MYC affects mitochondrial function in IgA nephropathy by promoting the degradation of MFN1 through HRD1

IgA nephropathy is characterized by the deposition of IgA and complement C3 in the glomerular mesangial region. Recent research has pointed out the critical role of mitochondrial damage during the occurrence and development of IgAN. During IgAN progression, elevated myc promotes the transcription of HRD1, which in turn induces the ubiquitination of MFN1, leading to mitochondrial dysfunction. We found that the expression levels of myc and HRD1 were elevated in IgAN. Down-regulation of HRD1 and myc successfully alleviated IgAN progression by promoting cell survival, reducing renal injury and improving mitochondrial homeostasis. Additionally, we observed reduced levels of MFN1 expression in IgAN. Overexpression of MFN1 significantly inhibited IgAN progression, while the deficiency of MFN1 exacerbated IgAN injury. In summary, our findings revealed that myc plays a critical role in regulating mitochondrial function in IgAN by promoting HRD1 transcription and inducing MFN1 ubiquitination. These results suggested that targeting myc/HRD1/MFN1 axis may offer a novel therapeutic strategy to combat IgAN progression.