Melatonin inhibits cytosolic mitochondrial DNA–induced neuroinflammatory signaling in accelerated aging and neurodegeneration
Abhishek Jauhari, … , Diane L. Carlisle, Robert M. Friedlander
Abhishek Jauhari, … , Diane L. Carlisle, Robert M. Friedlander
Published March 17, 2020
Citation Information: J Clin Invest. 2020;130(6):3124-3136. https://doi.org/10.1172/JCI135026.
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Research Article Inflammation Neuroscience Article has an altmetric score of 17

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

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.

Authors

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

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Figure 1

Melatonin deficiency–induced mtDNA release mediated neuroinflammation.

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Melatonin deficiency–induced mtDNA release mediated neuroinflammation. (...
(A) LC-MS quantification of melatonin in pineal gland isolated at 4:00 a.m. from 20-week-old WT and AANAT-KO mice (n = 3). (B) Quantification of malondialdehyde (MDA), an indicator of lipid peroxidation, and (C) protein carbonylation, an indicator of protein oxidation in whole brain of 8- and 20-week-old WT and AANAT-KO mouse brain lysate (n = 3). (D) Ventricle volume in 20-week-old WT and AANAT-KO brain (n = 3). (E) qPCR of cytosolic mtDNA in 8- and 20-week-old WT and AANAT-KO brain using primers for mt-CO1, mt-Dloop1, and mt-Dloop3, mitochondrial genes. Cytosolic mtDNA is plotted relative to amount of WT brain after normalization to β-actin from the corresponding total DNA lysate, n = 3 for 8 weeks, n = 4 for 20 weeks. (F) Representative immunoblots and (G) quantitation for cGAS, STING, IRF3, caspase-1, and β-actin in WT and AANAT-KO brain lysates. β-actin was used as a loading control; data are expressed as relative to WT control (n = 4). (H) Cytokine ELISA in brain lysate of 20-week-old WT and AANAT-KO mice expressed as pg of cytokine per mg of protein lysate (n = 4). All data are expressed as mean ± SD, analyzed by Student’s t test (A, D, G, and H), or ANOVA followed by Tukey’s test (B, C, and E). *P < 0.05; **P < 0.01; ***P < 0.001.