Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics
Mitochondria undergo dynamic fusion/fission, biogenesis and mitophagy in response to stimuli or stresses. Disruption of mitochondrial homeostasis could lead to cell senescence, although the underlying mechanism remains unclear. We show that deletion of mitochondrial phosphatase PGAM5 leads to accele...
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| Veröffentlicht in: | Nature communications 2020-05, Vol.11 (1), p.2549-2549, Article 2549 |
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| creator | Yu, Bo Ma, Jing Li, Jing Wang, Dazhi Wang, Zhigao Wang, Shusheng |
| description | Mitochondria undergo dynamic fusion/fission, biogenesis and mitophagy in response to stimuli or stresses. Disruption of mitochondrial homeostasis could lead to cell senescence, although the underlying mechanism remains unclear. We show that deletion of mitochondrial phosphatase PGAM5 leads to accelerated retinal pigment epithelial (RPE) senescence in vitro and in vivo. Mechanistically, PGAM5 is required for mitochondrial fission through dephosphorylating DRP1.
PGAM5
deletion leads to increased mitochondrial fusion and decreased mitochondrial turnover. As results, cellular ATP and reactive oxygen species (ROS) levels are elevated, mTOR and IRF/IFN-β signaling pathways are enhanced, leading to cellular senescence. Overexpression of Drp1 K38A or S637A mutant phenocopies or rescues mTOR activation and senescence in
PGAM5
−
/−
cells, respectively. Young but not aging
Pgam5
−/−
mice are resistant to sodium iodate-induced RPE cell death. Our studies establish a link between defective mitochondrial fission, cellular senescence and age-dependent oxidative stress response, which have implications in age-related diseases.
Mitochondria are a hub that can direct cellular outcomes in response to stress. Here, the authors show that mitochondrial phosphatase PGAM5 has a role in mitochondrial turnover and regulation of cellular senescence by altering organellar dynamics via fission regulator Drp1. |
| doi_str_mv | 10.1038/s41467-020-16312-7 |
| format | Article |
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PGAM5
deletion leads to increased mitochondrial fusion and decreased mitochondrial turnover. As results, cellular ATP and reactive oxygen species (ROS) levels are elevated, mTOR and IRF/IFN-β signaling pathways are enhanced, leading to cellular senescence. Overexpression of Drp1 K38A or S637A mutant phenocopies or rescues mTOR activation and senescence in
PGAM5
−
/−
cells, respectively. Young but not aging
Pgam5
−/−
mice are resistant to sodium iodate-induced RPE cell death. Our studies establish a link between defective mitochondrial fission, cellular senescence and age-dependent oxidative stress response, which have implications in age-related diseases.
Mitochondria are a hub that can direct cellular outcomes in response to stress. Here, the authors show that mitochondrial phosphatase PGAM5 has a role in mitochondrial turnover and regulation of cellular senescence by altering organellar dynamics via fission regulator Drp1.</description><identifier>ISSN: 2041-1723</identifier><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/s41467-020-16312-7</identifier><identifier>PMID: 32439975</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/31 ; 13/51 ; 13/95 ; 14/19 ; 45/77 ; 631/80/509 ; 631/80/642/333 ; 631/80/86 ; 64/60 ; 82/1 ; 82/51 ; 82/80 ; Age Factors ; Age related diseases ; Aging ; Animals ; Cell death ; Cell Line ; Cellular Senescence ; Cellular stress response ; Deletion ; Dynamins - genetics ; Dynamins - metabolism ; Fission ; Gene Expression Regulation ; Homeostasis ; Humanities and Social Sciences ; Humans ; Mice ; Mice, Knockout ; Mitochondria ; Mitochondria - metabolism ; Mitochondrial Dynamics ; multidisciplinary ; Multidisciplinary Sciences ; Oxidative stress ; Oxidative Stress - genetics ; Phosphatase ; Phosphoprotein Phosphatases - genetics ; Phosphoprotein Phosphatases - metabolism ; Reactive oxygen species ; Retinal Pigment Epithelium - metabolism ; Retinal Pigment Epithelium - pathology ; Science ; Science & Technology ; Science & Technology - Other Topics ; Science (multidisciplinary) ; Senescence ; Signal Transduction ; TOR protein ; β-Interferon</subject><ispartof>Nature communications, 2020-05, Vol.11 (1), p.2549-2549, Article 2549</ispartof><rights>The Author(s) 2020</rights><rights>The Author(s) 2020. