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

Jauhari, Abhishek ; Baranov, Sergei V ; Suofu, Yalikun ; Kim, Jinho ; Singh, Tanisha ; Yablonska, Svitlana ; Li, Fang ; Wang, Xiaomin ; Oberly, Patrick ; Minnigh, M Beth ; Poloyac, Samuel M ; Carlisle, Diane L ; Friedlander, Robert M

The Journal of clinical investigation, 2020-06, Vol.130 (6), p.3124-3136 [Periódico revisado por pares]

United States: American Society for Clinical Investigation

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Título:
Melatonin inhibits cytosolic mitochondrial DNA-induced neuroinflammatory signaling in accelerated aging and neurodegeneration
Autor: Jauhari, Abhishek ; Baranov, Sergei V ; Suofu, Yalikun ; Kim, Jinho ; Singh, Tanisha ; Yablonska, Svitlana ; Li, Fang ; Wang, Xiaomin ; Oberly, Patrick ; Minnigh, M Beth ; Poloyac, Samuel M ; Carlisle, Diane L ; Friedlander, Robert M
Assuntos: Aging ; Aging - genetics ; Aging - metabolism ; Aging - pathology ; Animals ; Aralkylamine N-acetyltransferase ; Biomedical research ; Brain ; Cytokines ; Cytosol - metabolism ; Cytosol - pathology ; Deoxyribonucleic acid ; Development and progression ; DNA ; DNA, Mitochondrial - genetics ; DNA, Mitochondrial - metabolism ; Female ; Homeostasis ; Humans ; Huntington Disease - genetics ; Huntington Disease - metabolism ; Huntington Disease - pathology ; Huntington's disease ; Huntingtons disease ; Inflammation ; Interferon regulatory factor 3 ; Male ; Melatonin ; Melatonin - pharmacology ; Membrane potential ; Mice ; Mice, Knockout ; Mitochondrial DNA ; Neurodegeneration ; Neurons ; Neurons - metabolism ; Neurons - pathology ; Oxidative stress ; Rodents ; Signal Transduction - drug effects
É parte de: The Journal of clinical investigation, 2020-06, Vol.130 (6), p.3124-3136
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Descrição: 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.
Editor: United States: American Society for Clinical Investigation
Idioma: Inglês

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

Jauhari, Abhishek ; Baranov, Sergei V ; Suofu, Yalikun ; Kim, Jinho ; Singh, Tanisha ; Yablonska, Svitlana ; Li, Fang ; Wang, Xiaomin ; Oberly, Patrick ; Minnigh, M Beth ; Poloyac, Samuel M ; Carlisle, Diane L ; Friedlander, Robert M

United States: American Society for Clinical Investigation

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