PERM1 regulates energy metabolism in the heart via ERRα/PGC-1α axis

Shin-Ichi Oka; Karthi Sreedevi; Thirupura S Shankar; Shreya Yedla; Sumaita Arowa; Amina James; Kathryn G Stone; Katia Olmos; Amira D Sabry; Amanda Horiuchi; Keiko M Cawley; Sean A O'very; Mingming Tong; Jaemin Byun; Xiaoyong Xu; Sanchita Kashyap; Youssef Mourad; Omair Vehra; Dallen Calder; Ty Lunde; Tong Liu; Hong Li; J Alan Mashchek; James Cox; Yukio Saijoh; Stavros G Drakos; Junco S Warren

doi:10.3389/fcvm.2022.1033457

PERM1 regulates energy metabolism in the heart via ERRα/PGC-1α axis

Front Cardiovasc Med. 2022 Nov 7:9:1033457. doi: 10.3389/fcvm.2022.1033457. eCollection 2022.

Authors

Shin-Ichi Oka¹, Karthi Sreedevi², Thirupura S Shankar³, Shreya Yedla², Sumaita Arowa², Amina James², Kathryn G Stone², Katia Olmos², Amira D Sabry³, Amanda Horiuchi³, Keiko M Cawley³, Sean A O'very³, Mingming Tong¹, Jaemin Byun¹, Xiaoyong Xu¹, Sanchita Kashyap¹, Youssef Mourad¹, Omair Vehra¹, Dallen Calder³, Ty Lunde³, Tong Liu⁴, Hong Li⁴, J Alan Mashchek⁵, James Cox^{5

6}, Yukio Saijoh³, Stavros G Drakos^{3

7}, Junco S Warren^{2

8

9

10}

Affiliations

¹ Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, Newark, NJ, United States.
² Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA, United States.
³ Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, United States.
⁴ Department of Microbiology, Biochemistry, and Molecular Genetics, Center for Advanced Proteomics Research, Rutgers New Jersey Medical School and Cancer Institute of New Jersey, Newark, NJ, United States.
⁵ Metabolomics Core Research Facility, University of Utah, Salt Lake City, UT, United States.
⁶ Department of Biochemistry, University of Utah, Salt Lake City, UT, United States.
⁷ Division of Cardiovascular Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States.
⁸ Center for Vascular and Heart Research, Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA, United States.
⁹ Department of Human Nutrition, Food and Exercise, Virginia Tech, Blacksburg, VA, United States.
¹⁰ Division of Developmental Genetics, Institute of Resource Developmental and Analysis, Kumamoto University, Kumamoto, Japan.

Abstract

Aims: 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.

Keywords: ERRα; PERM1; heart; metabolism; metabolomics; proteomics; transcription control.

Copyright © 2022 Oka, Sreedevi, Shankar, Yedla, Arowa, James, Stone, Olmos, Sabry, Horiuchi, Cawley, O’very, Tong, Byun, Xu, Kashyap, Mourad, Vehra, Calder, Lunde, Liu, Li, Mashchek, Cox, Saijoh, Drakos and Warren.

Abstract

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