Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity
Autophagy is a cellular self-digestion process that mediates protein quality control and serves to protect against neurodegenerative disorders, infections, inflammatory diseases and cancer. Current evidence suggests that autophagy can selectively remove damaged organelles such as the mitochondria. M...
Gespeichert in:
Veröffentlicht in: | Autophagy 2013-03, Vol.9 (3), p.328-344 |
---|---|
Hauptverfasser: | , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
container_end_page | 344 |
---|---|
container_issue | 3 |
container_start_page | 328 |
container_title | Autophagy |
container_volume | 9 |
creator | Dutta, Debapriya Xu, Jinze Kim, Jae-Sung Dunn Jr, William A. Leeuwenburgh, Christiaan |
description | Autophagy is a cellular self-digestion process that mediates protein quality control and serves to protect against neurodegenerative disorders, infections, inflammatory diseases and cancer. Current evidence suggests that autophagy can selectively remove damaged organelles such as the mitochondria. Mitochondria-induced oxidative stress has been shown to play a major role in a wide range of pathologies in several organs, including the heart. Few studies have investigated whether enhanced autophagy can offer protection against mitochondrially-generated oxidative stress. We induced mitochondrial stress in cardiomyocytes using antimycin A (AMA), which increased mitochondrial superoxide generation, decreased mitochondrial membrane potential and depressed cellular respiration. In addition, AMA augmented nuclear DNA oxidation and cell death in cardiomyocytes. Interestingly, although oxidative stress has been proposed to induce autophagy, treatment with AMA did not result in stimulation of autophagy or mitophagy in cardiomyocytes. Our results showed that the MTOR inhibitor rapamycin induced autophagy, promoted mitochondrial clearance and protected cardiomyocytes from the cytotoxic effects of AMA, as assessed by apoptotic marker activation and viability assays in both mouse atrial HL-1 cardiomyocytes and human ventricular AC16 cells. Importantly, rapamycin improved mitochondrial function, as determined by cellular respiration, mitochondrial membrane potential and morphology analysis. Furthermore, autophagy induction by rapamycin suppressed the accumulation of ubiquitinylated proteins induced by AMA. Inhibition of rapamycin-induced autophagy by pharmacological or genetic interventions attenuated the cytoprotective effects of rapamycin against AMA. We propose that rapamycin offers cytoprotection against oxidative stress by a combined approach of removing dysfunctional mitochondria as well as by degrading damaged, ubiquitinated proteins. We conclude that autophagy induction by rapamycin could be utilized as a potential therapeutic strategy against oxidative stress-mediated damage in cardiomyocytes. |
doi_str_mv | 10.4161/auto.22971 |
format | Article |
fullrecord | <record><control><sourceid>pubmed_infor</sourceid><recordid>TN_cdi_pubmed_primary_23298947</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>23298947</sourcerecordid><originalsourceid>FETCH-LOGICAL-c424t-e1c21aac268c1a8abe1424d5abf4f6e4478322268fb8f802f9126292676a0dba3</originalsourceid><addsrcrecordid>eNptkN1LwzAUxYMobk5f_AOkz0Jnk6Zp-yKI-AUDX7bncJuPLdI2JUmn_e_tnA4Fn-7lnnN-Fw5ClziZU8zwDfTBzgkpc3yEpjjLaFywNDs-7CSfoDPv35IkZUVJTtGEpKQsSppP0XLVObXuawhKRjtQt4H1EHXOBiWCjwQ4aWwzWDEE5SPtbBPZDyMhmK2KfHDK-9i0shdjPoyKMGE4Rycaaq8uvucMrR4flvfP8eL16eX-bhELSmiIFRYEAwjCCoGhgErh8S4zqDTVTFGaFykho6qrQhcJ0SUmjJSE5QwSWUE6Q7d7btdXjZJCtcFBzTtnGnADt2D4X6U1G762W55mZUIyOgKu9wDhrPdO6UMWJ3zXLd9Vwr-6Hc1Xv78drD9ljoZsbzCttq6Bd-tqyQMMtXXaQSuM5-k_4E8a8IwA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity</title><source>MEDLINE</source><source>EZB-FREE-00999 freely available EZB journals</source><source>PubMed Central</source><creator>Dutta, Debapriya ; Xu, Jinze ; Kim, Jae-Sung ; Dunn Jr, William A. ; Leeuwenburgh, Christiaan</creator><creatorcontrib>Dutta, Debapriya ; Xu, Jinze ; Kim, Jae-Sung ; Dunn Jr, William A. ; Leeuwenburgh, Christiaan</creatorcontrib><description>Autophagy is a cellular self-digestion process that mediates protein quality control and serves to protect against neurodegenerative disorders, infections, inflammatory diseases and cancer. Current evidence suggests that autophagy can selectively remove