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Ceramides Drive Mitochondrial Dysfunction and Tubular Injury in AKI

ABSTRACT: Perturbations in proximal tubule mitochondrial function and lipid metabolism potentiate kidney dysfunction in acute kidney injury (AKI). We identified the bioactive lipid ceramides as drivers of proximal tubule pathology in AKI. Ceramide synthesis was upregulated in humans and mice with AKI. We utilized a proteome-wide thermal shift assay to observe that ceramides interact with proximal tubule proteins involved in lipid and mitochondrial metabolism. Mechanistic studies revealed that ceramides altered assembly of the inner mitochondrial membrane MICOS complex and respiratory supercomplexes in proximal tubule cells leading to acute impacts on mitochondrial respiration, cristae architecture, and mitochondrial morphology. Effects of ceramides on complex assembly and mitochondrial function were dependent on the presence of the 4-5 trans double bond incorporated by dihydroceramide desaturase 1 (DES1). Blunting ceramide synthesis, via genetic or pharmacologic inhibition of DES1, prevented kidney injury in mice following renal ischemia reperfusion injury. Ceramides may be a novel therapeutic target to combat mitochondrial disruption during AKI.

ORGANISM(S): Mus musculus

PROVIDER: GSE284451 | GEO | 2025/12/17

REPOSITORIES: GEO

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Project description:BACKGROUND: Ischemia/reperfusion injury (IRI) is the leading cause of acute kidney injury (AKI). The current standard of care focuses on supporting kidney function, stating the need for more efficient and targeted therapies to enhance repair. Mesenchymal Stromal Cells (MSCs) and their secretome, either as conditioned medium (CM) or extracellular vesicles (EVs), have emerged as promising options for regenerative therapy, however, their full potential in treating AKI remains unknown.METHODS: In this study, we employed an in vitro model of chemically-induced ischemia using antimycin A combined with 2-deoxy-D-glucose to induce ischemic injury in proximal tubule epithelial cells. Afterwards, we evaluated the effects of MSC secretome, CM or EVs obtained from adipose tissue, bone marrow and umbilical cord, on ameliorating the detrimental effects of ischemia. To assess the damage and treatment outcomes, we analyzed cell morphology, mitochondrial health parameters (mitochondrial activity, ATP production, mass and membrane potential) and overall cell metabolism by metabolomics.RESULTS: Our findings show that ischemic injury caused cytoskeletal changes confirmed by disruption of the F-actin network, energetic imbalance as revealed by a 50% decrease in the oxygen consumption rate, increased oxidative stress, mitochondrial dysfunction and reduced cell metabolism. Upon treatment with MSC secretome, the morphological derangements were partly restored and ATP production increased by 40-50%, with umbilical cord-derived EVs being most effective. Furthermore, MSC treatment led to phenotype restoration as indicated by an increase in cell bioenergetics, including increased levels of glycolysis intermediates, as well as an accumulation of antioxidant metabolites.CONCLUSION: Our in vitro model effectively replicated the in vivo-like morphological and molecular changes observed during ischemic injury. Additionally, treatment with MSC secretome ameliorated proximal tubule damage, highlighting its potential as a viable therapeutic option for targeting AKI.

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Ceramides Drive Mitochondrial Dysfunction and Tubular Injury in AKI

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