TFEB-driven lysosomal biogenesis is pivotal for PGC1α-dependent renal stress resistance
Identifieur interne : 000685 ( Pmc/Curation ); précédent : 000684; suivant : 000686TFEB-driven lysosomal biogenesis is pivotal for PGC1α-dependent renal stress resistance
Auteurs : Matthew R. Lynch [États-Unis] ; Mei T. Tran [États-Unis] ; Kenneth M. Ralto [États-Unis] ; Zsuzsanna K. Zsengeller [États-Unis] ; Vinod Raman [États-Unis] ; Swati S. Bhasin [États-Unis] ; Nuo Sun [États-Unis] ; Xiuying Chen [États-Unis] ; Daniel Brown [États-Unis] ; Ilsa I. Rovira [États-Unis] ; Kensei Taguchi [États-Unis] ; Craig R. Brooks [États-Unis] ; Isaac E. Stillman [États-Unis] ; Manoj K. Bhasin [États-Unis] ; Toren Finkel [États-Unis] ; Samir M. Parikh [États-Unis]Source :
- JCI Insight [ 2379-3708 ] ; ????.
Abstract
Because injured mitochondria can accelerate cell death through the elaboration of oxidative free radicals and other mediators, it is striking that proliferator γ coactivator 1-α (PGC1α), a stimulator of increased mitochondrial abundance, protects stressed renal cells instead of potentiating injury. Here, we report that PGC1α’s induction of lysosomes via transcription factor EB (TFEB) may be pivotal for kidney protection. CRISPR and stable gene transfer showed that PGC1α-KO tubular cells were sensitized to the genotoxic stressor cisplatin, whereas Tg cells were protected. The biosensor mitochondrial-targeted Keima (mtKeima) unexpectedly revealed that cisplatin blunts mitophagy both in cells and mice. PGC1α and its downstream mediator NAD+ counteracted this effect. PGC1α did not consistently affect known autophagy pathways modulated by cisplatin. Instead RNA sequencing identified coordinated regulation of lysosomal biogenesis via TFEB. This effector pathway was sufficiently important that inhibition of TFEB or lysosomes unveiled a striking harmful effect of excess PGC1α in cells and conditional mice. These results uncover an unexpected effect of cisplatin on mitophagy and PGC1α’s reliance on lysosomes for kidney protection. Finally, the data illuminate TFEB as a potentially novel target for renal tubular stress resistance.
Url:
DOI: 10.1172/jci.insight.126749
PubMed: 30870143
PubMed Central: 6538327
Links toward previous steps (curation, corpus...)
- to stream Pmc, to step Corpus: Pour aller vers cette notice dans l'étape Curation :000685
Links to Exploration step
PMC:6538327Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">TFEB-driven lysosomal biogenesis is pivotal for PGC1<bold>α</bold>
-dependent renal stress resistance</title>
<author><name sortKey="Lynch, Matthew R" sort="Lynch, Matthew R" uniqKey="Lynch M" first="Matthew R." last="Lynch">Matthew R. Lynch</name>
<affiliation><nlm:aff id="A1">Division of Nephrology,</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Tran, Mei T" sort="Tran, Mei T" uniqKey="Tran M" first="Mei T." last="Tran">Mei T. Tran</name>
<affiliation><nlm:aff id="A1">Division of Nephrology,</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ralto, Kenneth M" sort="Ralto, Kenneth M" uniqKey="Ralto K" first="Kenneth M." last="Ralto">Kenneth M. Ralto</name>
<affiliation><nlm:aff id="A1">Division of Nephrology,</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Zsengeller, Zsuzsanna K" sort="Zsengeller, Zsuzsanna K" uniqKey="Zsengeller Z" first="Zsuzsanna K." last="Zsengeller">Zsuzsanna K. Zsengeller</name>
<affiliation><nlm:aff id="A1">Division of Nephrology,</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Raman, Vinod" sort="Raman, Vinod" uniqKey="Raman V" first="Vinod" last="Raman">Vinod Raman</name>
<affiliation><nlm:aff id="A1">Division of Nephrology,</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bhasin, Swati S" sort="Bhasin, Swati S" uniqKey="Bhasin S" first="Swati S." last="Bhasin">Swati S. Bhasin</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sun, Nuo" sort="Sun, Nuo" uniqKey="Sun N" first="Nuo" last="Sun">Nuo Sun</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Chen, Xiuying" sort="Chen, Xiuying" uniqKey="Chen X" first="Xiuying" last="Chen">Xiuying Chen</name>
<affiliation><nlm:aff id="A1">Division of Nephrology,</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Brown, Daniel" sort="Brown, Daniel" uniqKey="Brown D" first="Daniel" last="Brown">Daniel Brown</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Rovira, Ilsa I" sort="Rovira, Ilsa I" uniqKey="Rovira I" first="Ilsa I." last="Rovira">Ilsa I. Rovira</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Taguchi, Kensei" sort="Taguchi, Kensei" uniqKey="Taguchi K" first="Kensei" last="Taguchi">Kensei Taguchi</name>
<affiliation wicri:level="1"><nlm:aff id="A5">Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Brooks, Craig R" sort="Brooks, Craig R" uniqKey="Brooks C" first="Craig R." last="Brooks">Craig R. Brooks</name>
