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

Abstract

Accumulating data support a role for bioactive lipids as mediators 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, ceramide synthase (CerS)1-CerS6. Data support that specific ceramides and the enzymes that catalyze their formation play distinct roles in cell function. In a mouse model of diabetic cardiomyopathy, sphingolipid profiling revealed increases in not only the CerS5-derived ceramides but also in very long chain (VLC) ceramides derived from CerS2. 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.-Law, B. A., Liao, X., Moore, K. S., Southard, A., Roddy, P., Ji, R., Szulc, Z., Bielawska, A., Schulze, P. C., Cowart, L. A. Lipotoxic very-long-chain ceramides cause mitochondrial dysfunction, oxidative stress, and cell death in cardiomyocytes.

Novel function of ceramide for regulation of mitochondrial ATP release in astrocytes

“…It should be by guest, on May 11, 2018 www.jlr.org There is some discrepancy in which VDAC isoform is more critical for regulation of intracellular ATP, which is likely to be cell-type specific (51,52). Most recently, excess elevation of ceramide has been shown to induce mitophagy, suggesting that the physiological function of ceramide as discussed in our study requires limitation of its concentration at mitochondria (88,89). While ATP levels observed in our study are consistent with CATregulated ATP release under normal physiological conditions, several studies have shown that under pathophysiological conditions, reduction of ATP levels are concurrent with decreased mitochondrial motility and increased fragmentation (44,(90)(91)(92).…”

Delayed metabolic dysfunction in myocardium following exertional heat stroke in mice

“…2007; Law et al . 2018), induce Ca 2+ dysregulation (Egnatchik et al . 2014; Arruda & Hotamisligil, 2015), alter mitochondrial function (Hsu et al .…”

Ceramide Remodeling and Risk of Cardiovascular Events and Mortality

“…They may also reflect changes in the composition and function of cellular membranes within tissues, because in addition to the generation of plasma ceramides by secreted sphingomyelinases, ceramides are also secreted by parenchymal tissues 21, 22. Given observations that ceramides accumulate in the myocardium in the setting of metabolic cardiomyopathy and HF, and given that accumulation of ceramides promotes cardiomyocyte oxidative stress and mitophagy, it is possible that enhanced ability to export very–long‐chain ceramides from tissues underlies the inverse relationships between plasma ratios of C24:0/C16:0 and CHD and mortality 23, 24. Future studies will be required to elucidate the relation of plasma ratios to ceramide content in specific tissues and how this affects the pathogenesis of vascular disease and related outcomes.…”