Invest Ophthalmol Vis Sci. 2026 Jun 1;67(6):49. doi: 10.1167/iovs.67.6.49.
ABSTRACT
PURPOSE: To investigate whether SIRT4 protects the optic nerve by regulating mitochondrial function and lipid metabolism in neurotoxic reactive astrocytes in the retinal ischemia-reperfusion injury.
METHODS: Using SIRT4 knockout, wild-type, and overexpressing mouse ischemia-reperfusion (I/R) models, we assessed retinal ganglion cell loss, protein expression (SIRT4, APOL6, GBP2, mitochondrial dynamics), and conducted metabolomic/transcriptomic analyses. In vitro, primary astrocytes were treated with TIC cytokines; SIRT4 was knocked down via lentivirus, followed by measurement of ATP, lipid secretion, and mitochondrial morphology/function.
RESULTS: SIRT4 was highly expressed in astrocytes. Its knockdown exacerbated I/R injury, promoting a neurotoxic astrocyte phenotype with increased APOL6 expression, and elevated secretion of long-chain fatty acids and phosphatidylcholines and mitochondrial damage. SIRT4 deficiency enhanced astrocyte susceptibility to injury, further reducing ATP production and worsening lipid accumulation and optic nerve damage.
CONCLUSIONS: SIRT4 plays a protective role in retinal ischemia-reperfusion injury model by regulating astrocyte lipid metabolism and mitochondrial function, offering a potential therapeutic target for neuroprotection.
PMID:42346024 | DOI:10.1167/iovs.67.6.49