Mitochondrial dysfunction in iPSC-derived neurons of subjects with chronic mountain sickness

Abstract

Patients with chronic mountain sickness (CMS) suffer from hypoxemia, erythrocytosis, and numerous neurologic deficits. Here we used induced pluripotent stem cell (iPSC)-derived neurons from both CMS and non-CMS subjects to study CMS neuropathology. Using transmission electron microscopy, we report that CMS neurons have a decreased mitochondrial volume density, length, and less cristae membrane surface area. Real-time PCR confirmed a decreased mitochondrial fusion gene optic atrophy 1 (OPA1) expression. Immunoblot analysis showed an accumulation of the short isoform of OPA1 (S-OPA1) in CMS neurons, which have reduced ATP levels under normoxia and increased lactate dehydrogenase (LDH) release and caspase 3 activation after hypoxia. Improving the balance between the long isoform of OPA1 and S-OPA1 in CMS neurons increased the ATP levels and attenuated LDH release under hypoxia. Our data provide initial evidence for altered mitochondrial morphology and function in CMS neurons, and reveal increased cell death under hypoxia due in part to altered mitochondrial dynamics. NEW & NOTEWORTHY Induced pluripotent stem cell-derived neurons from chronic mountain sickness (CMS) subjects have altered mitochondrial morphology and dynamics, and increased sensitivity to hypoxic stress. Modification of OPA1 can attenuate cell death after hypoxic treatment, providing evidence that altered mitochondrial dynamics play an important role in increased vulnerability under stress in CMS neurons.

Reflections on the past three decades of high-altitude exercise research and the autonomic nervous system

“…Whereas normoxia-induced gene expression changes were previously found in Andeans, those changes were absent in Ethiopians, as they are in Himalayans. This is consistent with physiologic studies finding no increase in cerebral circulation and hypoxic ventilatory drive in Ethiopians and Himalayans at high altitude, and with the absence of chronic mountain sickness on the East African altitude plateau [ 5 ], as in Tibet—and in contrast to the Andes [ 11 , 12 ].…”

“…We found evidence of altered mitochondrial morphology and function in the cultured neurons of subjects with chronic mountain sickness. We also saw increased cell death under the hypoxia prevailing in Cerro de Pasco due, in part, to altered mitochondrial dynamics [ 6 , 8 , 12 ].…”

Neuroprotective Role of Akt in Hypoxia Adaptation in Andeans

“…We have previously reported that CMS neurons had altered mitochondrial dynamics and function ( Zhao et al, 2018 ). Due to the fact that ER and mitochondria form physical contact through MAM and interact with each other functionally ( Bouman et al, 2011 ; Senft and Ronai, 2015 ), we examined whether the altered mitochondrial function activates the ER stress response.…”

“…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.…”

Three-Dimensional Analysis of Mitochondrial Crista Ultrastructure in a Patient with Leigh Syndrome by In Situ Cryoelectron Tomography

“…More recently, LS and Leigh-like syndrome have been linked to pathogenic mutations in genes encoding proteins regulating crista architecture, including SLC25A46 ( Janer et al., 2016 ) and OPA1 ( Finsterer and Zarrouk-Mahjoub, 2017 ). Indeed, LS-causing mutations in SLC25A46 result in abnormal mitochondrial architecture, including significantly shortened cristae ( Janer et al., 2016 ), whereas disease mutations that reduce OPA1 expression produce decreased mitochondrial volume density and diminished cristae membrane surface area ( Zhao et al., 2017 ).…”