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>129</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000537068500006</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c606t-89047038e1ae83befa9fdb498c37754457f1f0bc27c07ccb86354e999af2db7c3</citedby><cites>FETCH-LOGICAL-c606t-89047038e1ae83befa9fdb498c37754457f1f0bc27c07ccb86354e999af2db7c3</cites><orcidid>0000-0002-8841-5432 ; 0000-0002-6544-4302</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/PMC7242393/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7242393/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2106,2118,27933,27934,28257,41129,42198,51585,53800,53802</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32439975$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yu, Bo</creatorcontrib><creatorcontrib>Ma, Jing</creatorcontrib><creatorcontrib>Li, Jing</creatorcontrib><creatorcontrib>Wang, Dazhi</creatorcontrib><creatorcontrib>Wang, Zhigao</creatorcontrib><creatorcontrib>Wang, Shusheng</creatorcontrib><title>Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><addtitle>NAT COMMUN</addtitle><addtitle>Nat Commun</addtitle><description>Mitochondria undergo dynamic fusion/fission, biogenesis and mitophagy in response to stimuli or stresses. Disruption of mitochondrial homeostasis could lead to cell senescence, although the underlying mechanism remains unclear. We show that deletion of mitochondrial phosphatase PGAM5 leads to accelerated retinal pigment epithelial (RPE) senescence in vitro and in vivo. Mechanistically, PGAM5 is required for mitochondrial fission through dephosphorylating DRP1.
PGAM5
deletion leads to increased mitochondrial fusion and decreased mitochondrial turnover. As results, cellular ATP and reactive oxygen species (ROS) levels are elevated, mTOR and IRF/IFN-β signaling pathways are enhanced, leading to cellular senescence. Overexpression of Drp1 K38A or S637A mutant phenocopies or rescues mTOR activation and senescence in
PGAM5
−
/−
cells, respectively. Young but not aging
Pgam5
−/−
mice are resistant to sodium iodate-induced RPE cell death. Our studies establish a link between defective mitochondrial fission, cellular senescence and age-dependent oxidative stress response, which have implications in age-related diseases.
Mitochondria are a hub that can direct cellular outcomes in response to stress. Here, the authors show that mitochondrial phosphatase PGAM5 has a role in mitochondrial turnover and regulation of cellular senescence by altering organellar dynamics via fission regulator Drp1.</description><subject>13/31</subject><subject>13/51</subject><subject>13/95</subject><subject>14/19</subject><subject>45/77</subject><subject>631/80/509</subject><subject>631/80/642/333</subject><subject>631/80/86</subject><subject>64/60</subject><subject>82/1</subject><subject>82/51</subject><subject>82/80</subject><subject>Age Factors</subject><subject>Age related diseases</subject><subject>Aging</subject><subject>Animals</subject><subject>Cell death</subject><subject>Cell Line</subject><subject>Cellular Senescence</subject><subject>Cellular stress response</subject><subject>Deletion</subject><subject>Dynamins - genetics</subject><subject>Dynamins - metabolism</subject><subject>Fission</subject><subject>Gene Expression Regulation</subject><subject>Homeostasis</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Mitochondria</subject><subject>Mitochondria - metabolism</subject><subject>Mitochondrial Dynamics</subject><subject>multidisciplinary</subject><subject>Multidisciplinary Sciences</subject><subject>Oxidative