao¹, Jonathan Lin^2,3,4, Gary Sieck⁵ and Gabriel G. Haddad^1,6,7*

• ¹Department of Pediatrics (Respiratory Medicine), University of California, San Diego, La Jolla, CA, United States
• ²Department of Pathology, University of California, San Diego, La Jolla, CA, United States
• ³Department of Pathology, Stanford University, Stanford, CA, United States
• ⁴VA Palo Alto Healthcare System, Palo Alto, CA, United States
• ⁵Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States
• ⁶Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States
• ⁷The Rady Children’s Hospital, San Diego, CA, United States

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.

Introduction

Chronic Mountain Sickness (CMS) is a maladaptation to hypoxia that is characterized by severe hypoxemia, excessive erythrocytosis and many neurologic manifestations, including migraine, headache, mental fatigue, confusion, and memory loss. CMS disease threatens a large segment of the high-altitude population (more than 100 million highlanders) during extended living at altitudes above 2,500 m. Since hypoxia is a common feature of many diseases at sea level including cardiovascular diseases, neurodegenerative diseases, stroke, diabetes and cancer, we believe that investigating the underlying mechanisms of hypoxia maladaptation or adaptation in CMS and non-CMS subjects may lead us to a better understanding of many hypoxia-related diseases as well. However, due to sample availability and ethical issues, our understanding of CMS neuropathology in humans remains largely unexplored at cellular and molecular levels. By using CMS disease-specific iPSC-derived neurons, we have previously reported mitochondrial dysfunction in CMS neurons under normoxia and an increased vulnerability to hypoxia-induced cell death after 48 h (Zhao et al., 2018). Here, we are interested in investigating the underlying mechanisms that contribute to hypoxia-induced cell death in CMS neurons.

Recent clinical studies have shown that CMS patients have blunted cerebral blood flow and exaggerated systemic oxidative-inflammatory-nitrosative stress with impaired cognition (Bao et al., 2017; Bailey et al., 2019) and CMS is believed to have clinical manifestations of aging at high altitude (Sime et al., 1975). In the brain, reduced cerebral blood flow and hypoxia disturb normal physiological functions and lead to metabolic stress. In conditions of stress including hypoxia, organisms activate endogenous adaptive cytoprotection mechanisms including the endoplasmic reticulum (ER) unfolded protein response (ER stress response), ER associated degradation (ERAD), autophagy, mitophagy, and/or mitochondrial biogenesis to restore cellular homeostasis (Senft and Ronai, 2015; Wu and Chen, 2015; Xu et al., 2015; Maekawa and Inagi, 2017; Delbrel et al., 2018; Yamashita and Kanki, 2018). Indeed, under pathological conditions, when an element of the endogenous adaptive cytoprotection mechanisms is impaired, the overall cellular homeostasis can be disturbed (Senft and Ronai, 2015).

Considering that the ER and mitochondria form a direct physical contact via mitochondria associated membrane (MAM) and functionally interact with each other (Bouman et al., 2011; Senft and Ronai, 2015), we hypothesize that mitochondrial dysfunction might therefore affect ER function as well as other endogenous adaptive mechanisms such as mitophagy. Akt is a pro-survival signaling protein and the PI3K/Akt/mTORC pathway cross links with both ER stress and autophagy (Qin et al., 2010; Kabir et al., 2018). In CMS patients, the Akt gene is shown to associate with chronic mountain sickness (Buroker et al., 2017) and plays an important role in regulating apoptosis in CMS patients with excessive erythrocytosis (Li et al., 2017; Zhao et al., 2017a). Therefore, in the current study, we explored the relationship between mitochondria and ER stress in iPSCs-derived CMS neurons and non-CMS neurons and investigated the potential rescue role of Akt from progression to hypoxia-induced cell death in CMS neurons.

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