Ivanova Margarita
Lysosomal and Rare Disorders Research and Treatment Center, Faitfax, VA 22030, USA.
J Clin Med. 2020 Apr 14;9(4):1116. doi: 10.3390/jcm9041116.
Sphingolipids represent a class of bioactive lipids that modulate the biophysical properties of biological membranes and play a critical role in cell signal transduction. Multiple studies have demonstrated that sphingolipids control crucial cellular functions such as the cell cycle, senescence, autophagy, apoptosis, cell migration, and inflammation. Sphingolipid metabolism is highly compartmentalized within the subcellular locations. However, the majority of steps of sphingolipids metabolism occur in lysosomes. Altered sphingolipid metabolism with an accumulation of undigested substrates in lysosomes due to lysosomal enzyme deficiency is linked to lysosomal storage disorders (LSD). Trapping of sphingolipids and their metabolites in the lysosomes inhibits lipid recycling, which has a direct effect on the lipid composition of cellular membranes, including the inner mitochondrial membrane. Additionally, lysosomes are not only the house of digestive enzymes, but are also responsible for trafficking organelles, sensing nutrients, and repairing mitochondria. However, lysosomal abnormalities lead to alteration of autophagy and disturb the energy balance and mitochondrial function. In this review, an overview of mitochondrial function in cells with altered sphingolipid metabolism will be discussed focusing on the two most common sphingolipid disorders, Gaucher and Fabry diseases. The review highlights the status of mitochondrial energy metabolism and the regulation of mitochondria-autophagy-lysosome crosstalk.
鞘脂是一类生物活性脂质，可调节生物膜的生物物理特性，并在细胞信号转导中发挥关键作用。多项研究表明，鞘脂可控制关键的细胞功能，如细胞周期、衰老、自噬、凋亡、细胞迁移和炎症。鞘脂代谢在亚细胞位置高度分区。然而，鞘脂代谢的大部分步骤发生在溶酶体中。由于溶酶体酶缺乏导致溶酶体中未消化底物积累，从而改变鞘脂代谢，这与溶酶体贮积症（LSD）有关。鞘脂及其代谢产物被困在溶酶体中会抑制脂质循环，这对细胞膜（包括线粒体内膜）的脂质组成有直接影响。此外，溶酶体不仅是消化酶的储存场所，还负责细胞器运输、感知营养物质和修复线粒体。然而，溶酶体异常会导致自噬改变，并扰乱能量平衡和线粒体功能。在本综述中，将讨论鞘脂代谢改变的细胞中线粒体功能的概况，重点关注两种最常见的鞘脂疾病，戈谢病和法布里病。本综述强调了线粒体能量代谢的状态以及线粒体-自噬-溶酶体相互作用的调节。