damaged organelles such as the mitochondria. Mitochondria-induced oxidative stress has been shown to play a major role in a wide range of pathologies in several organs, including the heart. Few studies have investigated whether enhanced autophagy can offer protection against mitochondrially-generated oxidative stress. We induced mitochondrial stress in cardiomyocytes using antimycin A (AMA), which increased mitochondrial superoxide generation, decreased mitochondrial membrane potential and depressed cellular respiration. In addition, AMA augmented nuclear DNA oxidation and cell death in cardiomyocytes. Interestingly, although oxidative stress has been proposed to induce autophagy, treatment with AMA did not result in stimulation of autophagy or mitophagy in cardiomyocytes. Our results showed that the MTOR inhibitor rapamycin induced autophagy, promoted mitochondrial clearance and protected cardiomyocytes from the cytotoxic effects of AMA, as assessed by apoptotic marker activation and viability assays in both mouse atrial HL-1 cardiomyocytes and human ventricular AC16 cells. Importantly, rapamycin improved mitochondrial function, as determined by cellular respiration, mitochondrial membrane potential and morphology analysis. Furthermore, autophagy induction by rapamycin suppressed the accumulation of ubiquitinylated proteins induced by AMA. Inhibition of rapamycin-induced autophagy by pharmacological or genetic interventions attenuated the cytoprotective effects of rapamycin against AMA. We propose that rapamycin offers cytoprotection against oxidative stress by a combined approach of removing dysfunctional mitochondria as well as by degrading damaged, ubiquitinated proteins. We conclude that autophagy induction by rapamycin could be utilized as a potential therapeutic strategy against oxidative stress-mediated damage in cardiomyocytes.</description><identifier>ISSN: 1554-8627</identifier><identifier>EISSN: 1554-8635</identifier><identifier>DOI: 10.4161/auto.22971</identifier><identifier>PMID: 23298947</identifier><language>eng</language><publisher>United States: Taylor & Francis</publisher><subject>Animals ; Antimycin A - pharmacology ; Autophagy ; Basic Research Paper ; cardiomyocytes ; Cell Line ; Dose-Response Relationship, Drug ; Electron Transport ; Humans ; Membrane Potential, Mitochondrial ; Mice ; mitochondrial dysfunction ; MTOR ; Myocytes, Cardiac - cytology ; Myocytes, Cardiac - pathology ; Oxidation-Reduction ; Oxidative Stress ; Oxygen - metabolism ; rapamycin ; Reactive Oxygen Species - metabolism ; Sirolimus - metabolism ; TOR Serine-Threonine Kinases - metabolism ; Up-Regulation</subject><ispartof>Autophagy, 2013-03, Vol.9 (3), p.328-344</ispartof><rights>Copyright © 2013 Landes Bioscience 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c424t-e1c21aac268c1a8abe1424d5abf4f6e4478322268fb8f802f9126292676a0dba3</citedby><cites>FETCH-LOGICAL-c424t-e1c21aac268c1a8abe1424d5abf4f6e4478322268fb8f802f9126292676a0dba3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590254/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3590254/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23298947$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Dutta, Debapriya</creatorcontrib><creatorcontrib>Xu, Jinze</creatorcontrib><creatorcontrib>Kim, Jae-Sung</creatorcontrib><creatorcontrib>Dunn Jr, William A.</creatorcontrib><creatorcontrib>Leeuwenburgh, Christiaan</creatorcontrib><title>Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity</title><title>Autophagy</title><addtitle>Autophagy</addtitle><description>Autophagy is a cellular self-digestion process that mediates protein quality control and serves to protect against neurodegenerative disorders, infections, inflammatory diseases and cancer. Current evidence suggests that autophagy can selectively remove damaged organelles such as the mitochondria. Mitochondria-induced oxidative stress has been shown to play a major role in a wide range of pathologies in several organs, including the heart. Few studies have investigated whether enhanced autophagy can offer protection against mitochondrially-generated oxidative stress. We induced mitochondrial stress in cardiomyocytes using antimycin A (AMA), which increased mitochondrial superoxide generation, decreased mitochondrial membrane potential and depressed cellular respiration. In addition, AMA augmented