<affiliation wicri:level="1"><nlm:aff id="A5">Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Stillman, Isaac E" sort="Stillman, Isaac E" uniqKey="Stillman I" first="Isaac E." last="Stillman">Isaac E. Stillman</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bhasin, Manoj K" sort="Bhasin, Manoj K" uniqKey="Bhasin M" first="Manoj K." last="Bhasin">Manoj K. Bhasin</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Finkel, Toren" sort="Finkel, Toren" uniqKey="Finkel T" first="Toren" last="Finkel">Toren Finkel</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A6">Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, Pennsylvania, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Parikh, Samir M" sort="Parikh, Samir M" uniqKey="Parikh S" first="Samir M." last="Parikh">Samir M. Parikh</name>
<affiliation><nlm:aff id="A1">Division of Nephrology,</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
</titleStmt>
<publicationStmt><idno type="wicri:source">PMC</idno>
<idno type="pmid">30870143</idno>
<idno type="pmc">6538327</idno>
<idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538327</idno>
<idno type="RBID">PMC:6538327</idno>
<idno type="doi">10.1172/jci.insight.126749</idno>
<date when="????">????</date>
<idno type="wicri:Area/Pmc/Corpus">000685</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000685</idno>
<idno type="wicri:Area/Pmc/Curation">000685</idno>
<idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000685</idno>
</publicationStmt>
<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">TFEB-driven lysosomal biogenesis is pivotal for PGC1<bold>α</bold>
-dependent renal stress resistance</title>
<author><name sortKey="Lynch, Matthew R" sort="Lynch, Matthew R" uniqKey="Lynch M" first="Matthew R." last="Lynch">Matthew R. Lynch</name>
<affiliation><nlm:aff id="A1">Division of Nephrology,</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Tran, Mei T" sort="Tran, Mei T" uniqKey="Tran M" first="Mei T." last="Tran">Mei T. Tran</name>
<affiliation><nlm:aff id="A1">Division of Nephrology,</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Ralto, Kenneth M" sort="Ralto, Kenneth M" uniqKey="Ralto K" first="Kenneth M." last="Ralto">Kenneth M. Ralto</name>
<affiliation><nlm:aff id="A1">Division of Nephrology,</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Zsengeller, Zsuzsanna K" sort="Zsengeller, Zsuzsanna K" uniqKey="Zsengeller Z" first="Zsuzsanna K." last="Zsengeller">Zsuzsanna K. Zsengeller</name>
<affiliation><nlm:aff id="A1">Division of Nephrology,</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Raman, Vinod" sort="Raman, Vinod" uniqKey="Raman V" first="Vinod" last="Raman">Vinod Raman</name>
<affiliation><nlm:aff id="A1">Division of Nephrology,</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bhasin, Swati S" sort="Bhasin, Swati S" uniqKey="Bhasin S" first="Swati S." last="Bhasin">Swati S. Bhasin</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Sun, Nuo" sort="Sun, Nuo" uniqKey="Sun N" first="Nuo" last="Sun">Nuo Sun</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Chen, Xiuying" sort="Chen, Xiuying" uniqKey="Chen X" first="Xiuying" last="Chen">Xiuying Chen</name>
<affiliation><nlm:aff id="A1">Division of Nephrology,</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Brown, Daniel" sort="Brown, Daniel" uniqKey="Brown D" first="Daniel" last="Brown">Daniel Brown</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Rovira, Ilsa I" sort="Rovira, Ilsa I" uniqKey="Rovira I" first="Ilsa I." last="Rovira">Ilsa I. Rovira</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Taguchi, Kensei" sort="Taguchi, Kensei" uniqKey="Taguchi K" first="Kensei" last="Taguchi">Kensei Taguchi</name>
<affiliation wicri:level="1"><nlm:aff id="A5">Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Brooks, Craig R" sort="Brooks, Craig R" uniqKey="Brooks C" first="Craig R." last="Brooks">Craig R. Brooks</name>
<affiliation wicri:level="1"><nlm:aff id="A5">Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Stillman, Isaac E" sort="Stillman, Isaac E" uniqKey="Stillman I" first="Isaac E." last="Stillman">Isaac E. Stillman</name>
<affiliation wicri:level="1"><nlm:aff id="A4">Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Bhasin, Manoj K" sort="Bhasin, Manoj K" uniqKey="Bhasin M" first="Manoj K." last="Bhasin">Manoj K. Bhasin</name>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Finkel, Toren" sort="Finkel, Toren" uniqKey="Finkel T" first="Toren" last="Finkel">Toren Finkel</name>
<affiliation wicri:level="1"><nlm:aff id="A3">Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland</wicri:regionArea>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A6">Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, Pennsylvania, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, Pennsylvania</wicri:regionArea>
