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      Melatonin inhibits cytosolic mitochondrial DNA–induced neuroinflammatory signaling in accelerated aging and neurodegeneration

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          Abstract

          Chronic inflammation is a pathologic feature of neurodegeneration and aging; however, the mechanism regulating this process is not understood. Melatonin, an endogenous free radical scavenger synthesized by neuronal mitochondria, decreases with aging and neurodegeneration. We proposed that insufficient melatonin levels impair mitochondrial homeostasis, resulting in mitochondrial DNA (mtDNA) release and activation of cytosolic DNA-mediated inflammatory response in neurons. We found increased mitochondrial oxidative stress and decreased mitochondrial membrane potential, with higher mtDNA release in brain and primary cerebro-cortical neurons of melatonin-deficient aralkylamine N-acetyltransferase (AANAT) knockout mice. Cytosolic mtDNA activated the cGAS/STING/IRF3 pathway, stimulating inflammatory cytokine generation. We found that Huntington’s disease mice had increased mtDNA release, cGAS activation, and inflammation, all inhibited by exogenous melatonin. Thus, we demonstrated that cytosolic mtDNA activated the inflammatory response in aging and neurodegeneration, a process modulated by melatonin. Furthermore, our data suggest that AANAT knockout mice are a model of accelerated aging.

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          Author and article information

          Contributors
          Journal
          J Clin Invest
          J. Clin. Invest
          J Clin Invest
          The Journal of Clinical Investigation
          American Society for Clinical Investigation
          0021-9738
          1558-8238
          11 May 2020
          11 May 2020
          1 June 2020
          1 September 2020
          : 130
          : 6
          : 3124-3136
          Affiliations
          [1 ]Department of Neurological Surgery and
          [2 ]Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
          Author notes
          Address correspondence to: Robert M. Friedlander, 200 Lothrop Street, B400 Presbyterian Hospital, Pittsburgh, Pennsylvania 15213, USA. Phone: 412.647.6358; Email: friedlanderr@ 123456upmc.edu .
          Author information
          http://orcid.org/0000-0002-0688-640X
          http://orcid.org/0000-0002-1728-4228
          http://orcid.org/0000-0002-6455-6337
          Article
          PMC7260019 PMC7260019 7260019 135026
          10.1172/JCI135026
          7260019
          32182222
          1efcd7c8-f52c-42f0-b2af-a0c4004ec730
          © 2020 American Society for Clinical Investigation
          History
          : 15 November 2019
          : 5 March 2020
          Funding
          Funded by: National institute of health, United states
          Award ID: NIHR01NS100743
          Funded by: Pittsburgh Foundation Walter L Copeland Fund
          Award ID: UN2018-96996
          Categories
          Research Article

          Neurodegeneration,Inflammation,Mitochondria,Neuroscience

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