Role of Mitophagy in Ischemia-Reperfusion Renal Injury: New Insights from Bioinformatics Analysis

Mitophagy is central to acute kidney injury (AKI) pathogenesis. Elucidating its molecular interplay with AKI is crucial for novel therapeutics.

This study is based on transcriptome sequencing combined with single-cell sequencing and applies bioinformatics analysis. Finally, it is verified by in vitro, in vivo, and clinical specimen experiments.

In transcriptome analysis, combining protein-protein interaction mapping with machine intelligence algorithms, we screened out two mitophagy-related differentially expressed genes (MitoDEGs), solute carrier family 3 member 2 (SLC3A2) and thioredoxin (TXN). The immunological analysis revealed a notable rise in monocyte infiltration in the immune microenvironment of ischemia-reperfusion injury (IRI)-AKI. Spearman analysis indicated hub MitoDEGs were positively correlated with pro-inflammatory immune cell infiltration and negatively correlated with anti-inflammatory or regulatory immune cell infiltration. Based on the highest binding score, 506-26-3 CTD (gamma-linolenic acid) was determined to be the top promising therapeutic candidate. At the single-cell level, hub MitoDEGs were mainly expressed in proximal tubular. In cell experiments, mitophagy was inhibited after hypoxia-reoxygenation, SLC3A2 matched earlier results, while TXN was contrary to the previous analysis results. In the IRI-AKI rat experiments, the findings regarding hub MitoDEGs aligned with our prior analysis, revealing a decrease in the expression of genes associated with mitophagy. Consequently, we directed our attention to the expression levels of SLC3A2 in clinical cases of AKI, where we observed a notable increase.

Our research indicates that SLC3A2 could be a crucial target for enhancing IRI-AKI through the modulation of the mitophagy pathway.