Adaptation of the heart to frataxin depletion: evidence that integrated stress response can predominate over mTORC1 activation
Abstract Friedreich’s ataxia is an inherited disorder caused by depletion of frataxin (FXN), a mitochondrial protein required for iron–sulfur cluster (ISC) biogenesis. Cardiac dysfunction is the main cause of death. Yet pathogenesis, and, more generally, how the heart adapts to FXN loss, remains poo...
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Veröffentlicht in: | Human molecular genetics 2021-09, Vol.33 (8), p.637-654 |
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creator | Vásquez-Trincado, César Patel, Monika Sivaramakrishnan, Aishwarya Bekeová, Carmen Anderson-Pullinger, Lauren Wang, Nadan Tang, Hsin-Yao Seifert, Erin L |
description | Abstract
Friedreich’s ataxia is an inherited disorder caused by depletion of frataxin (FXN), a mitochondrial protein required for iron–sulfur cluster (ISC) biogenesis. Cardiac dysfunction is the main cause of death. Yet pathogenesis, and, more generally, how the heart adapts to FXN loss, remains poorly understood, though it is expected to be linked to an energy deficit. We modified a transgenic (TG) mouse model of inducible FXN depletion that permits phenotypic evaluation of the heart at different FXN levels and focused on substrate-specific bioenergetics and stress signaling. When FXN protein in the TG heart was 17% of normal, bioenergetics and signaling were not different from control. When, 8 weeks later, FXN was ~ 97% depleted in the heart, TG heart mass and cardiomyocyte cross-sectional area were less, without evidence of fibrosis or apoptosis. mTORC1 signaling was activated, as was the integrated stress response, evidenced by greater phosphorylation of eIF2α relative to total eIF2α, and decreased protein translation. We interpret these results to suggest that, in TG hearts, an anabolic stimulus was constrained by eIF2α phosphorylation. Cardiac contractility was maintained in the 97% FXN-depleted hearts, possibly contributed by an unexpected preservation of β-oxidation, though pyruvate oxidation was lower. Bioenergetics alterations were matched by changes in the mitochondrial proteome, including a non-uniform decrease in abundance of ISC-containing proteins. Altogether, these findings suggest that the FXN-depleted heart can suppress a major ATP-demanding process such as protein translation, which, together with some preservation of β-oxidation, could be adaptive, at least in the short term. |
doi_str_mv | 10.1093/hmg/ddab216 |
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Friedreich’s ataxia is an inherited disorder caused by depletion of frataxin (FXN), a mitochondrial protein required for iron–sulfur cluster (ISC) biogenesis. Cardiac dysfunction is the main cause of death. Yet pathogenesis, and, more generally, how the heart adapts to FXN loss, remains poorly understood, though it is expected to be linked to an energy deficit. We modified a transgenic (TG) mouse model of inducible FXN depletion that permits phenotypic evaluation of the heart at different FXN levels and focused on substrate-specific bioenergetics and stress signaling. When FXN protein in the TG heart was 17% of normal, bioenergetics and signaling were not different from control. When, 8 weeks later, FXN was ~ 97% depleted in the heart, TG heart mass and cardiomyocyte cross-sectional area were less, without evidence of fibrosis or apoptosis. mTORC1 signaling was activated, as was the integrated stress response, evidenced by greater phosphorylation of eIF2α relative to total eIF2α, and decreased protein translation. We interpret these results to suggest that, in TG hearts, an anabolic stimulus was constrained by eIF2α phosphorylation. Cardiac contractility was maintained in the 97% FXN-depleted hearts, possibly contributed by an unexpected preservation of β-oxidation, though pyruvate oxidation was lower. Bioenergetics alterations were matched by changes in the mitochondrial proteome, including a non-uniform decrease in abundance of ISC-containing proteins. Altogether, these findings suggest that the FXN-depleted heart can suppress a major ATP-demanding process such as protein translation, which, together with some preservation of β-oxidation, could be adaptive, at least in the short term.