Ciliary neurotrophic factor-mediated neuroprotection involves enhanced glycolysis and anabolism in degenerating mouse retinas

Kun Rhee, Yanjie Wang, Johanna ten Hoeve, Linsey Stiles, Thao Thi Thu Nguyen, Xiangmei Zhang, Laurent Vergnes, Karen Reue, Orian Shirihai, Dean Bok and Xian-Jie Yang ()
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Kun Rhee: University of California, Davide Geffen School of Medicine
Yanjie Wang: University of California, Davide Geffen School of Medicine
Johanna ten Hoeve: University of California, Davide Geffen School of Medicine
Linsey Stiles: University of California, Davide Geffen School of Medicine
Thao Thi Thu Nguyen: University of California, Davide Geffen School of Medicine
Xiangmei Zhang: University of California, Davide Geffen School of Medicine
Laurent Vergnes: University of California, Davide Geffen School of Medicine
Karen Reue: University of California, Davide Geffen School of Medicine
Orian Shirihai: University of California, Davide Geffen School of Medicine
Dean Bok: University of California, Davide Geffen School of Medicine
Xian-Jie Yang: University of California, Davide Geffen School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Ciliary neurotrophic factor (CNTF) acts as a potent neuroprotective cytokine in multiple models of retinal degeneration. To understand mechanisms underlying its broad neuroprotective effects, we have investigated the influence of CNTF on metabolism in a mouse model of photoreceptor degeneration. CNTF treatment improves the morphology of photoreceptor mitochondria, but also leads to reduced oxygen consumption and suppressed respiratory chain activities. Molecular analyses show elevated glycolytic pathway gene transcripts and active enzymes. Metabolomics analyses detect significantly higher levels of ATP and the energy currency phosphocreatine, elevated glycolytic pathway metabolites, increased TCA cycle metabolites, lipid biosynthetic pathway intermediates, nucleotides, and amino acids. Moreover, CNTF treatment restores the key antioxidant glutathione to the wild type level. Therefore, CNTF significantly impacts the metabolic status of degenerating retinas by promoting aerobic glycolysis and augmenting anabolic activities. These findings reveal cellular mechanisms underlying enhanced neuronal viability and suggest potential therapies for treating retinal degeneration.

Date: 2022
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DOI: 10.1038/s41467-022-34443-x

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