Combining mitochondrial proteomes and Mendelian randomization to identify novel therapeutic targets for diabetic nephropathy

Diabetic nephropathy (DN) is a common microvascular complication of diabetes. Mitochondrial dysfunction in the kidney caused by diabetes has previously been linked to the pathogenesis of DN. By mass spectrometry, we identified characteristic proteins of DN from the renal mitochondria in mouse model. To identify the core proteins among them, Mendelian randomization (MR) analysis, microarray data validation, and drug-target interaction analysis were employed. MR analysis found that 189 candidate targets had a causal link with DN risk factors (estimated glomerular filtration rate (eGFR), urinary albumin excretion, and serum creatinine). After systematic analysis, we validated that SLC25A16, CTNND1, C2CD2L, ALDH3A2, NEU1, APEH, CORO1A, NUDT19, and NDUFA4L2 are the core proteins with promising druggability in DN. This study suggests the feasibility of using MR analysis for DN drug target screening, and provides potential insights into mitochondrial dysfunction research, which may contribute to further DN pathogenesis exploration.