</affiliation>
</author>
<author><name sortKey="Parikh, Samir M" sort="Parikh, Samir M" uniqKey="Parikh S" first="Samir M." last="Parikh">Samir M. Parikh</name>
<affiliation><nlm:aff id="A1">Division of Nephrology,</nlm:aff>
</affiliation>
<affiliation wicri:level="1"><nlm:aff id="A2">Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</nlm:aff>
<country xml:lang="fr" wicri:curation="lc">États-Unis</country>
<wicri:regionArea>Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts</wicri:regionArea>
</affiliation>
</author>
</analytic>
<series><title level="j">JCI Insight</title>
<idno type="eISSN">2379-3708</idno>
<imprint><date when="????">????</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass></textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p>Because injured mitochondria can accelerate cell death through the elaboration of oxidative free radicals and other mediators, it is striking that proliferator γ coactivator 1-α (PGC1α), a stimulator of increased mitochondrial abundance, protects stressed renal cells instead of potentiating injury. Here, we report that PGC1α’s induction of lysosomes via transcription factor EB (TFEB) may be pivotal for kidney protection. CRISPR and stable gene transfer showed that PGC1α-KO tubular cells were sensitized to the genotoxic stressor cisplatin, whereas Tg cells were protected. The biosensor mitochondrial-targeted Keima (mtKeima) unexpectedly revealed that cisplatin blunts mitophagy both in cells and mice. PGC1α and its downstream mediator NAD<sup>+</sup>
counteracted this effect. PGC1α did not consistently affect known autophagy pathways modulated by cisplatin. Instead RNA sequencing identified coordinated regulation of lysosomal biogenesis via TFEB. This effector pathway was sufficiently important that inhibition of TFEB or lysosomes unveiled a striking harmful effect of excess PGC1α in cells and conditional mice. These results uncover an unexpected effect of cisplatin on mitophagy and PGC1α’s reliance on lysosomes for kidney protection. Finally, the data illuminate TFEB as a potentially novel target for renal tubular stress resistance.</p>
</div>
</front>
<back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Emma, F" uniqKey="Emma F">F Emma</name>
</author>
<author><name sortKey="Montini, G" uniqKey="Montini G">G Montini</name>
</author>
<author><name sortKey="Parikh, Sm" uniqKey="Parikh S">SM Parikh</name>
</author>
<author><name sortKey="Salviati, L" uniqKey="Salviati L">L Salviati</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mills, El" uniqKey="Mills E">EL Mills</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="West, Ap" uniqKey="West A">AP West</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Chouchani, Et" uniqKey="Chouchani E">ET Chouchani</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Balaban, Rs" uniqKey="Balaban R">RS Balaban</name>
</author>
<author><name sortKey="Nemoto, S" uniqKey="Nemoto S">S Nemoto</name>
</author>
<author><name sortKey="Finkel, T" uniqKey="Finkel T">T Finkel</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Tran, Mt" uniqKey="Tran M">MT Tran</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Kang, Hm" uniqKey="Kang H">HM Kang</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="St Pierre, J" uniqKey="St Pierre J">J St-Pierre</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Wu, Z" uniqKey="Wu Z">Z Wu</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Yang, C" uniqKey="Yang C">C Yang</name>
</author>
<author><name sortKey="Kaushal, V" uniqKey="Kaushal V">V Kaushal</name>
</author>
<author><name sortKey="Shah, Sv" uniqKey="Shah S">SV Shah</name>
</author>
<author><name sortKey="Kaushal, Gp" uniqKey="Kaushal G">GP Kaushal</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Periyasamy Thandavan, S" uniqKey="Periyasamy Thandavan S">S Periyasamy-Thandavan</name>
</author>
<author><name sortKey="Jiang, M" uniqKey="Jiang M">M Jiang</name>
</author>
<author><name sortKey="Wei, Q" uniqKey="Wei Q">Q Wei</name>
</author>
<author><name sortKey="Smith, R" uniqKey="Smith R">R Smith</name>
</author>
<author><name sortKey="Yin, Xm" uniqKey="Yin X">XM Yin</name>
</author>
<author><name sortKey="Dong, Z" uniqKey="Dong Z">Z Dong</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Wang, Y" uniqKey="Wang Y">Y Wang</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ichinomiya, M" uniqKey="Ichinomiya M">M Ichinomiya</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Zhao, C" uniqKey="Zhao C">C Zhao</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Zhao, C" uniqKey="Zhao C">C Zhao</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Jiang, M" uniqKey="Jiang M">M Jiang</name>
