Melatonin inhibits cytosolic mitochondrial DNA-induced neuroinflammatory signaling in accelerated aging and neurodegeneration
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 insufficie...
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| Veröffentlicht in: | The Journal of clinical investigation 2020-06, Vol.130 (6), p.3124-3136 |
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| creator | 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 |
| description | 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. |
| doi_str_mv | 10.1172/JCI135026 |
| format | Article |
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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.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI135026</identifier><identifier>PMID: 32182222</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>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</subject><ispartof>The Journal of clinical investigation, 2020-06, Vol.130 (6), p.3124-3136</ispartof><rights>COPYRIGHT 2020 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Jun 2020</rights><rights>2020 American Society for Clinical Investigation 2020 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c647t-fa6b9da5c41e5ca53fcd21aefcee9449cf64891ab95f5f67ec75dfe3b89b42b33</citedby><cites>FETCH-LOGICAL-c647t-fa6b9da5c41e5ca53fcd21aefcee9449cf64891ab95f5f67ec75dfe3b89b42b33</cites><orcidid>0000-0002-1728-4228 ; 0000-0002-0688-640X ; 0000-0002-6455-6337</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260019/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7260019/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32182222$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Jauhari, Abhishek</creatorcontrib><creatorcontrib>Baranov, Sergei V</creatorcontrib><creatorcontrib>Suofu, Yalikun</creatorcontrib><creatorcontrib>Kim, Jinho</creatorcontrib><creatorcontrib>Singh, Tanisha</creatorcontrib><creatorcontrib>Yablonska, Svitlana</creatorcontrib><creatorcontrib>Li, Fang</creatorcontrib><creatorcontrib>Wang, Xiaomin</creatorcontrib><creatorcontrib>Oberly, Patrick</creatorcontrib><creatorcontrib>Minnigh, M Beth</creatorcontrib><creatorcontrib>Poloyac, Samuel M</creatorcontrib><creatorcontrib>Carlisle, Diane L</creatorcontrib><creatorcontrib>Friedlander, Robert M</creatorcontrib><title>Melatonin inhibits cytosolic mitochondrial DNA-induced neuroinflammatory signaling in accelerated aging and neurodegeneration</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>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.</description><subject>Aging</subject><subject>Aging - genetics</subject><subject>Aging - metabolism</subject><subject>Aging - pathology</subject><subject>Animals</subject><subject>Aralkylamine N-acetyltransferase</subject><subject>Biomedical research</subject><subject>Brain</subject><subject>Cytokines</subject><subject>Cytosol - metabolism</subject><subject>Cytosol - pathology</subject><subject>Deoxyribonucleic acid</subject><subject>Development and progression</subject><subject>DNA</subject><subject>DNA, Mitochondrial - genetics</subject><subject>DNA, Mitochondrial - metabolism</subject><subject>Female</subject><subject>Homeostasis</subject><subject>Humans</subject><subject>Huntington Disease - genetics</subject><subject>Huntington Disease - metabolism</subject><subject>Huntington Disease - pathology</subject><subject>Huntington's disease</subject><subject>Huntingtons disease</subject><subject>Inflammation</subject><subject>Interferon regulatory factor 3</subject><subject>Male</subject><subject>Melatonin</subject><subject>Melatonin - pharmacology</subject><subject>Membrane potential</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mitochondrial DNA</subject><subject>Neurodegeneration</subject><subject>Neurons</subject><subject>Neurons - metabolism</subject><subject>Neurons - pathology</subject><subject>Oxidative stress</subject><subject>Rodents</subject><subject>Signal Transduction - drug effects</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><recordid>eNqNkktv1DAUhSMEokNhwR9AkZAQLFLiRxJnU2k0vAYVKvHaWo5znXHl2MV2ELPgv-Oow9BBs8BeWLr-zrF878myx6g8Q6jBL9-v1ohUJa7vZAtUVaxgmLC72aIsMSrahrCT7EEIV2WJKK3o_eyEYMRwWovs1wcwIjqrba7tRnc6hlxuowvOaJmPOjq5cbb3Wpj81cdloW0_SehzC5N32iojxjHp_TYPerDCaDsko1xICQa8iAkVw1wUdifqYQA7X2lnH2b3lDABHu3O0-zrm9dfVu-Ki8u369XyopA1bWKhRN21vagkRVBJUREle4wEKAnQUtpKVVPWItG1lapU3YBsql4B6VjbUdwRcpqd3_heT90IvQQbvTD82utR-C13QvPDG6s3fHA_eIPr1LU2GTzfGXj3fYIQ-ahD-qIRFtwUOCYNY4yguk7o03_QKzf51JpE0TQATFvM_lKDMMBTI116V86mfFnjBjesbGiiiiPUTf-Ms6B0Kh_wZ0f4tHsYtTwqeHEgSEyEn3EQUwh8_fnT_7OX3w7ZZ7fYDQgTNylS0zz0cNRUeheCB7UfCir5HG6-D3din9ye4p78k2byG4tn9GY</recordid><startdate>20200601</startdate><enddate>20200601</enddate><creator>Jauhari, Abhishek</creator><creator>Baranov, Sergei V</creator><creator>Suofu, Yalikun</creator><creator>Kim, Jinho</creator><creator>Singh, Tanisha</creator><creator>Yablonska, Svitlana</creator><creator>Li, Fang</creator><creator>Wang, Xiaomin</creator><creator>Oberly, Patrick</creator><creator>Minnigh, M Beth</creator><creator>Poloyac, Samuel M</creator><creator>Carlisle, Diane L</creator><creator>Friedlander, Robert M</creator><general>American Society for Clinical Investigation</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>IOV</scope><scope>ISR</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1728-4228</orcidid><orcidid>https://orcid.org/0000-0002-0688-640X</orcidid><orcidid>https://orcid.org/0000-0002-6455-6337</orcidid></search><sort><creationdate>20200601</creationdate><title>Melatonin inhibits cytosolic mitochondrial DNA-induced neuroinflammatory signaling in accelerated aging and neurodegeneration</title><author>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</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c647t-fa6b9da5c41e5ca53fcd21aefcee9449cf64891ab95f5f67ec75dfe3b89b42b33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Aging</topic><topic>Aging - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of clinical investigation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jauhari, Abhishek</au><au>Baranov, Sergei V</au><au>Suofu, Yalikun</au><au>Kim, Jinho</au><au>Singh, Tanisha</au><au>Yablonska, Svitlana</au><au>Li, Fang</au><au>Wang, Xiaomin</au><au>Oberly, Patrick</au><au>Minnigh, M Beth</au><au>Poloyac, Samuel M</au><au>Carlisle, Diane L</au><au>Friedlander, Robert M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Melatonin inhibits cytosolic mitochondrial DNA-induced neuroinflammatory signaling in accelerated aging and neurodegeneration</atitle><jtitle>The Journal of clinical investigation</jtitle><addtitle>J Clin Invest</addtitle><date>2020-06-01</date><risdate>2020</risdate><volume>130</volume><issue>6</issue><spage>3124</spage><epage>3136</epage><pages>3124-3136</pages><issn>0021-9738</issn><eissn>1558-8238</eissn><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.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>32182222</pmid><doi>10.1172/JCI135026</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0002-1728-4228</orcidid><orcidid>https://orcid.org/0000-0002-0688-640X</orcidid><orcidid>https://orcid.org/0000-0002-6455-6337</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 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 |
| title | Melatonin inhibits cytosolic mitochondrial DNA-induced neuroinflammatory signaling in accelerated aging and neurodegeneration |
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