Purpose <p>Previous studies have extensively reported some alterations in mitochondrial-related proteins in patients with chronic kidney disease (CKD). Herein, we used a two-sample Mendelian randomization (MR) to investigate the potential causal relationship between serum mitochondrial-related protein function and CKD.</p> Methods <p>The data related to CKD and mitochondrial 2,4-dienoyl CoA reductase 1 were obtained from the genome-wide association studies (GWAS) database; data on other mitochondrial-related proteins were sourced from the IEU (Integrative Epidemiology Unit) database. Inverse-variance weighted (IVW) was used as the main approach for data analysis; weighted median, MR-Egger, and weighted mode methods were used to validate the robustness of the results. MR-Egger regression method was applied to explore the presence of horizontal pleiotropy, while the MR pleiotropy residual sum and outlier (MR-PRESSO) method was used to detect potential outliers. Leave-one-out (LOO) analyses were used to evaluate the presence of predominant instrumental variables (IVs). Cochran’s Q test was used to assess heterogeneity among IVs.</p> Results <p>The IVW approach showed that NADH dehydrogenase (ubiquinone) iron-sulfur protein 4 might be a risk factor for CKD (OR = 0.9825, 95% CI: 0.9659—0.9994, <i>P</i> = 0.0430). In addition, genetically predicted NADH dehydrogenase (ubiquinone) flavoprotein 2, serine tRNA ligase, NADH dehydrogenase (ubiquinone) 1 beta subcomplex subunit 8, NADH dehydrogenase (ubiquinone) iron-sulfur protein 4, 2,4-Dienoyl CoA Reduction, Diablo Homolog and NAD-dependent protein deacylase sirtuin-5 showed causal association with CKD markers (all <i>P</i> &lt; 0.05). The MR-Egger regression results and MR-PRESSO analysis further confirmed this data.</p> Conclusion <p>These exploratory findings suggest that these genes may play an important role in CKD pathogenesis and represent potential targets for future therapeutic strategies.</p>