</author>
<author><name sortKey="Wei, Q" uniqKey="Wei Q">Q Wei</name>
</author>
<author><name sortKey="Dong, G" uniqKey="Dong G">G Dong</name>
</author>
<author><name sortKey="Komatsu, M" uniqKey="Komatsu M">M Komatsu</name>
</author>
<author><name sortKey="Su, Y" uniqKey="Su Y">Y Su</name>
</author>
<author><name sortKey="Dong, Z" uniqKey="Dong Z">Z Dong</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Herzog, C" uniqKey="Herzog C">C Herzog</name>
</author>
<author><name sortKey="Yang, C" uniqKey="Yang C">C Yang</name>
</author>
<author><name sortKey="Holmes, A" uniqKey="Holmes A">A Holmes</name>
</author>
<author><name sortKey="Kaushal, Gp" uniqKey="Kaushal G">GP Kaushal</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Katayama, H" uniqKey="Katayama H">H Katayama</name>
</author>
<author><name sortKey="Kogure, T" uniqKey="Kogure T">T Kogure</name>
</author>
<author><name sortKey="Mizushima, N" uniqKey="Mizushima N">N Mizushima</name>
</author>
<author><name sortKey="Yoshimori, T" uniqKey="Yoshimori T">T Yoshimori</name>
</author>
<author><name sortKey="Miyawaki, A" uniqKey="Miyawaki A">A Miyawaki</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sun, N" uniqKey="Sun N">N Sun</name>
</author>
<author><name sortKey="Malide, D" uniqKey="Malide D">D Malide</name>
</author>
<author><name sortKey="Liu, J" uniqKey="Liu J">J Liu</name>
</author>
<author><name sortKey="Rovira" uniqKey="Rovira">Rovira</name>
</author>
<author><name sortKey="Combs, Ca" uniqKey="Combs C">CA Combs</name>
</author>
<author><name sortKey="Finkel, T" uniqKey="Finkel T">T Finkel</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sun, N" uniqKey="Sun N">N Sun</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Poyan Mehr, A" uniqKey="Poyan Mehr A">A Poyan Mehr</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Settembre, C" uniqKey="Settembre C">C Settembre</name>
</author>
<author><name sortKey="Fraldi, A" uniqKey="Fraldi A">A Fraldi</name>
</author>
<author><name sortKey="Medina, Dl" uniqKey="Medina D">DL Medina</name>
</author>
<author><name sortKey="Ballabio, A" uniqKey="Ballabio A">A Ballabio</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Tsunemi, T" uniqKey="Tsunemi T">T Tsunemi</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Settembre, C" uniqKey="Settembre C">C Settembre</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Settembre, C" uniqKey="Settembre C">C Settembre</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Tran, M" uniqKey="Tran M">M Tran</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Arany, Z" uniqKey="Arany Z">Z Arany</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Patten, Is" uniqKey="Patten I">IS Patten</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Lin, J" uniqKey="Lin J">J Lin</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Han, Sh" uniqKey="Han S">SH Han</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Han, Sh" uniqKey="Han S">SH Han</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Zsengeller, Zk" uniqKey="Zsengeller Z">ZK Zsengellér</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Bai, P" uniqKey="Bai P">P Bai</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ebrahimkhani, Mr" uniqKey="Ebrahimkhani M">MR Ebrahimkhani</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Rodgers, Jt" uniqKey="Rodgers J">JT Rodgers</name>
</author>
<author><name sortKey="Lerin, C" uniqKey="Lerin C">C Lerin</name>
</author>
<author><name sortKey="Haas, W" uniqKey="Haas W">W Haas</name>
</author>
<author><name sortKey="Gygi, Sp" uniqKey="Gygi S">SP Gygi</name>
</author>
<author><name sortKey="Spiegelman, Bm" uniqKey="Spiegelman B">BM Spiegelman</name>
</author>
<author><name sortKey="Puigserver, P" uniqKey="Puigserver P">P Puigserver</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mouchiroud, L" uniqKey="Mouchiroud L">L Mouchiroud</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Shpilka, T" uniqKey="Shpilka T">T Shpilka</name>
</author>
<author><name sortKey="Haynes, Cm" uniqKey="Haynes C">CM Haynes</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Havasi, A" uniqKey="Havasi A">A Havasi</name>
</author>
<author><name sortKey="Dong, Z" uniqKey="Dong Z">Z Dong</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Najafian, B" uniqKey="Najafian B">B Najafian</name>
</author>
<author><name sortKey="Fogo, Ab" uniqKey="Fogo A">AB Fogo</name>
</author>
<author><name sortKey="Lusco, Ma" uniqKey="Lusco M">MA Lusco</name>
</author>
<author><name sortKey="Alpers, Ce" uniqKey="Alpers C">CE Alpers</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sardiello, M" uniqKey="Sardiello M">M Sardiello</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Palmieri, M" uniqKey="Palmieri M">M Palmieri</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Ran, Fa" uniqKey="Ran F">FA Ran</name>