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddab216</identifier><identifier>PMID: 34550363</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><ispartof>Human molecular genetics, 2021-09, Vol.33 (8), p.637-654</ispartof><rights>The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2024</rights><rights>The Author(s) 2021. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c413t-a4751c74c85de8a1b5f342d574d5a2e7eaa3929abfca36c9e79a7dc9346082c53</citedby><cites>FETCH-LOGICAL-c413t-a4751c74c85de8a1b5f342d574d5a2e7eaa3929abfca36c9e79a7dc9346082c53</cites><orcidid>0000-0001-5996-5083 ; 0000-0002-8416-5763</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,780,784,885,1584,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34550363$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Vásquez-Trincado, César</creatorcontrib><creatorcontrib>Patel, Monika</creatorcontrib><creatorcontrib>Sivaramakrishnan, Aishwarya</creatorcontrib><creatorcontrib>Bekeová, Carmen</creatorcontrib><creatorcontrib>Anderson-Pullinger, Lauren</creatorcontrib><creatorcontrib>Wang, Nadan</creatorcontrib><creatorcontrib>Tang, Hsin-Yao</creatorcontrib><creatorcontrib>Seifert, Erin L</creatorcontrib><title>Adaptation of the heart to frataxin depletion: evidence that integrated stress response can predominate over mTORC1 activation</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>Abstract
Friedreich’s ataxia is an inherited disorder caused by depletion of frataxin (FXN), a mitochondrial protein required for iron–sulfur cluster (ISC) biogenesis. Cardiac dysfunction is the main cause of death. Yet pathogenesis, and, more generally, how the heart adapts to FXN loss, remains poorly understood, though it is expected to be linked to an energy deficit. We modified a transgenic (TG) mouse model of inducible FXN depletion that permits phenotypic evaluation of the heart at different FXN levels and focused on substrate-specific bioenergetics and stress signaling. When FXN protein in the TG heart was 17% of normal, bioenergetics and signaling were not different from control. When, 8 weeks later, FXN was ~ 97% depleted in the heart, TG heart mass and cardiomyocyte cross-sectional area were less, without evidence of fibrosis or apoptosis. mTORC1 signaling was activated, as was the integrated stress response, evidenced by greater phosphorylation of eIF2α relative to total eIF2α, and decreased protein translation. We interpret these results to suggest that, in TG hearts, an anabolic stimulus was constrained by eIF2α phosphorylation. Cardiac contractility was maintained in the 97% FXN-depleted hearts, possibly contributed by an unexpected preservation of β-oxidation, though pyruvate oxidation was lower. Bioenergetics alterations were matched by changes in the mitochondrial proteome, including a non-uniform decrease in abundance of ISC-containing proteins. Altogether, these findings suggest that the FXN-depleted heart can suppress a major ATP-demanding process such as protein translation, which, together with some preservation of β-oxidation, could be adaptive, at least in the short term.</description><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp90UuLFDEUBeAgitOOrtxLViJIOUnlUVVuhqHxBQMDMq7D7eRWd6QqKZN0oxt_uxm7HXTjJlnk49xwDyHPOXvD2SAudvP2wjnYtFw_ICsuNWta1ouHZMUGLRs9MH1GnuT8lTGupegekzMhlWJCixX5eeVgKVB8DDSOtOyQ7hBSoSXSMUGB7z5Qh8uEd-QtxYN3GCxWCYX6UHBbFTqaS8KcaT2WGDJSC4EuCV2cfaiAxgMmOt_efF5zCrb4w--ZT8mjEaaMz073Ofny_t3t-mNzffPh0_rqurGSi9KA7BS3nbS9ctgD36hRyNapTjoFLXYIIIZ2gM1oQWg7YDdA5-wg6jL61ipxTi6Puct-M6OzGEqCySzJz5B-mAje_PsS_M5s48FwzhjTWteEV6eEFL_tMRcz-2xxmiBg3GfTqk6JjsueVfr6SG2KOScc7-dwZu4qM7Uyc6qs6hd_f-3e_umogpdHEPfLf5N-ATfVo6w</recordid><startdate>20210922</startdate><enddate>20210922</enddate><creator>Vásquez-Trincado, César</creator><creator>Patel, Monika</creator><creator>Sivaramakrishnan, Aishwarya</creator><creator>Bekeová, Carmen</creator><creator>Anderson-Pullinger, Lauren</creator><creator>Wang, Nadan</creator><creator>Tang, Hsin-Yao</creator><creator>Seifert, Erin