Ceramides Drive Mitochondrial Dysfunction and Tubular Injury in AKI

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. Overall design: Bulk RNA sequencing of kidney cortex tissue from Degs1 inducible global knockout (Degs1iGKO) mice or Degs1 fl/fl controls 24 hours after challenge with bilateral ischemia reperfusion injury or sham operations.