CerS6-Derived Sphingolipids Interact with Mff and Promote Mitochondrial Fragmentation in Obesity

• Published in: Cell 2019-05, Vol.177 (6), p.1536-1552.e23
• Main Authors: Hammerschmidt, Philipp, Ostkotte, Daniela, Nolte, Hendrik, Gerl, Mathias J., Jais, Alexander, Brunner, Hanna L., Sprenger, Hans-Georg, Awazawa, Motoharu, Nicholls, Hayley T., Turpin-Nolan, Sarah M., Langer, Thomas, Krüger, Marcus, Brügger, Britta, Brüning, Jens C.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Cell Line; HeLa Cells; Humans; Insulin Resistance - physiology; Liver - metabolism; Male; Membrane Proteins - metabolism; Membrane Proteins - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitochondria - metabolism; Mitochondria - physiology; Mitochondrial Proteins - metabolism; Obesity - metabolism; Obesity - physiopathology; Sphingolipids - metabolism; Sphingolipids - physiology; Sphingosine N-Acyltransferase - metabolism; Sphingosine N-Acyltransferase - physiology
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2019.05.008

Ectopic lipid deposition and altered mitochondrial dynamics contribute to the development of obesity and insulin resistance. However, the mechanistic link between these processes remained unclear. Here we demonstrate that the C16:0 sphingolipid synthesizing ceramide synthases, CerS5 and CerS6, affect distinct sphingolipid pools and that abrogation of CerS6 but not of CerS5 protects from obesity and insulin resistance. We identify proteins that specifically interact with C16:0 sphingolipids derived from CerS5 or CerS6. Here, only CerS6-derived C16:0 sphingolipids bind the mitochondrial fission factor (Mff). CerS6 and Mff deficiency protect from fatty acid-induced mitochondrial fragmentation in vitro, and the two proteins genetically interact in vivo in obesity-induced mitochondrial fragmentation and development of insulin resistance. Our experiments reveal an unprecedented specificity of sphingolipid signaling depending on specific synthesizing enzymes, provide a mechanistic link between hepatic lipid deposition and mitochondrial fragmentation in obesity, and define the CerS6-derived sphingolipid/Mff interaction as a therapeutic target for metabolic diseases. [Display omitted] •CerS6, but not CerS5, deficiency protects from obesity-associated insulin resistance•CerS6, but not CerS5, regulates C16:0 ceramides in mitochondria and MAMs•CerS6-derived C16:0 sphingolipids interact with Mff•CerS6 and Mff regulate mitochondrial dynamics and insulin resistance in obesity Although the ceramide synthases CerS5 and CerS6 both produce C16:0 sphingolipids, only the abrogation of CerS6 protects from obesity and insulin resistance, and this is due to their selective impacts on spatially-distinct sphingolipid pools in the cell.