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.