</author>
<author><name sortKey="Hsu, Pd" uniqKey="Hsu P">PD Hsu</name>
</author>
<author><name sortKey="Wright, J" uniqKey="Wright J">J Wright</name>
</author>
<author><name sortKey="Agarwala, V" uniqKey="Agarwala V">V Agarwala</name>
</author>
<author><name sortKey="Scott, Da" uniqKey="Scott D">DA Scott</name>
</author>
<author><name sortKey="Zhang, F" uniqKey="Zhang F">F Zhang</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Sanjana, Ne" uniqKey="Sanjana N">NE Sanjana</name>
</author>
<author><name sortKey="Shalem, O" uniqKey="Shalem O">O Shalem</name>
</author>
<author><name sortKey="Zhang, F" uniqKey="Zhang F">F Zhang</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Campeau, E" uniqKey="Campeau E">E Campeau</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Puigserver, P" uniqKey="Puigserver P">P Puigserver</name>
</author>
<author><name sortKey="Wu, Z" uniqKey="Wu Z">Z Wu</name>
</author>
<author><name sortKey="Park, Cw" uniqKey="Park C">CW Park</name>
</author>
<author><name sortKey="Graves, R" uniqKey="Graves R">R Graves</name>
</author>
<author><name sortKey="Wright, M" uniqKey="Wright M">M Wright</name>
</author>
<author><name sortKey="Spiegelman, Bm" uniqKey="Spiegelman B">BM Spiegelman</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Smyth, Gk" uniqKey="Smyth G">GK Smyth</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Brooks, C" uniqKey="Brooks C">C Brooks</name>
</author>
<author><name sortKey="Wei, Q" uniqKey="Wei Q">Q Wei</name>
</author>
<author><name sortKey="Cho, Sg" uniqKey="Cho S">SG Cho</name>
</author>
<author><name sortKey="Dong, Z" uniqKey="Dong Z">Z Dong</name>
</author>
</analytic>
</biblStruct>
<biblStruct><analytic><author><name sortKey="Mei, S" uniqKey="Mei S">S Mei</name>
</author>
<author><name sortKey="Livingston, M" uniqKey="Livingston M">M Livingston</name>
</author>
<author><name sortKey="Hao, J" uniqKey="Hao J">J Hao</name>
</author>
<author><name sortKey="Li, L" uniqKey="Li L">L Li</name>
</author>
<author><name sortKey="Mei, C" uniqKey="Mei C">C Mei</name>
</author>
<author><name sortKey="Dong, Z" uniqKey="Dong Z">Z Dong</name>
</author>
</analytic>
</biblStruct>
<biblStruct></biblStruct>
<biblStruct><analytic><author><name sortKey="Mukhopadhyay, P" uniqKey="Mukhopadhyay P">P Mukhopadhyay</name>
</author>
</analytic>
</biblStruct>
</listBibl>
</div1>
</back>
</TEI>
<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">JCI Insight</journal-id>
<journal-id journal-id-type="iso-abbrev">JCI Insight</journal-id>
<journal-id journal-id-type="publisher-id">JCI Insight</journal-id>
<journal-title-group><journal-title>JCI Insight</journal-title>
</journal-title-group>
<issn pub-type="epub">2379-3708</issn>
<publisher><publisher-name>American Society for Clinical Investigation</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">30870143</article-id>
<article-id pub-id-type="pmc">6538327</article-id>
<article-id pub-id-type="publisher-id">126749</article-id>
<article-id pub-id-type="doi">10.1172/jci.insight.126749</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject>
</subj-group>
</article-categories>
<title-group><article-title>TFEB-driven lysosomal biogenesis is pivotal for PGC1<bold>α</bold>
-dependent renal stress resistance</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Lynch</surname>
<given-names>Matthew R.</given-names>
</name>
<email>matthew_lynch@brown.edu</email>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0003-1114-0984</contrib-id>
<name><surname>Tran</surname>
<given-names>Mei T.</given-names>
</name>
<email>mtran3@bidmc.harvard.edu</email>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0002-7788-6116</contrib-id>
<name><surname>Ralto</surname>
<given-names>Kenneth M.</given-names>
</name>
<email>ken.ralto@gmail.com</email>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0002-4540-5728</contrib-id>
<name><surname>Zsengeller</surname>
<given-names>Zsuzsanna K.</given-names>
</name>
<email>zzsengel@bidmc.harvard.edu</email>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Raman</surname>
<given-names>Vinod</given-names>
</name>
<email>vinod.raman02@gmail.com</email>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bhasin</surname>
<given-names>Swati S.</given-names>
</name>
<email>sbhasin@bidmc.harvard.edu</email>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Sun</surname>
<given-names>Nuo</given-names>
</name>
<email>Nuo.Sun@osumc.edu</email>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Chen</surname>
<given-names>Xiuying</given-names>
</name>
<email>xchen6@bidmc.harvard.edu</email>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Brown</surname>
<given-names>Daniel</given-names>
