Long-term HIF-1alpha stabilization reduces respiration, promotes mitophagy, and results in retinal cell death

Date
2023-11-24
ORCID
0000-0002-8522-4112 (Inman, Denise M.)
Journal Title
Journal ISSN
Volume Title
Publisher
Springer Nature
Abstract

Ocular hypertension during glaucoma can lead to hypoxia, activation of the HIF transcription factors, and a metabolic shift toward glycolysis. This study aims to test whether chronic HIF activation and the attendant metabolic reprogramming can initiate glaucoma-associated pathology independently of ocular hypertension. HIF-1alpha stabilization was induced in mice for 2 and 4 weeks by inhibiting prolyl hydroxylases using the small molecule Roxadustat. HIF-1alpha stabilization and the expression of its downstream bioenergetic targets were investigated in the retina by immunofluorescence, capillary electrophoresis, and biochemical enzyme activity assays. Roxadustat dosing resulted in significant stabilization of HIF-1alpha in the retina by 4 weeks, and upregulation in glycolysis-associated proteins (GLUT3, PDK-1) and enzyme activity in both neurons and glia. Accordingly, succinate dehydrogenase, mitochondrial marker MTCO1, and citrate synthase activity were significantly decreased at 4 weeks, while mitophagy was significantly increased. TUNEL assay showed significant apoptosis of cells in the retina, and PERG amplitude was significantly decreased with 4 weeks of HIF-1alpha stabilization. A significant increase in AMPK activation and glial hypertrophy, concomitant with decreases in retinal ganglion cell function and inner retina cell death suggests that chronic HIF-1alpha stabilization alone is detrimental to retina metabolic homeostasis and cellular survival.

Description
Citation
Nsiah, N. Y., Morgan, A. B., Donkor, N., & Inman, D. M. (2023). Long-term HIF-1α stabilization reduces respiration, promotes mitophagy, and results in retinal cell death. Scientific reports, 13(1), 20541. https://doi.org/10.1038/s41598-023-47942-8