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Targeting PRMT5 alleviates diabetic cardiomyopathy: mechanisms involve Ndufs2 R118 dimethylation-mediated complex I protection and serum PRMT5 as a biomarker
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DOI：10.1186/s10020-026-01594-2.png)
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Abstract
En 中文
Diabetic cardiomyopathy (DCM) is defined by progressive cardiac dysfunction driven by myocardial ATP depletion, where mitochondrial electron transport chain (ETC) Complex I dysfunction acts as a critical factor. Protein arginine methyltransferase 5 (PRMT5) maintains cardiac homeostasis, yet its function in DCM and association with Complex I remain elusive. This study aimed to investigate the function, key substrate, and mechanism of PRMT5 in DCM, and evaluate serum PRMT5 as a potential biomarker for DCM. Gain- and loss-of-function experiments of PRMT5 were conducted to explore the function of PRMT5 in DCM. IP-MS proteomics and post-translational modification analysis were applied to identify the substrates of PRMT5 and their modified sites. By employing ELISA assay, serum levels of PRMT5, lactate, and lactate/pyruvate (L/P) ratio were measured in DCM patients, and the association between serum PRMT5 level and hospital readmission risk was analyzed. PRMT5 overexpression protected against DCM pathogenesis, while its knockdown or inhibition exacerbated disease progression. PRMT5 mediated symmetric di-methylation (SDMA) of Ndufs2 at R118 to prevent its ubiquitin-proteasomal degradation and preserve mitochondrial Complex I function. DCM patients had significantly lower serum PRMT5, which correlated positively with serum lactate and L/P ratio and was associated with higher hospital readmission risk. Our findings unveil a novel PRMT5/Ndufs2 regulatory axis where arginine methylation maintains bioenergetic capacity of Complex I through methylation-ubiquitination crosstalk. PRMT5 shows potential as a therapeutic target and biomarker for DCM, which may aid the establishment of innovative diagnostic and treatment frameworks for DCM pending further translational validation.
Keywords:
PRMT5
Ndufs2
Symmetric di-methylation (SDMA)
Complex I
Diabetic cardiomyopathy (DCM)
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