</name>
<email>dbrown@bidmc.harvard.edu</email>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Rovira</surname>
<given-names>Ilsa I.</given-names>
</name>
<email>rovirai@nhlbi.nih.gov</email>
<xref ref-type="aff" rid="A3">3</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0002-5555-1809</contrib-id>
<name><surname>Taguchi</surname>
<given-names>Kensei</given-names>
</name>
<email>kensei.taguchi@vumc.org</email>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0001-8113-2993</contrib-id>
<name><surname>Brooks</surname>
<given-names>Craig R.</given-names>
</name>
<email>craig.brooks@vumc.org</email>
<xref ref-type="aff" rid="A5">5</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0002-4224-5060</contrib-id>
<name><surname>Stillman</surname>
<given-names>Isaac E.</given-names>
</name>
<email>istillma@bidmc.harvard.edu</email>
<xref ref-type="aff" rid="A4">4</xref>
</contrib>
<contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0001-5172-420X</contrib-id>
<name><surname>Bhasin</surname>
<given-names>Manoj K.</given-names>
</name>
<email>mbhasin@bidmc.harvard.edu</email>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Finkel</surname>
<given-names>Toren</given-names>
</name>
<email>FINKELT@Pitt.edu</email>
<xref ref-type="aff" rid="A3">3</xref>
<xref ref-type="aff" rid="A6">6</xref>
</contrib>
<contrib contrib-type="author" corresp="yes"><contrib-id contrib-id-type="orcid" authenticated="true">http://orcid.org/0000-0002-1038-981X</contrib-id>
<name><surname>Parikh</surname>
<given-names>Samir M.</given-names>
</name>
<email>sparikh1@bidmc.harvard.edu</email>
<xref ref-type="aff" rid="A1">1</xref>
<xref ref-type="aff" rid="A2">2</xref>
</contrib>
</contrib-group>
<aff id="A1"><label>1</label>
Division of Nephrology,</aff>
<aff id="A2"><label>2</label>
Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</aff>
<aff id="A3"><label>3</label>
Center for Molecular Medicine, National Heart, Lung and Blood Institute, NIH, Bethesda, Maryland, USA.</aff>
<aff id="A4"><label>4</label>
Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.</aff>
<aff id="A5"><label>5</label>
Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.</aff>
<aff id="A6"><label>6</label>
Aging Institute of UPMC and the University of Pittsburgh, Pittsburgh, Pennsylvania, USA.</aff>
<author-notes><corresp>Address correspondence to: Samir Parikh, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, RN 330C, Boston, Massachusetts 02215, USA. Phone: 617.667.8000; Email: <email>sparikh1@bidmc.harvard.edu</email>
.</corresp>
<fn><p><bold>Authorship note:</bold>
MRL, MTT, and KMR contributed equally to the work.</p>
</fn>
</author-notes>
<pub-date date-type="pub" publication-format="electronic" iso-8601-date="2019-04-18T09:00:00-0400"><day>18</day>
<month>4</month>
<year>2019</year>
</pub-date>
<pub-date date-type="collection" publication-format="electronic" iso-8601-date="2019-04-18T09:00:00-0400"><day>18</day>
<month>4</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="pmc-release"><day>18</day>
<month>4</month>
<year>2019</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and
0 days and was based on the . </pmc-comment>
<volume>4</volume>
<issue>8</issue>
<elocation-id>e126749</elocation-id>
<history><date date-type="received"><day>11</day>
<month>12</month>
<year>2018</year>
</date>
<date date-type="accepted"><day>12</day>
<month>3</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© 2019 Lynch et al.</copyright-statement>
<copyright-year>2019</copyright-year>
<copyright-holder>Lynch et al.</copyright-holder>
<license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p><pmc-comment>CREATIVE COMMONS</pmc-comment>
This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit <ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
.</license-p>
</license>
</permissions>
<self-uri xlink:href="https://insight.jci.org/articles/view/126749">This article is available online at https://insight.jci.org/articles/view/126749</self-uri>
<abstract><p>Because injured mitochondria can accelerate cell death through the elaboration of oxidative free radicals and other mediators, it is striking that proliferator γ coactivator 1-α (PGC1α), a stimulator of increased mitochondrial abundance, protects stressed renal cells instead of potentiating injury. Here, we report that PGC1α’s induction of lysosomes via transcription factor EB (TFEB) may be pivotal for kidney protection. CRISPR and stable gene transfer showed that PGC1α-KO tubular cells were sensitized to the genotoxic stressor cisplatin, whereas Tg cells were protected. The biosensor mitochondrial-targeted Keima (mtKeima) unexpectedly revealed that cisplatin blunts mitophagy both in cells and mice. PGC1α and its downstream mediator NAD<sup>+</sup>