stress</subject><subject>Oxidative Stress - genetics</subject><subject>Phosphatase</subject><subject>Phosphoprotein Phosphatases - genetics</subject><subject>Phosphoprotein Phosphatases - metabolism</subject><subject>Reactive oxygen species</subject><subject>Retinal Pigment Epithelium - metabolism</subject><subject>Retinal Pigment Epithelium - pathology</subject><subject>Science</subject><subject>Science & Technology</subject><subject>Science & Technology - Other Topics</subject><subject>Science (multidisciplinary)</subject><subject>Senescence</subject><subject>Signal Transduction</subject><subject>TOR protein</subject><subject>β-Interferon</subject><issn>2041-1723</issn><issn>2041-1723</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>AOWDO</sourceid><sourceid>EIF</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>DOA</sourceid><recordid>eNqNkktv1DAUhSMEolXpH2CBIrFBQgG_HxukakQfUitYwNpyHHvGo8Qe7KRo_j1OU4YOC4Q3tuzvHt1zfarqNQQfIMDiYyaQMN4ABBrIMEQNf1adIkBgAznCz5-cT6rznLegLCyhIORldYIRwVJyelq1d36MZhNDl7zu690m5t1Gjzrb-uvVxR2th9hNvR5tro3t-3JMdbbBZmODsXW7r5Ndz4AP63o40ur2QQ_e5FfVC6f7bM8f97Pq--Xnb6vr5vbL1c3q4rYxDLCxERIQXpxZqK3ArXVauq4lUhjMOSWEcgcdaA3iBnBjWsEwJVZKqR3qWm7wWXWz6HZRb9Uu-UGnvYraq4eLmNZKp9Gb3iouXBmAdhhITbAWQkqKjACMaiwA4kXr06K1m9rBdsXsmHR_JHr8EvxGreO94oggLHERePcokOKPyeZRDT7PE9TBxikrRADDgGAqC_r2L3QbpxTKqGaKUskAJYVCC2VSzDlZd2gGAjUnQi2JUCUR6iERarbx5qmNQ8nv_y_A-wX4advosvHzrx6wEhmKOWCCzulhhRb_T6_8WFIRwypOYSyleCnNBQ9rm_6Y_Ef_vwCaaeJt</recordid><startdate>20200521</startdate><enddate>20200521</enddate><creator>Yu, Bo</creator><creator>Ma, Jing</creator><creator>Li, Jing</creator><creator>Wang, Dazhi</creator><creator>Wang, Zhigao</creator><creator>Wang, Shusheng</creator><general>Nature Publishing Group UK</general><general>Springer Nature</general><general>Nature Publishing Group</general><general>Nature Portfolio</general><scope>C6C</scope><scope>AOWDO</scope><scope>BLEPL</scope><scope>DTL</scope><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>3V.</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7ST</scope><scope>7T5</scope><scope>7T7</scope><scope>7TM</scope><scope>7TO</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>RC3</scope><scope>SOI</scope><scope>7X8</scope><scope>5PM</scope><scope>DOA</scope><orcidid>https://orcid.org/0000-0002-8841-5432</orcidid><orcidid>https://orcid.org/0000-0002-6544-4302</orcidid></search><sort><creationdate>20200521</creationdate><title>Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics</title><author>Yu, Bo ; Ma, Jing ; Li, Jing ; Wang, Dazhi ; Wang, Zhigao ; Wang, Shusheng</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c606t-89047038e1ae83befa9fdb498c37754457f1f0bc27c07ccb86354e999af2db7c3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>13/31</topic><topic>13/51</topic><topic>13/95</topic><topic>14/19</topic><topic>45/77</topic><topic>631/80/509</topic><topic>631/80/642/333</topic><topic>631/80/86</topic><topic>64/60</topic><topic>82/1</topic><topic>82/51</topic><topic>82/80</topic><topic>Age Factors</topic><topic>Age related diseases</topic><topic>Aging</topic><topic>Animals</topic><topic>Cell death</topic><topic>Cell Line</topic><topic>Cellular Senescence</topic><topic>Cellular stress response</topic><topic>Deletion</topic><topic>Dynamins - genetics</topic><topic>Dynamins - metabolism</topic><topic>Fission</topic><topic>Gene Expression Regulation</topic><topic>Homeostasis</topic><topic>Humanities and Social Sciences</topic><topic>Humans</topic><topic>Mice</topic><topic>Mice, Knockout</topic><topic>Mitochondria</topic><topic>Mitochondria - metabolism</topic><topic>Mitochondrial Dynamics</topic><topic>multidisciplinary</topic><topic>Multidisciplinary Sciences</topic><topic>Oxidative stress</topic><topic>Oxidative Stress - genetics</topic><topic>Phosphatase</topic><topic>Phosphoprotein Phosphatases - genetics</topic><topic>Phosphoprotein Phosphatases - metabolism</topic><topic>Reactive oxygen species</topic><topic>Retinal Pigment Epithelium - metabolism</topic><topic>Retinal