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Lessons Learned from Gaucher and Fabry Diseases

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Lessons Learned from Gaucher and Fabry Diseases Journal of Clinical Medicine Communication Altered Sphingolipids Metabolism Damaged Mitochondrial Functions: Lessons Learned from Gaucher and Fabry Diseases Margarita Ivanova Lysosomal and Rare Disorders Research and Treatment Center, Faitfax, VA 22030, USA; mivanova@ldrtc.org Received: 9 February 2020; Accepted: 10 April 2020; Published: 14 April 2020 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. Keywords: Gaucher disease; Fabry disease; sphingolipids; mitochondria; autophagy 1. Mitophagy 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]. Usually, mitophagy is initiated by the damaged mitochondrion itself to compensate for the energy crisis [3]. 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 next 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. During autophagic flux, 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]. Sequestosome 1 (SQSTM1/p62) links autophagic cargo to the autophagic membrane [6,7]. The next step is the fusion of autophagic vacuoles with lysosomes to form autophagolysosomes, where the macromolecular components are broken down into metabolites [8]. Autophagosomes maturate into autolysosomes by one of the two pathways: fuse first with late endosomes to form amphisomes, then with lysosomes, or, autophagosomes fuse directly with lysosomes [9]. Then, autophagic cargo is delivered to lysosomes where materials are degraded by acidic lysosomal hydrolases. J. Clin. Med. 2020, 9, 1116; doi:10.3390/jcm9041116 www.mdpi.com/journal/jcm J. Clin.J. Clin. Med. Med.2020 2020, 9,, 11169, x FOR PEER REVIEW 2 of 11 2 of 11 or, autophagosomes fuse directly with lysosomes [9]. Then, autophagic cargo is delivered to 2. Gaucherlysosomes Disease where materials and Mitochondrial are degraded Functionby acidic lysosomal hydrolases. 2.1.2. Gaucher Gaucher Disease Disease and Mitochondrial Function Gaucher disease (GD) (Online Mendelian Inheritance in Man (OMIM) 23080, 231000, 231005), 2.1. Gaucher Disease the most common lysosomal storage disorder (LSD), is caused by mutations in the glucocerebrosidase gene (GBA)Gaucher(OMIM disease 606463) (GD) which(Online results Mendelian in the Inheritance deficiency in ofMan lysosomal (OMIM) enzyme23080, 231000, glucocerebrosidase 231005), the most common lysosomal storage disorder (LSD), is caused by mutations in the (GCase) (Enzyme commission number (EC) 3.2.1.45). The GBA mutations lead to misfolding of GCase glucocerebrosidase gene (GBA) (OMIM 606463) which results in the deficiency of lysosomal enzyme proteinglucocerebrosidase in the endoplasmic (GCase) reticulum, (Enzyme inhibitioncommission of number protein (EC) traffi 3.2.1.45).cking to The the GBA lysosomes, mutations and, lead as to a result, inhibitionmisfolding of GCase of GCase enzymatic protein activityin the endoplasmic [10]. The deficiency reticulum, of inhibition GCase results of protein in chronic trafficking accumulation to the of its substratelysosomes, glucosylceramide and, as a result, inhibition (Gl-1) in of lysosomes. GCase enzymatic Recessively activity inherited [10]. The GD deficiency presents of withGCase a broad spectrumresults ofin symptomschronic accumulation encompassing of its primary substrate nervous glucosylceramide system, immune (Gl-1) in system lysosomes. involvement, Recessively enlarged spleeninherited and liver, GD presents anemia, with low thrombocytea broad spectrum counts of symptoms due to bone encompassing marrow involvement, primary nervous and severesystem, skeletal disorderimmune with system pain involvement, and permanent enlarged disabilities spleen [an11d,12 liver,]. Three anemia, distinguished low thrombocyte phenotypic counts presentationsdue to of GDbone are marrow described involvement, based on and increasing severe skeletal severity. disord GDer type with 1 pain is a non-neuropathicand permanent disabilities form of [11,12]. GD, GD type 2 andThree 3 are distinguished termed neuronopathic phenotypic presentations forms of GD. of GD are described based on increasing severity. GD type 1 is a non-neuropathic form of GD, GD type 2 and 3 are termed neuronopathic forms of GD. GCase catalyzes the cleavage of the glycolipid glucosylceramide (Gl-1) into glucose and ceramide GCase catalyzes the cleavage of the glycolipid glucosylceramide (Gl-1) into glucose and (Cer)ceramide [13]. The (Cer) lipid [13]. The tails lipid of glycolipid,tails of glycolipid, GCase, GC andase, and the the reaction reaction facilitator facilitator saposin C C (SAPC) (SAPC) are embeddedare embedded within within the intralysosomal the intralysosomal membrane membrane where where cleavage cleavage occurs occurs (Figure(Figure1 1))[ [14].14]. Gl-1, Gl-1, as as with glycosphingolipidswith glycosphingolipids in general, in general, is involved is involved in a largein a large number number of cellularof cellular processes, processes, including including signal transduction,signal transduction, membrane membrane trafficking, trafficking, or cytoskeletal or cytoskeletal processes processes [13,15 [13,15].]. Since Since Gl-1 Gl-1 is a primaryis a primary precursor of complexprecursor glycosphingolipids, of complex glycosphingolipids, synthesis andsynthesis degradation and degradation of Gl-1 areof Gl-1 crucial are stepscrucial in steps sphingolipid in metabolismsphingolipid (Figure metabolism1)[ 16]. (Figure In the absence1) [16]. In of the functional absence of GCase functional in GD, GCase glucosylceramide in GD, glucosylceramide is deacetylated to formis deacetylated Lyso-Gl-1 to [ 17form,18 ].Lyso-Gl-1 When sphingolipids [17,18]. When sphingolipids accumulate accumulate in the lysosomes, in the lysosomes, the pH increases the pH and mediatesincreases lysosomal and mediates destabilization lysosomal destabilization [19–21]. Therefore, [19–21]. dysfunctional Therefore, dysfunctional lysosomes withlysosomes excessive with levels excessive levels of Lyso-Gl-1 amass in every cell and interfere with cellular pathways outside the of Lyso-Gl-1 amass in every cell and interfere with cellular pathways outside the lysosomes. lysosomes. Figure 1. Sphingolipid metabolism in Gaucher and Fabry diseases (GD, FD). Ceramide (Cer), Figure 1. Sphingolipid metabolism in Gaucher and Fabry diseases (GD, FD). Ceramide (Cer), glucosylceramide (Gl-1) and globotriaosylceramide (Gb-3) shifts between endoplasmic reticulum glucosylceramide (Gl-1) and globotriaosylceramide (Gb-3) shifts between endoplasmic reticulum ER, ER, Golgi apparatus, lysosomes, and cellular membranes. UDP-Glucose Ceramide Golgi apparatus, lysosomes, and cellular membranes. UDP-Glucose Ceramide Glucosyltransferase (UGCG) Glucosyltransferase (UGCG) converts Cer to Gl-1 in the ER. Gl-1 localized in the intralysosomal converts Cer to Gl-1 in the ER. Gl-1 localized in the intralysosomal membrane is broken down by glucocerebrosidase (GCase) enzyme in the present of SAPC. Gb-3 is synthesized from lactosylceramide (Gal-Glc-Cer) by Golgi-localized enzyme Gb-3 synthase. Gal-Glc-Cer is synthesized by LacCer synthase (GalT2) from Gl-1. Lysosomal accumulation of Gl-1 is linked to GD. Lysosomal accumulation of Gb-3 is linked to FD. J. Clin. Med. 2020, 9, 1116 3 of 11 2.2. Gaucher Disease and Mitophagy Lysosomal dysfunction in LSD is associated with mitochondrial dysregulation and accumulation of damaged mitochondria. What happens with the mitophagy process in GD when lysosomes do not function properly? Increased mitochondrial fragmentation due to inhibition of autophagy was / described
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