nuclear DNA oxidation and cell death in cardiomyocytes. Interestingly, although oxidative stress has been proposed to induce autophagy, treatment with AMA did not result in stimulation of autophagy or mitophagy in cardiomyocytes. Our results showed that the MTOR inhibitor rapamycin induced autophagy, promoted mitochondrial clearance and protected cardiomyocytes from the cytotoxic effects of AMA, as assessed by apoptotic marker activation and viability assays in both mouse atrial HL-1 cardiomyocytes and human ventricular AC16 cells. Importantly, rapamycin improved mitochondrial function, as determined by cellular respiration, mitochondrial membrane potential and morphology analysis. Furthermore, autophagy induction by rapamycin suppressed the accumulation of ubiquitinylated proteins induced by AMA. Inhibition of rapamycin-induced autophagy by pharmacological or genetic interventions attenuated the cytoprotective effects of rapamycin against AMA. We propose that rapamycin offers cytoprotection against oxidative stress by a combined approach of removing dysfunctional mitochondria as well as by degrading damaged, ubiquitinated proteins. We conclude that autophagy induction by rapamycin could be utilized as a potential therapeutic strategy against oxidative stress-mediated damage in cardiomyocytes.</description><subject>Animals</subject><subject>Antimycin A - pharmacology</subject><subject>Autophagy</subject><subject>Basic Research Paper</subject><subject>cardiomyocytes</subject><subject>Cell Line</subject><subject>Dose-Response Relationship, Drug</subject><subject>Electron Transport</subject><subject>Humans</subject><subject>Membrane Potential, Mitochondrial</subject><subject>Mice</subject><subject>mitochondrial dysfunction</subject><subject>MTOR</subject><subject>Myocytes, Cardiac - cytology</subject><subject>Myocytes, Cardiac - pathology</subject><subject>Oxidation-Reduction</subject><subject>Oxidative Stress</subject><subject>Oxygen - metabolism</subject><subject>rapamycin</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Sirolimus - metabolism</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><subject>Up-Regulation</subject><issn>1554-8627</issn><issn>1554-8635</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkN1LwzAUxYMobk5f_AOkz0Jnk6Zp-yKI-AUDX7bncJuPLdI2JUmn_e_tnA4Fn-7lnnN-Fw5ClziZU8zwDfTBzgkpc3yEpjjLaFywNDs-7CSfoDPv35IkZUVJTtGEpKQsSppP0XLVObXuawhKRjtQt4H1EHXOBiWCjwQ4aWwzWDEE5SPtbBPZDyMhmK2KfHDK-9i0shdjPoyKMGE4Rycaaq8uvucMrR4flvfP8eL16eX-bhELSmiIFRYEAwjCCoGhgErh8S4zqDTVTFGaFykho6qrQhcJ0SUmjJSE5QwSWUE6Q7d7btdXjZJCtcFBzTtnGnADt2D4X6U1G762W55mZUIyOgKu9wDhrPdO6UMWJ3zXLd9Vwr-6Hc1Xv78drD9ljoZsbzCttq6Bd-tqyQMMtXXaQSuM5-k_4E8a8IwA</recordid><startdate>20130301</startdate><enddate>20130301</enddate><creator>Dutta, Debapriya</creator><creator>Xu, Jinze</creator><creator>Kim, Jae-Sung</creator><creator>Dunn Jr, William A.</creator><creator>Leeuwenburgh, Christiaan</creator><general>Taylor & Francis</general><general>Landes Bioscience</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>5PM</scope></search><sort><creationdate>20130301</creationdate><title>Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity</title><author>Dutta, Debapriya ; Xu, Jinze ; Kim, Jae-Sung ; Dunn Jr, William A. ; Leeuwenburgh, Christiaan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c424t-e1c21aac268c1a8abe1424d5abf4f6e4478322268fb8f802f9126292676a0dba3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Antimycin A - pharmacology</topic><topic>Autophagy</topic><topic>Basic Research Paper</topic><topic>cardiomyocytes</topic><topic>Cell Line</topic><topic>Dose-Response Relationship, Drug</topic><topic>Electron Transport</topic><topic>Humans</topic><topic>Membrane Potential, Mitochondrial</topic><topic>Mice</topic><topic>mitochondrial dysfunction</topic><topic>MTOR</topic><topic>Myocytes, Cardiac - cytology</topic><topic>Myocytes, Cardiac - pathology</topic><topic>Oxidation-Reduction</topic><topic>Oxidative Stress</topic><topic>Oxygen - metabolism</topic><topic>rapamycin</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Sirolimus - metabolism</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><topic>Up-Regulation</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Dutta, Debapriya</creatorcontrib><creatorcontrib>Xu, Jinze</creatorcontrib><creatorcontrib>Kim, Jae-Sung</creatorcontrib><creatorcontrib>Dunn Jr, William A.