Sphingomyelinases are phosphodiesterases that cleave the phosphorylcholine head group of sphingomyelin to generate ceramide. During cell signaling they are the main pathway that generates ceramide, a bioactive lipid that regulates cell growth, differentiation, and apoptosis; hence, the sphingomyelinases have been exhaustedly studied for more than two decades. Only recently, however, have the sphingomyelinases begun to reveal their molecular personalities. One acid sphingomyelinase (aSMase1) and three neutral sphingomyelinases (nSMase 1,2, and 3) are encoded by four different genes (smpd1, 2, 3, and 4, respectively) and are found in different subcellular compartments. ASMase1 is located in the endo-lysosomes, nSMase1 in the ER, nSMase2, in the plasma membrane, and nSMase3 in the ER/Golgi. Now, a recent article by Wu, et al. (1) describes a novel neutral sphingomyelinase, encoded by smpd5, that seems to be preferentially located in the mitochondria!
This newly described mitochondria-associated neutral SMase, MA-nSMase, shares significant sequence homology with mammalian nSMase2 as well as the zebrafish mitochondrial SMase. MA-nSMase has characteristics that are typical of neutral sphingomyelinases: it is Mg2+-dependent and is activated by anionic lipids like phosphatidylserine and the mitochondrial-specific phospholipid, cardiolipin. Overexpression of MA-nSMase in MCF7 cells decreases cellular levels of sphingomyelin while increasing those of ceramide, indicating that mitochondria contain a pool of sphingomyelin that is accessible for turnover and ceramide production. The mitochondrial location is important because mitochondrial-generated ceramide plays an essential role in Bax translocation to mitochondria, cytochrome c release, and cell death.
The most interesting observation of this paper, however, is the fact that in some cell lines, MA-nSMase also partially localizes to the ER, in addition to mitochondria, thereby resembling the bimodal localization of the yeast nSMase homologue ISC1 that is dependent upon the growth phase of the yeast. It seems likely that locations of yeast and mammalian MA-nSMase2 are similarly regulated. Such a possibility provides an unexpected angle on the current question of how mitochondrial sphingolipid composition is determined.
1. Wu BX, Rajagopalan V, Roddy PL, Clarke CJ, Hannun YA. Identification and characterization of murine mitochondria-associated neutral phingomyelinase (MA-nSMase), the mammalian sphingomyelin phosphodiesterase 5. J Biol Chem. 2010 Jun 4;285(23):17993-8002.PMID: 20378533
Posted on: 28 June 2010