L</creator><general>Oxford University Press</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-5996-5083</orcidid><orcidid>https://orcid.org/0000-0002-8416-5763</orcidid></search><sort><creationdate>20210922</creationdate><title>Adaptation of the heart to frataxin depletion: evidence that integrated stress response can predominate over mTORC1 activation</title><author>Vásquez-Trincado, César ; Patel, Monika ; Sivaramakrishnan, Aishwarya ; Bekeová, Carmen ; Anderson-Pullinger, Lauren ; Wang, Nadan ; Tang, Hsin-Yao ; Seifert, Erin L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c413t-a4751c74c85de8a1b5f342d574d5a2e7eaa3929abfca36c9e79a7dc9346082c53</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vásquez-Trincado, César</creatorcontrib><creatorcontrib>Patel, Monika</creatorcontrib><creatorcontrib>Sivaramakrishnan, Aishwarya</creatorcontrib><creatorcontrib>Bekeová, Carmen</creatorcontrib><creatorcontrib>Anderson-Pullinger, Lauren</creatorcontrib><creatorcontrib>Wang, Nadan</creatorcontrib><creatorcontrib>Tang, Hsin-Yao</creatorcontrib><creatorcontrib>Seifert, Erin L</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vásquez-Trincado, César</au><au>Patel, Monika</au><au>Sivaramakrishnan, Aishwarya</au><au>Bekeová, Carmen</au><au>Anderson-Pullinger, Lauren</au><au>Wang, Nadan</au><au>Tang, Hsin-Yao</au><au>Seifert, Erin L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Adaptation of the heart to frataxin depletion: evidence that integrated stress response can predominate over mTORC1 activation</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2021-09-22</date><risdate>2021</risdate><volume>33</volume><issue>8</issue><spage>637</spage><epage>654</epage><pages>637-654</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><abstract>Abstract
Friedreich’s ataxia is an inherited disorder caused by depletion of frataxin (FXN), a mitochondrial protein required for iron–sulfur cluster (ISC) biogenesis. Cardiac dysfunction is the main cause of death. Yet pathogenesis, and, more generally, how the heart adapts to FXN loss, remains poorly understood, though it is expected to be linked to an energy deficit. We modified a transgenic (TG) mouse model of inducible FXN depletion that permits phenotypic evaluation of the heart at different FXN levels and focused on substrate-specific bioenergetics and stress signaling. When FXN protein in the TG heart was 17% of normal, bioenergetics and signaling were not different from control. When, 8 weeks later, FXN was ~ 97% depleted in the heart, TG heart mass and cardiomyocyte cross-sectional area were less, without evidence of fibrosis or apoptosis. mTORC1 signaling was activated, as was the integrated stress response, evidenced by greater phosphorylation of eIF2α relative to total eIF2α, and decreased protein translation. We interpret these results to suggest that, in TG hearts, an anabolic stimulus was constrained by eIF2α phosphorylation. Cardiac contractility was maintained in the 97% FXN-depleted hearts, possibly contributed by an unexpected preservation of β-oxidation, though pyruvate oxidation was lower. Bioenergetics alterations were matched by changes in the mitochondrial proteome, including a non-uniform decrease in abundance of ISC-containing proteins. Altogether, these findings suggest that the FXN-depleted heart can suppress a major ATP-demanding process such as protein translation, which, together with some preservation of β-oxidation, could be adaptive, at least in the short term.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>34550363</pmid><doi>10.1093/hmg/ddab216</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0001-5996-5083</orcidid><orcidid>https://orcid.org/0000-0002-8416-5763</orcidid><oa>free_for_read</oa></addata></record> |
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title | Adaptation of the heart to frataxin depletion: evidence that integrated stress response can predominate over mTORC1 activation |
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