counteracted this effect. PGC1α did not consistently affect known autophagy pathways modulated by cisplatin. Instead RNA sequencing identified coordinated regulation of lysosomal biogenesis via TFEB. This effector pathway was sufficiently important that inhibition of TFEB or lysosomes unveiled a striking harmful effect of excess PGC1α in cells and conditional mice. These results uncover an unexpected effect of cisplatin on mitophagy and PGC1α’s reliance on lysosomes for kidney protection. Finally, the data illuminate TFEB as a potentially novel target for renal tubular stress resistance.</p>
</abstract>
<abstract abstract-type="graphical"><p><graphic xlink:href="jciinsight-4-126749-g220.jpg" position="float" orientation="portrait"></graphic>
</p>
</abstract>
<abstract abstract-type="toc"><p>PGC1α is renoprotective in the setting of platinum-based chemotherapy through the induction of mitophagy and lysosomal biogenesis via transcription factor EB.</p>
</abstract>
<kwd-group kwd-group-type="specialties"><kwd>Nephrology</kwd>
</kwd-group>
<kwd-group kwd-group-type="keywords"><kwd>Mitochondria</kwd>
</kwd-group>
<funding-group><award-group><funding-source><institution-wrap><institution>National Institutes of Health</institution>
<institution-id>https://doi.org/10.13039/100000002</institution-id>
</institution-wrap>
</funding-source>
<award-id>R01-DK095072</award-id>
</award-group>
</funding-group>
</article-meta>
</front>
<floats-group><fig id="F1" orientation="portrait" position="float"><label>Figure 1</label>
<caption><title>Loss or gain of PGC1α confers concordant effects against cisplatin toxicity in cells and in mice.</title>
<p>(<bold>A</bold>
and <bold>B</bold>
) Heatmaps comparing mitochondrial and NAD<sup>+</sup>
biosynthetic enzyme expression patterns of PGC1α-KO vs. Tg renal tubular cells and renal expression in KO mice vs. iNephPGC1α (Tg) mice. Each cell represents average expression scaled to respective control (<italic>n</italic>
= 3–6/group). Multiple comparison <italic>P</italic>
values by ANOVA. Gene abbreviations defined in Methods. (<bold>C</bold>
and <bold>D</bold>
) ATP abundance in Ctrl and PGC1α-KO cells at baseline (<bold>C</bold>
) and after cisplatin (<bold>D</bold>
) (10 μM, 24 hours). Data in <bold>D</bold>
normalized to Ctrl cells at baseline. (<bold>E</bold>
and <bold>F</bold>
) ATP abundance in vector and PGC1α Tg cells at baseline (<bold>E</bold>
) and after cisplatin (<bold>F</bold>
) (10 μM, 24 hours). Data in <bold>F</bold>
normalized to vector cells at baseline. (<bold>G</bold>
and <bold>H</bold>
) Viability via XTT assay after cisplatin (10 μM, 24 hours). Results normalized to respective controls at baseline. <italic>n</italic>
= 4/group for <bold>C–H</bold>
. (<bold>I</bold>
and <bold>J</bold>
) Serum creatinine (Cr, mg/dl) in PGC1α-KO mice (<bold>I</bold>
, <italic>n</italic>
= 18 WT vs. 25 KO mice) or iNephPGC1α (<bold>J</bold>
, <italic>n</italic>
= 9 Ctrl vs. 10 Tg mice) 72 hours after cisplatin (20 mg/kg i.p. in PGC1α-KO and 30 mg/kg in iNephPGC1α) vs. respective controls. (<bold>K–N</bold>
) Toluidine blue–stained plastic sections of renal cortex from (representative of 3–4 mice from <bold>I</bold>
and <bold>J</bold>
) with black arrows to necrotic tubules. Scale bars: 100 μm. *<italic>P</italic>
< 0.05 by Mann-Whitney <italic>U</italic>
test for <bold>C–J</bold>
.</p>
</caption>
<graphic xlink:href="jciinsight-4-126749-g213"></graphic>
</fig>
<fig id="F2" orientation="portrait" position="float"><label>Figure 2</label>
<caption><title>Cisplatin reduces mitophagy which PGC1α counteracts.</title>
<p>(<bold>A</bold>
) Color shift in mtKeima indicates mitophagy from green (neutral) to red (acidic). (<bold>B–M</bold>
) PGC1α-KO cells or controls treated with vehicle or cisplatin (10 M, 24 hours). Scale bars: 5 μm. (<bold>N</bold>
) Quantification of mitophagy index for <bold>B–M</bold>
relative to control condition. <italic>n</italic>
= 32, 16, 20, and 12 fields left to right from 3–4 biological replicates per condition. (<bold>O</bold>
) Mitophagy index for PGC1α Tg cells or vector controls treated with vehicle or cisplatin (10 μM, 24 hours). <italic>n</italic>
= 31, 27, 54, and 31 fields left to right from 3–6 biological replicates per condition. (<bold>P</bold>
) PGC1α-KO cells treated with cisplatin (10 μM, 24 hours) ± concurrent nicotinamide mononucleotide (NMN, 1 mM). <italic>n</italic>
= 16, 20, 12, and 20 fields left to right from 3–4 biological replicates per condition. Results analyzed by 2-way ANOVA on biological replicates with <italic>P</italic>
values as indicated.</p>
</caption>
<graphic xlink:href="jciinsight-4-126749-g214"></graphic>
</fig>
<fig id="F3" orientation="portrait" position="float"><label>Figure 3</label>
