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E-Poster Submission Deadline
Please prepare and upload your E-Poster no later than March 14, 2026 11.59PM CET. After this date, you will no longer be able to prepare and upload your E-poster and it will not be displayed and accessible on the congress website.
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Abstract titles should be brief and reflect the content of the abstract.
Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI), with oxidative stress playing a key role, particularly through mitochondrial dysfunction. The MAP3K family, especially MAP3K1, is involved in AKI and chronic kidney disease (CKD) pathogenesis, functioning as both a kinase and an E3 ubiquitin ligase. Mitochondrial autophagy, especially via the PINK-Parkin pathway, protects against IRI-AKI. However, the role of MAP3K1 in regulating mitochondrial autophagy through ubiquitination in IRI-AKI remains unclear. Our study aims to explore whether MAP3K1 can alleviate IRI-AKI-induced renal injury by promoting mitochondrial autophagy.
1.The team developed MEC1 (Mitophagy-Enhancing Chimera 1), a small-molecule drug using PROTAC technology, to target and recruit the E3 ubiquitin ligase MAP3K1 to the outer mitochondrial membrane, enhancing mitochondrial autophagy. One end of MEC1 targets MAP3K1, while the other end targets the mitochondrial outer membrane protein TSPO (Fig A).
2.A mouse model of bilateral renal ischemia-reperfusion injury (IRI) was created with 26 minutes of ischemia. MEC1 was administered via tail vein injection immediately after arterial clamp release (Fig B).
3.Mouse survival was monitored for 14 days; renal function was assessed by serum creatinine levels. Renal histopathological damage was evaluated by hematoxylin and eosin (HE) staining, mitochondrial damage was observed by electron microscopy, and mitochondrial injury and autophagy in renal tissues were assessed using MitoSOX, KIM-1, LC3, and p62 immunofluorescence staining.
1. In the IRI-AKI mouse model, peak mortality occurred at 72 hours post-surgery. The survival rate in the IRI group (no drug intervention) was 56% over 14 days, while in the IRI + MEC1 group (drug intervention), survival increased in a dose-dependent manner, with the high-dose group (500 µg/kg) achieving 80% survival (Fig C).
2. Serum creatinine levels, reflecting renal function, showed that MEC1-mediated MAP3K1 recruitment effectively reduced creatinine levels early in AKI (1st and 3rd days), improving renal function (Fig D).
3. PLA experiments revealed that IRI injury caused MAP3K1 aggregation on the outer mitochondrial membrane, and MEC1 enhanced this accumulation (Fig E).
4. HE staining showed that MAP3K1 recruitment alleviated early renal injury (1 day) in IRI-AKI mice, including tubular epithelial cell shedding, cast formation, and dilation, with the high-dose group showing the most prominent effects. Electron microscopy revealed severe mitochondrial damage in the IRI group, which was significantly reduced by MAP3K1 recruitment (Fig F).
5. MitoSOX and KIM-1 staining showed that MEC1 reduced mitochondrial ROS and alleviated renal damage. LC3 and p62 staining showed enhanced mitochondrial autophagy in MEC1-treated proximal tubular cells, with reduced p62 accumulation, increased LC3, and activated autophagic flux (Fig G-J).
1.MAP3K1 recruitment to the outer mitochondrial membrane alleviates IRI-AKI-induced renal and mitochondrial damage.
2.MEC1 enhances MAP3K1 recruitment, promoting mitochondrial autophagy in proximal tubular cells to mitigate renal injury.