Pigment Epithelium - pathology</topic><topic>Science</topic><topic>Science & Technology</topic><topic>Science & Technology - Other Topics</topic><topic>Science (multidisciplinary)</topic><topic>Senescence</topic><topic>Signal Transduction</topic><topic>TOR protein</topic><topic>β-Interferon</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yu, Bo</creatorcontrib><creatorcontrib>Ma, Jing</creatorcontrib><creatorcontrib>Li, Jing</creatorcontrib><creatorcontrib>Wang, Dazhi</creatorcontrib><creatorcontrib>Wang, Zhigao</creatorcontrib><creatorcontrib>Wang, Shusheng</creatorcontrib><collection>Springer Nature OA/Free Journals</collection><collection>Web of Science - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Nature communications</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yu, Bo</au><au>Ma, Jing</au><au>Li, Jing</au><au>Wang, Dazhi</au><au>Wang, Zhigao</au><au>Wang, Shusheng</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics</atitle><jtitle>Nature communications</jtitle><stitle>Nat Commun</stitle><stitle>NAT COMMUN</stitle><addtitle>Nat Commun</addtitle><date>2020-05-21</date><risdate>2020</risdate><volume>11</volume><issue>1</issue><spage>2549</spage><epage>2549</epage><pages>2549-2549</pages><artnum>2549</artnum><issn>2041-1723</issn><eissn>2041-1723</eissn><abstract>Mitochondria undergo dynamic fusion/fission, biogenesis and mitophagy in response to stimuli or stresses. Disruption of mitochondrial homeostasis could lead to cell senescence, although the underlying mechanism remains unclear. We show that deletion of mitochondrial phosphatase PGAM5 leads to accelerated retinal pigment epithelial (RPE) senescence in vitro and in vivo. Mechanistically, PGAM5 is required for mitochondrial fission through dephosphorylating DRP1.
PGAM5
deletion leads to increased mitochondrial fusion and decreased mitochondrial turnover. As results, cellular ATP and reactive oxygen species (ROS) levels are elevated, mTOR and IRF/IFN-β signaling pathways are enhanced, leading to cellular senescence. Overexpression of Drp1 K38A or S637A mutant phenocopies or rescues mTOR activation and senescence in
PGAM5
−
/−
cells, respectively. Young but not aging
Pgam5
−/−
mice are resistant to sodium iodate-induced RPE cell death. Our studies establish a link between defective mitochondrial fission, cellular senescence and age-dependent oxidative stress response, which have implications in age-related diseases.
Mitochondria are a hub that can direct cellular outcomes in response to stress. Here, the authors show that mitochondrial phosphatase PGAM5 has a role in mitochondrial turnover and regulation of cellular senescence by altering organellar dynamics via fission regulator Drp1.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32439975</pmid><doi>10.1038/s41467-020-16312-7</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-8841-5432</orcidid><orcidid>https://orcid.org/0000-0002-6544-4302</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | 13/31 13/51 13/95 14/19 45/77 631/80/509 631/80/642/333 631/80/86 64/60 82/1 82/51 82/80 Age Factors Age related diseases Aging Animals Cell death Cell Line Cellular Senescence Cellular stress response Deletion Dynamins - genetics Dynamins - metabolism Fission Gene Expression Regulation Homeostasis Humanities and Social Sciences Humans Mice Mice, Knockout Mitochondria Mitochondria - metabolism Mitochondrial Dynamics multidisciplinary Multidisciplinary Sciences Oxidative stress Oxidative Stress - genetics Phosphatase Phosphoprotein Phosphatases - genetics Phosphoprotein Phosphatases - metabolism Reactive oxygen species Retinal Pigment Epithelium - metabolism Retinal Pigment Epithelium - pathology Science Science & Technology Science & Technology - Other Topics Science (multidisciplinary) Senescence Signal Transduction TOR protein β-Interferon |
| title | Mitochondrial phosphatase PGAM5 modulates cellular senescence by regulating mitochondrial dynamics |
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