Abstract
Lysosomal storage diseases (LSDs) describe a heterogeneous group of rare inherited metabolic disorders that result from the absence or loss of function of lysosomal hydrolases or transporters, resulting in the progressive accumulation of undigested material in lysosomes. The accumulation of substances affects the function of lysosomes and other organelles, resulting in secondary alterations such as impairment of autophagy, mitochondrial dysfunction, inflammation and apoptosis. LSDs frequently involve the central nervous system (CNS), where neuronal dysfunction or loss results in progressive neurodegeneration and premature death. Many LSDs exhibit signs of mitochondrial dysfunction, which include mitochondrial morphological changes, decreased mitochondrial membrane potential (ΔΨm), diminished ATP production and increased generation of reactive oxygen species (ROS). Furthermore, reduced autophagic flux may lead to the persistence of dysfunctional mitochondria. Gaucher disease (GD), the LSD with the highest prevalence, is caused by mutations in the GBA1 gene that results in defective and insufficient activity of the enzyme β-glucocerebrosidase (GCase). Decreased catalytic activity and/or instability of GCase leads to accumulation of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph) in the lysosomes of macrophage cells and visceral organs. Mitochondrial dysfunction has been reported to occur in numerous cellular and mouse models of GD. The aim of this manuscript is to review the current knowledge and implications of mitochondrial dysfunction in LSDs.
Highlights
Mitochondria are double-membrane organelles that are found in most eukaryotic cells and that execute many metabolic functions including ATP synthesis through oxidative phosphorylation (OXPHOS) [1]
These results suggest that mitochondrial dysfunctions and subsequent ATP deficiency, which are induced by altered cholesterol metabolism in mitochondria, may be responsible for neuronal impairment in NPC1 disease
Given that defects in mitochondrial function and oxidative stress have been demonstrated to play a role in the pathogenesis of many lysosomal storage diseases (LSDs), we envisioned that treatment with antioxidants and mitochondria energizers such as coenzyme Q10 (CoQ) could exert beneficial therapeutic effects
Summary
Mitochondria are double-membrane organelles that are found in most eukaryotic cells and that execute many metabolic functions including ATP synthesis through oxidative phosphorylation (OXPHOS) [1]. Mitochondria undergo constant morphological changes by the process of continuous cycles of fusion and fission that determines their morphology and most mitochondrial functions [3] Given their central role in cellular homeostasis, mitochondrial dysfunction has been linked to many age-related disorders including mitochondrial diseases, cancers, metabolic diseases and Diseases 2016, 4, 31; doi:10.3390/diseases4040031 www.mdpi.com/journal/diseases. Dysfunctional mitochondria, impaired autophagy and accumulation of cytoplasmic protein aggregates are frequent alterations shared by LSDs and more common neurodegenerative disorders [7,8,9]. Abnormal lysosomal function in LSDs has been associated with alterations in macroautophagy due to impaired autophagosome-lysosome fusion or deficient degradation of autophagy substrates [14]. It is easy to speculate that lysosomal dysfunction such as in LSDs [16] leads to the abnormal accumulation of non-hydrolysed autophagy cargos such as mitochondria and other organelles. LSDs, with particular interest in data derived from various cellular and animal models in Gaucher disease (GD)
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