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

Abstract

AimsPERM1 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 resultsEchocardiography 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.ConclusionThis 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.

Native lamin A/C proteomes and novel partners from heart and skeletal muscle in a mouse chronic inflammation model of human frailty

“…As a disordered protein, Perm1 lacks conventional structure and is likely controlled by differential posttranslational modifications. Other partners for Perm1 in the heart include transcription co-activators BAG6, Kank2, ERRα and PGC-1α ( Oka et al, 2022 ); among these we identified Kank2 as lamin A/C-associated (and unaffected by IL10-KO) in the heart.…”

“…Transcription co-activator Perm1, an essential regulator of mitochondrial and cardiac energetics ( Oka et al, 2022 ) and fatty acid metabolism ( Huang et al, 2022 ), was lamin A/C-associated in hearts and recognized by mature lamin A in the peptide array. Perm1 is attractive to consider in the context of frailty because it also regulates genes required for endurance exercise and promotes mitochondrial biogenesis and oxidative capacity in muscle ( Cho et al, 2016 ; Cho et al, 2019 ; Cho et al, 2021 ).…”

Genetic architecture of the HLA/MHC locus in cardiometabolic disease, severe mental illness, and related traits.

“…There is limited understanding of the role of the ATF6B protein, however it appears to protect neurons (30) and pancreatic beta cells (31) from endoplasmic reticulum stress-induced cell death, albeit the relative levels of ATF6A and ATF6B could be more important that levels of ATF6B alone (32). BAG6 (also called BAT3) is located within the HLA class III gene cluster and is implicated in many functions (reviewed in (33)) including apoptosis (34), removal of mitochondria (35) and neurodegeneration-associated protein aggregates (36), modulating immune (37) and anti-viral response (38), de ning dendritic cell functions (39) and energy switching in cardiomyocytes (40). BAG6 is also required for glucose uptake by adipose and muscle tissues, via regulation of SLC2A4 (or GLUT4) translocation to the cell surface (41) and alternative splicing of BAG6 has been observed in an obesity and/or glycaemic control-dependent manner (42).…”

Estrogen-Related Receptor α: A Key Transcription Factor in the Regulation of Energy Metabolism at an Organismic Level and a Target of the ABA/LANCL Hormone Receptor System

“…PERM1 expression levels increase during normal murine cardiomyocyte development and are conversely reduced in the human ailing heart, and its overexpression in murine neonatal cardiomyocytes increases the mitochondrial number, respiration, oxidative metabolism, and resistance to hypoxia/reoxygenation [75]. PERM1 physically interacts with both PGC-1α and ERRα and PERM1 KO mice show profound contractile, metabolic, and energy metabolism shortcomings [76]. These results suggest that pharmacologic activation of the PGC-1α/ERRα/PERM1 axis could improve cardiac function in different pathological conditions of the heart, including contractile dysfunctions caused by chronic heart diseases, mitochondrial dysfunction induced by doxorubicin therapy and hypoxia/reoxygenation-derived injury.…”