TFEB-driven lysosomal biogenesis is pivotal for PGC1α-dependent renal stress resistance
Identifieur interne : 000503 ( Ncbi/Curation ); précédent : 000502; suivant : 000504TFEB-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
- to stream Pmc, to step Curation: Pour aller vers cette notice dans l'étape Curation :000685
- to stream Pmc, to step Checkpoint: Pour aller vers cette notice dans l'étape Curation :000B06
- to stream Ncbi, to step Merge: Pour aller vers cette notice dans l'étape Curation :000503
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="2"><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><placeName><region type="state">Massachusetts</region></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Sun, Nuo" sort="Sun, Nuo" uniqKey="Sun N" first="Nuo" last="Sun">Nuo Sun</name><affiliation wicri:level="2"><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><placeName><region type="state">Maryland</region></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Brown, Daniel" sort="Brown, Daniel" uniqKey="Brown D" first="Daniel" last="Brown">Daniel Brown</name><affiliation wicri:level="2"><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><placeName><region type="state">Massachusetts</region></placeName></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="2"><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><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Taguchi, Kensei" sort="Taguchi, Kensei" uniqKey="Taguchi K" first="Kensei" last="Taguchi">Kensei Taguchi</name><affiliation wicri:level="2"><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><placeName><region type="state">Tennessee</region></placeName></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="2"><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><placeName><region type="state">Tennessee</region></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Finkel, Toren" sort="Finkel, Toren" uniqKey="Finkel T" first="Toren" last="Finkel">Toren Finkel</name><affiliation wicri:level="2"><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><placeName><region type="state">Maryland</region></placeName></affiliation><affiliation wicri:level="4"><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><placeName><region type="state">Pennsylvanie</region><settlement type="city">Pittsburgh</settlement></placeName><orgName type="university">Université de Pittsburgh</orgName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></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><idno type="wicri:Area/Pmc/Checkpoint">000B06</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000B06</idno><idno type="wicri:Area/Ncbi/Merge">000503</idno><idno type="wicri:Area/Ncbi/Curation">000503</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="2"><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><placeName><region type="state">Massachusetts</region></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Sun, Nuo" sort="Sun, Nuo" uniqKey="Sun N" first="Nuo" last="Sun">Nuo Sun</name><affiliation wicri:level="2"><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><placeName><region type="state">Maryland</region></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Brown, Daniel" sort="Brown, Daniel" uniqKey="Brown D" first="Daniel" last="Brown">Daniel Brown</name><affiliation wicri:level="2"><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><placeName><region type="state">Massachusetts</region></placeName></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="2"><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><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Taguchi, Kensei" sort="Taguchi, Kensei" uniqKey="Taguchi K" first="Kensei" last="Taguchi">Kensei Taguchi</name><affiliation wicri:level="2"><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><placeName><region type="state">Tennessee</region></placeName></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="2"><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><placeName><region type="state">Tennessee</region></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Finkel, Toren" sort="Finkel, Toren" uniqKey="Finkel T" first="Toren" last="Finkel">Toren Finkel</name><affiliation wicri:level="2"><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><placeName><region type="state">Maryland</region></placeName></affiliation><affiliation wicri:level="4"><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><placeName><region type="state">Pennsylvanie</region><settlement type="city">Pittsburgh</settlement></placeName><orgName type="university">Université de Pittsburgh</orgName></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="2"><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><placeName><region type="state">Massachusetts</region></placeName></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></record>Pour manipuler ce document sous Unix (Dilib)
EXPLOR_STEP=$WICRI_ROOT/Sante/explor/ChloroquineV1/Data/Ncbi/Curation
HfdSelect -h $EXPLOR_STEP/biblio.hfd -nk 000503 | SxmlIndent | more
Ou
HfdSelect -h $EXPLOR_AREA/Data/Ncbi/Curation/biblio.hfd -nk 000503 | SxmlIndent | more
Pour mettre un lien sur cette page dans le réseau Wicri
{{Explor lien
|wiki= Sante
|area= ChloroquineV1
|flux= Ncbi
|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/Ncbi/Curation/RBID.i -Sk "pubmed:30870143" \
| HfdSelect -Kh $EXPLOR_AREA/Data/Ncbi/Curation/biblio.hfd \
| NlmPubMed2Wicri -a ChloroquineV1
| This area was generated with Dilib version V0.6.33. |  |