PERM1 regulates energy metabolism in the heart via ERR alpha/PGC-1 alpha axis

Simple item page
dc.contributor.authorOka, Shin-ichi I.en
dc.contributor.authorSreedevi, Karthien
dc.contributor.authorShankar, Thirupura S.en
dc.contributor.authorYedla, Shreyaen
dc.contributor.authorArowa, Sumaitaen
dc.contributor.authorJames, Aminaen
dc.contributor.authorStone, Kathryn G.en
dc.contributor.authorOlmos, Katiaen
dc.contributor.authorSabry, Amira D.en
dc.contributor.authorHoriuchi, Amandaen
dc.contributor.authorCawley, Keiko M.en
dc.contributor.authorO'very, Sean A.en
dc.contributor.authorTong, Mingmingen
dc.contributor.authorByun, Jaeminen
dc.contributor.authorXu, Xiaoyongen
dc.contributor.authorKashyap, Sanchitaen
dc.contributor.authorMourad, Youssefen
dc.contributor.authorVehra, Omairen
dc.contributor.authorCalder, Dallenen
dc.contributor.authorLunde, Tyen
dc.contributor.authorLiu, Tongen
dc.contributor.authorLi, Hongen
dc.contributor.authorMashchek, J. Alanen
dc.contributor.authorCox, Jamesen
dc.contributor.authorSaijoh, Yukioen
dc.contributor.authorDrakos, Stavros G.en
dc.contributor.authorWarren, Junco S.en
dc.date.accessioned2024-02-05T13:14:06Zen
dc.date.available2024-02-05T13:14:06Zen
dc.date.issued2022-11-07en
dc.description.abstractAims: PERM1 is a striated muscle-specific regulator of mitochondrial bioenergetics. We previously demonstrated that PERM1 is downregulated in the failing heart and that PERM1 positively regulates metabolic genes known as targets of the transcription factor ERRα and its coactivator PGC-1α in cultured cardiomyocytes. The aims of this study were to determine the effect of loss of PERM1 on cardiac function and energetics using newly generated Perm1-knockout (Perm1–/–) mice and to investigate the molecular mechanisms of its transcriptional control. Methods and results: Echocardiography showed that ejection fraction and fractional shortening were lower in Perm1–/– mice than in wild-type mice (both p < 0.05), and the phosphocreatine-to-ATP ratio was decreased in Perm1–/– hearts (p < 0.05), indicating reduced contractile function and energy reserves of the heart. Integrated proteomic and metabolomic analyses revealed downregulation of oxidative phosphorylation and upregulation of glycolysis and polyol pathways in Perm1–/– hearts. To examine whether PERM1 regulates energy metabolism through ERRα, we performed co-immunoprecipitation assays, which showed that PERM1 bound to ERRα in cardiomyocytes and the mouse heart. DNA binding and reporter gene assays showed that PERM1 was localized to and activated the ERR target promoters partially through ERRα. Mass spectrometry-based screening in cardiomyocytes identified BAG6 and KANK2 as potential PERM1’s binding partners in transcriptional regulation. Mammalian one-hybrid assay, in which PERM1 was fused to Gal4 DNA binding domain, showed that the recruitment of PERM1 to a gene promoter was sufficient to activate transcription, which was blunted by silencing of either PGC-1α, BAG6, or KANK2. Conclusion: This study demonstrates that PERM1 is an essential regulator of cardiac energetics and function and that PERM1 is a novel transcriptional coactivator in the ERRα/PGC-1α axis that functionally interacts with BAG6 and KANK2.en
dc.description.versionPublished versionen
dc.format.extent19 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifierARTN 1033457 (Article number)en
dc.identifier.doihttps://doi.org/10.3389/fcvm.2022.1033457en
dc.identifier.eissn2297-055Xen
dc.identifier.issn2297-055Xen
dc.identifier.orcidWarren, Junko [0000-0001-5231-4181]en
dc.identifier.otherPMC9676655en
dc.identifier.pmid36419485en
dc.identifier.urihttps://hdl.handle.net/10919/117853en
dc.identifier.volume9en
dc.language.isoenen
dc.publisherFrontiersen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/36419485en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectPERM1en
dc.subjecthearten
dc.subjectERR alphaen
dc.subjectmetabolomicsen
dc.subjectproteomicsen
dc.subjectmetabolismen
dc.subjecttranscription controlen
dc.titlePERM1 regulates energy metabolism in the heart via ERR alpha/PGC-1 alpha axisen
dc.title.serialFrontiers in Cardiovascular Medicineen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2022-10-11en
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/University Research Institutes/Fralin Biomedical Research Institute at VTCen

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
Oka_Frontiers.pdf
Size:
3.49 MB
Format:
Adobe Portable Document Format
Description:
Published version
Download
License bundle
Now showing 1 - 1 of 1
Name:
license.txt
Size:
1.5 KB
Format:
Plain Text
Description:
Download

Collections

All Faculty Deposits
Scholarly Works, Fralin Biomedical Research Institute at VTC
Scholarly Works, Human Nutrition, Foods, and Exercise