Glial swip-10 controls systemic mitochondrial function, oxidative stress, and neuronal viability via copper ion homeostasis.

Autor:	Rodriguez P; Department of Biological Sciences, Charles E. Schmidt College of Science, Boca Raton, FL 33412., Kalia V; Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032., Fenollar-Ferrer C; Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, Bethesda, MD 20892.; Stiles-Nicholson Brain Institute, Florida Atlantic University, Jupiter, FL 33458., Gibson CL; Department of Biological Sciences, Charles E. Schmidt College of Science, Boca Raton, FL 33412.; Oak Ridge Institute for Science and Education, Oak Ridge, TN 37830., Gichi Z; Department of Biomedical Science, Charles E. Schmidt College of Medicine, Jupiter, FL 33458., Rajoo A; Department of Biology, Harriet L. Wilkes Honors College, Florida Atlantic University, Jupiter, FL 33458., Matier CD; Department of Chemistry, University of California, Berkeley, CA 94720.; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720., Pezacki AT; Department of Chemistry, University of California, Berkeley, CA 94720.; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.; Princeton University, Princeton, NJ 08544., Xiao T; Department of Chemistry, University of California, Berkeley, CA 94720.; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.; Princeton University, Princeton, NJ 08544., Carvelli L; Stiles-Nicholson Brain Institute, Florida Atlantic University, Jupiter, FL 33458.; Department of Biomedical Science, Charles E. Schmidt College of Medicine, Jupiter, FL 33458.; Department of Biology, Harriet L. Wilkes Honors College, Florida Atlantic University, Jupiter, FL 33458., Chang CJ; Department of Chemistry, University of California, Berkeley, CA 94720.; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720.; Princeton University, Princeton, NJ 08544., Miller GW; Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, NY 10032., Khamoui AV; Stiles-Nicholson Brain Institute, Florida Atlantic University, Jupiter, FL 33458.; Department of Exercise Science and Health Promotion, Charles E. Schmidt College of Science, Florida Atlantic University, Boca Raton, FL 33431., Boerner J; Stiles-Nicholson Brain Institute, Florida Atlantic University, Jupiter, FL 33458., Blakely RD; Stiles-Nicholson Brain Institute, Florida Atlantic University, Jupiter, FL 33458.; Department of Biomedical Science, Charles E. Schmidt College of Medicine, Jupiter, FL 33458.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2024 Sep 24; Vol. 121 (39), pp. e2320611121. Date of Electronic Publication: 2024 Sep 17.
DOI:	10.1073/pnas.2320611121
Abstrakt:	Cuprous copper [Cu(I)] is an essential cofactor for enzymes that support many fundamental cellular functions including mitochondrial respiration and suppression of oxidative stress. Neurons are particularly reliant on mitochondrial production of ATP, with many neurodegenerative diseases, including Parkinson's disease, associated with diminished mitochondrial function. The gene MBLAC1 encodes a ribonuclease that targets pre-mRNA of replication-dependent histones, proteins recently found in yeast to reduce Cu(II) to Cu(I), and when mutated disrupt ATP production, elevates oxidative stress, and severely impacts cell growth. Whether this process supports neuronal and/or systemic physiology in higher eukaryotes is unknown. Previously, we identified swip-10 , the putative Caenorhabditis elegans ortholog of MBLAC1 , establishing a role for glial swip-10 in limiting dopamine (DA) neuron excitability and sustaining DA neuron viability. Here, we provide evidence from computational modeling that SWIP-10 protein structure mirrors that of MBLAC1 and locates a loss of function coding mutation at a site expected to disrupt histone RNA hydrolysis. Moreover, we find through genetic, biochemical, and pharmacological studies that deletion of swip-10 in worms negatively impacts systemic Cu(I) levels, leading to deficits in mitochondrial respiration and ATP production, increased oxidative stress, and neurodegeneration. These phenotypes can be offset in swip-10 mutants by the Cu(I) enhancing molecule elesclomol and through glial expression of wildtype swip-10 . Together, these studies reveal a glial-expressed pathway that supports systemic mitochondrial function and neuronal health via regulation of Cu(I) homeostasis, a mechanism that may lend itself to therapeutic strategies to treat devastating neurodegenerative diseases. Competing Interests: Competing interests statement:The authors declare no competing interest.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu