Abstract
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.
Highlights
Sphingolipids represent a class of bioactive lipids that modulate the biophysical properties of biological membranes and play a critical role in cell signal transduction
Since the lysosomal and mitochondrial functions are intricately related and critical for maintaining cellular homeostasis, it is intuitive to assume that autophagy-mitophagy processes are affected in Gaucher disease (GD) [1,2]
The GBA mutations lead to misfolding of GCase glucocerebrosidase gene (GBA) (OMIM 606463) which results in the deficiency of lysosomal enzyme protein in the endoplasmic reticulum, inhibition of protein trafficking to the lysosomes, and, as a result, glucocerebrosidase (GCase) (Enzyme commission number (EC) 3.2.1.45)
Summary
Since the lysosomal and mitochondrial functions are intricately related and critical for maintaining cellular homeostasis, it is intuitive to assume that autophagy-mitophagy processes are affected in Gaucher disease (GD) [1,2]. In an effort to prevent cell death, damaged mitochondria trigger mitophagy initiation via the ubiquitination of mitochondrial outer membrane proteins, which are recognized by mitophagy receptors [4]. In the step, activated mitophagy receptors recruit the microtubule-associated protein 1 light chain 3 (LC3) and GABA type A receptor-associated protein (GABARAP) proteins and trigger the autophagy flux process. Cytosolic LC3-1 is conjugated to form LC3-II, and LC3-II is incorporated into the autophagosomal membrane. Some data suggest that ceramide (Cer) anchors LC3B-II autophagosomes to mitochondrial membranes to induce mitophagy [5]. The step is the fusion of autophagic vacuoles with lysosomes to form autophagolysosomes, where the macromolecular components are broken down into metabolites [8]. Autophagic cargo is delivered to lysosomes where materials are degraded by acidic lysosomal hydrolases.
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