<caption><title>Cisplatin reduces mitophagy in vivo which NMN counteracts.</title>
<p>(<bold>A</bold>
) Schematic depicting experimental interventions in mtKeima Tg mice. <bold>(29. AUTHOR: Query 28.)</bold>
(<bold>B–J</bold>
) Renal cortex of mtKeima mice treated with vehicle or cisplatin (20 mg/kg i.p., 72 hours) ± NMN (400 mg/kg i.p. as indicated). Scale bars: 50 μm. (<bold>K</bold>
) Quantification of mitophagy index for <bold>B–J</bold>
relative to control condition. <italic>n</italic>
= 12 fields from 3 mice per condition. <italic>P</italic>
value calculated by ANOVA on biological replicates.</p>
</caption>
<graphic xlink:href="jciinsight-4-126749-g215"></graphic>
</fig>
<fig id="F4" orientation="portrait" position="float"><label>Figure 4</label>
<caption><title>PGC1α promotes lysosomal biogenesis via TFEB.</title>
<p>(<bold>A</bold>
) Hierarchical clustering of cisplatin-treated (10 μM, 24 hours) PGC1α-KO cells or Tg cells and respective controls. (<bold>B</bold>
) Gene expression clusters identified by self-organizing maps analysis. (<bold>C</bold>
) Heatmap of transcripts in clusters 2 and 5 (i.e., oppositely regulated PGC1α transcripts). (<bold>D–G</bold>
) Representative Western analysis and densitometry of TFEB in cisplatin-treated (10 μM, 12 hours) PGC1α-KO cells vs. controls. <italic>n</italic>
= 6/condition (<bold>D</bold>
and <bold>E</bold>
); analogous for PGC1α Tg cells (<bold>F</bold>
and <bold>G</bold>
), <italic>n</italic>
= 5–9/condition. <italic>P</italic>
values as indicated by 2-way ANOVA. (<bold>H</bold>
and <bold>I</bold>
) Lysosomal abundance quantified from LysoTracker-stained PGC1α-KO (<italic>n</italic>
= 18 control vs. 22 KO) or Tg cells (<italic>n</italic>
= 18 vector vs. 23 Tg). (<bold>J</bold>
) Representative LysoTracker images (from <italic>n</italic>
= 18–24/condition) following cisplatin (10 μM, 24 hours) ± concurrent NMN (1 mM). Scale bar: 20 μm. *<italic>P</italic>
< 0.05, ****<italic>P</italic>
< 0.0001 by Mann-Whitney <italic>U</italic>
test.</p>
</caption>
<graphic xlink:href="jciinsight-4-126749-g216"></graphic>
</fig>
<fig id="F5" orientation="portrait" position="float"><label>Figure 5</label>
<caption><title>Lysosomes are pivotal for PGC1α-dependent protection against cisplatin.</title>
<p>(<bold>A–D</bold>
) Representative bright-field images (from <italic>n</italic>
= 5/condition) of cisplatin-treated (10 μM, 24 hours) PGC1α Tg cells or vector controls TFEB siRNA knockdown (siCTRL or siTFEB, 50 μM, 72 hours). Scale bar: 1mm. (<bold>E</bold>
) Viability via XTT assay in <bold>A–D</bold>
. <italic>n</italic>
= 6/condition. (<bold>F</bold>
) Mitochondrial ROS (mtROS) via mitoSOX in (<bold>A–D</bold>
). <italic>n</italic>
= 6/condition. <bold>E</bold>
and <bold>F</bold>
analyzed by 2-way ANOVA. (<bold>G–J</bold>
) Representative low- and high-power transmission electron microscopy (TEM, <italic>n</italic>
= 3–5 mice/condition) of PGC1α-KO or WT proximal tubule 72 hours after cisplatin (20 mg/kg i.p.) showing swollen mitochondria (arrowheads). (<bold>K–N</bold>
) Representative TEM of control or iNephPGC1α proximal tubule 72 hours after cisplatin (30 mg/kg i.p.) showing numerous electron-dense lysosomes (arrows), swollen mitochondria (arrowheads), and a swollen mitochondrion inside a membrane-bound structure consistent with mitophagy (plus sign). Scale bars: 2 μm (low power), 500 nm (high power). (<bold>O</bold>
) Serum creatinine (Cr, mg/dl) in controls (<italic>n</italic>
= 11) or iNephPGC1α (<italic>n</italic>
= 12 mice) 72 hours after concurrent cisplatin (30 mg/kg i.p.) and chloroquine (10 mg/kg i.p.). (<bold>P</bold>
and <bold>Q</bold>
) Representative renal cortex staining (from <italic>n</italic>
= 3–5 mice/condition) for 3-nitrotyrosine, a product of oxidative stress, in conditions indicated in (<bold>O</bold>
). Scale bar: 200 μm. *<italic>P</italic>
< 0.05 by Mann-Whitney <italic>U</italic>
test.</p>
</caption>
<graphic xlink:href="jciinsight-4-126749-g217"></graphic>
</fig>
</floats-group>
</pmc>
</record>
Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/ChloroquineV1/Data/Pmc/Curation
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000685 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Pmc/Curation/biblio.hfd -nk 000685 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien |wiki= Sante |area= ChloroquineV1 |flux= Pmc |étape= Curation |type= RBID |clé= PMC:6538327 |texte= TFEB-driven lysosomal biogenesis is pivotal for PGC1α-dependent renal stress resistance }}
Pour générer des pages wiki
HfdIndexSelect -h $EXPLOR_AREA/Data/Pmc/Curation/RBID.i -Sk "pubmed:30870143" \ | HfdSelect -Kh $EXPLOR_AREA/Data/Pmc/Curation/biblio.hfd \ | NlmPubMed2Wicri -a ChloroquineV1
![]() | This area was generated with Dilib version V0.6.33. | ![]() |