</creatorcontrib><creatorcontrib>Leeuwenburgh, Christiaan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Autophagy</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Dutta, Debapriya</au><au>Xu, Jinze</au><au>Kim, Jae-Sung</au><au>Dunn Jr, William A.</au><au>Leeuwenburgh, Christiaan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity</atitle><jtitle>Autophagy</jtitle><addtitle>Autophagy</addtitle><date>2013-03-01</date><risdate>2013</risdate><volume>9</volume><issue>3</issue><spage>328</spage><epage>344</epage><pages>328-344</pages><issn>1554-8627</issn><eissn>1554-8635</eissn><abstract>Autophagy is a cellular self-digestion process that mediates protein quality control and serves to protect against neurodegenerative disorders, infections, inflammatory diseases and cancer. Current evidence suggests that autophagy can selectively remove damaged organelles such as the mitochondria. Mitochondria-induced oxidative stress has been shown to play a major role in a wide range of pathologies in several organs, including the heart. Few studies have investigated whether enhanced autophagy can offer protection against mitochondrially-generated oxidative stress. We induced mitochondrial stress in cardiomyocytes using antimycin A (AMA), which increased mitochondrial superoxide generation, decreased mitochondrial membrane potential and depressed cellular respiration. In addition, AMA augmented nuclear DNA oxidation and cell death in cardiomyocytes. Interestingly, although oxidative stress has been proposed to induce autophagy, treatment with AMA did not result in stimulation of autophagy or mitophagy in cardiomyocytes. Our results showed that the MTOR inhibitor rapamycin induced autophagy, promoted mitochondrial clearance and protected cardiomyocytes from the cytotoxic effects of AMA, as assessed by apoptotic marker activation and viability assays in both mouse atrial HL-1 cardiomyocytes and human ventricular AC16 cells. Importantly, rapamycin improved mitochondrial function, as determined by cellular respiration, mitochondrial membrane potential and morphology analysis. Furthermore, autophagy induction by rapamycin suppressed the accumulation of ubiquitinylated proteins induced by AMA. Inhibition of rapamycin-induced autophagy by pharmacological or genetic interventions attenuated the cytoprotective effects of rapamycin against AMA. We propose that rapamycin offers cytoprotection against oxidative stress by a combined approach of removing dysfunctional mitochondria as well as by degrading damaged, ubiquitinated proteins. We conclude that autophagy induction by rapamycin could be utilized as a potential therapeutic strategy against oxidative stress-mediated damage in cardiomyocytes.</abstract><cop>United States</cop><pub>Taylor & Francis</pub><pmid>23298947</pmid><doi>10.4161/auto.22971</doi><tpages>17</tpages><oa>free_for_read</oa></addata></record> |
fulltext | fulltext |
identifier | ISSN: 1554-8627 |
ispartof | Autophagy, 2013-03, Vol.9 (3), p.328-344 |
issn | 1554-8627 1554-8635 |
language | eng |
recordid | cdi_pubmed_primary_23298947 |
source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central |
subjects | Animals Antimycin A - pharmacology Autophagy Basic Research Paper cardiomyocytes Cell Line Dose-Response Relationship, Drug Electron Transport Humans Membrane Potential, Mitochondrial Mice mitochondrial dysfunction MTOR Myocytes, Cardiac - cytology Myocytes, Cardiac - pathology Oxidation-Reduction Oxidative Stress Oxygen - metabolism rapamycin Reactive Oxygen Species - metabolism Sirolimus - metabolism TOR Serine-Threonine Kinases - metabolism Up-Regulation |
title | Upregulated autophagy protects cardiomyocytes from oxidative stress-induced toxicity |
url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-02T14%3A05%3A57IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-pubmed_infor&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Upregulated%20autophagy%20protects%20cardiomyocytes%20from%20oxidative%20stress-induced%20toxicity&rft.jtitle=Autophagy&rft.au=Dutta,%20Debapriya&rft.date=2013-03-01&rft.volume=9&rft.issue=3&rft.spage=328&rft.epage=344&rft.pages=328-344&rft.issn=1554-8627&rft.eissn=1554-8635&rft_id=info:doi/10.4161/auto.22971&rft_dat=%3Cpubmed_infor%3E23298947%3C/pubmed_infor%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_id=info:pmid/23298947&rfr_iscdi=true |