Journal Article Research Support, Non-U.S. Gov't Research Support, N.I.H., Extramural Epublish 5 citations
PubMed: 37887340 DOI: 10.3390/cells12202496
Mitophagy in Astrocytes Is Required for the Health of Optic Nerve.
Cells 12(20)
Authors: Meysam Yazdankhah, Sayan Ghosh, Haitao Liu, Stacey Hose, J Samuel Zigler, Debasish Sinha
Affiliations
- Department of Ophthalmology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
- Department of Ophthalmology, The Wilmer Eye Institute, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Abstract
Mitochondrial dysfunction in astrocytes has been implicated in the development of various neurological disorders. Mitophagy, mitochondrial autophagy, is required for proper mitochondrial function by preventing the accumulation of damaged mitochondria. The importance of mitophagy, specifically in the astrocytes of the optic nerve (ON), has been little studied. We introduce an animal model in which two separate mutations act synergistically to produce severe ON degeneration. The first mutation is in , which encodes βA3/A1-crystallin, a lens protein also expressed in astrocytes, where it regulates lysosomal pH. The second mutation is in , which encodes branched-chain ketoacid dehydrogenase kinase, which is ubiquitously expressed in the mitochondrial matrix and involved in the catabolism of the branched-chain amino acids. BCKDK is essential for mitochondrial function and the amelioration of oxidative stress. Neither of the mutations in isolation has a significant effect on the ON, but animals homozygous for both mutations (DM) exhibit very serious ON degeneration. ON astrocytes from these double-mutant (DM) animals have lysosomal defects, including impaired mitophagy, and dysfunctional mitochondria. Urolithin A can rescue the mitophagy impairment in DM astrocytes and reduce ON degeneration. These data demonstrate that efficient mitophagy in astrocytes is required for ON health and functional integrity.
MeSH
Mitochondria, Cells, Lysosomes, Mutation, Optic Nerve, Astrocytes, Amino Acids, Branched-Chain, Autophagy, Mitophagy
Cited by
- Retinal Cell Biology in Health and Disease. Cells, 2024
- Targeting autophagy in astrocytes: a potential for neurodegenerative disease intervention. Front Cell Neurosci, 2025
- Lysosomal acidification impairment in astrocyte-mediated neuroinflammation. J Neuroinflammation, 2025
- Sustained Lysosomal Delivery of Enhanced Cy3-Labeled Acid Nanoparticles Restores Lysosomal pH in Retinal Pigment Epithelial Cells and Astrocytes. bioRxiv, 2025