Lipotoxic very-long-chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes

Abstract

Accumulating data support a role for bioactive lipids asmediators of lipotixicity in cardiomyocytes.One class of these, the ceramides, constitutes a family of molecules that differ in structure and are synthesized by distinct enzymes, ceramidesynthase(CerS)1-CerS6.Datasupportthat specific ceramidesandtheenzymesthat catalyzetheir formationplay distinct roles in cell function. In amouse model of diabetic cardiomyopathy, sphingolipid profiling revealed increases in not only theCerS5-derived ceramides but alsoinvery longchain (VLC) ceramides derived fromCerS2.Overexpression of CerS2 elevated VLC ceramides caused insulin resistance, oxidative stress, mitochondrial dysfunction, and mitophagy. Palmitate induced CerS2 and oxidative stress, mitophagy, and apoptosis, which were prevented by depletion of CerS2. Neither overexpression nor knockdown of CerS5 had any function in these processes, suggesting a chain-length dependent impact of ceramides on mitochondrial function. This concept was also supported by the observation that synthetic mitochondria-targeted ceramides led to mitophagy in a manner proportional to N-acyl chain length. Finally, blocking mitophagy exacerbated cell death. Taken together, our results support a model by which CerS2 and VLC ceramides have a distinct role in lipotoxicity, leading to mitochondrial damage, which results in subsequent adaptive mitophagy. Our data reveal a novel lipotoxic pathway through CerS2.