HUWE1-Mediated Degradation of MUTYH Facilitates DNA Damage and Mitochondrial Dysfunction to Promote Acute Kidney Injury.

The role of MUTYH, a DNA repair glycosylase in the pathogenesis of acute kidney injury (AKI) is unclear. In this study, it is found that MUTYH protein levels are significantly decreased in the kidneys of cisplatin- or folic acid (FA)-induced mouse AKI models and patients with AKI. MUTYH deficiency aggravates renal dysfunction and tubular injury following cisplatin and FA treatment, along with the accumulation of 7, 8-dihydro-8-oxoguanine (8-oxoG) and impairs mitochondrial function. Importantly, the overexpression of type 2 MUTYH (nuclear) significantly ameliorates cisplatin-induced apoptosis, oxidative stress, mitochondrial dysfunction, and DNA damage in vivo and in vitro. In contrast, overexpression of type 1 MUTYH (mitochondrial) shows a marginal effect against cisplatin-induced injury, indicating the chief role of type 2 MUTYH in antagonizing AKI. Interestingly, the results also indicate that the upregulation of the E3 ligase HUWE1 causes the ubiquitination and degradation of MUTYH in tubular epithelial cells. HUWE1 knockout or treatment with the HUWE1 inhibitor BI8622 significantly protect against cisplatin-induced AKI. Taken together, these results suggest that the ubiquitin E3 ligase HUWE1-mediates ubiquitination and degradation of MUTYH can aggravate DNA damage in the nucleus and mitochondria and promote AKI. Targeting the HUWE1/MUTYH pathway may be a potential strategy for AKI treatment.