Potential Treatment of Lysosomal Storage Disease through Modulation of the Mitochondrial—Lysosomal Axis

Abstract

Lysosomal storage disease (LSD) is an inherited metabolic disorder caused by enzyme deficiency in lysosomes. Some treatments for LSD can slow progression, but there are no effective treatments to restore the pathological phenotype to normal levels. Lysosomes and mitochondria interact with each other, and this crosstalk plays a role in the maintenance of cellular homeostasis. Deficiency of lysosome enzymes in LSD impairs the turnover of mitochondrial defects, leading to deterioration of the mitochondrial respiratory chain (MRC). Cells with MRC impairment are associated with reduced lysosomal calcium homeostasis, resulting in impaired autophagic and endolysosomal function. This malicious feedback loop between lysosomes and mitochondria exacerbates LSD. In this review, we assess the interactions between mitochondria and lysosomes and propose the mitochondrial–lysosomal axis as a research target to treat LSD. The importance of the mitochondrial–lysosomal axis has been systematically characterized in several studies, suggesting that proper regulation of this axis represents an important investigative guide for the development of therapeutics for LSD. Therefore, studying the mitochondrial–lysosomal axis will not only add knowledge of the essential physiological processes of LSD, but also provide new strategies for treatment of LSD.

Delivery and assessment of a CRISPR/nCas9-based genome editing system on in vitro models of mucopolysaccharidoses IVA assisted by magnetite-based nanoparticles

“…KS and QS). Nevertheless, this build-up does not fully explain the pathophysiology of the disease, and it has been reported that the abnormal lysosomal function may alter other lysosomal enzymes, such as β-hexosaminidases (Hex) 36 , 37 , as well as lead to an increase in cellular oxidative stress 3 , 4 , 38 . In this sense, we observed a lower total Hex activity in all the untreated MPS IVA fibroblasts (fold change: 0.44–0.84) compared to WT levels (4089 ± 648 U/mg) (Fig.…”

Activation of mitochondrial TRAP1 stimulates mitochondria-lysosome crosstalk and correction of lysosomal dysfunction

“…The ability of the TRAP1 agonists to increase the residual activity of mutant LSD enzymes ( Figure 4 E) suggests that they may be of therapeutic value in diseases in which the protein defect is an ER-targeted protein, such as cystic fibrosis or one of the more than 60 LSDs ( Carlile et al., 2007 ; Gelsthorpe et al., 2008 ). Thus, therapeutics that can target and activate TRAP1 may be of great benefit for many devastating disorders ( Davis et al., 2021 ; Klein and Mazzulli, 2018 ; Kuk et al., 2021 ).…”

Examining the Role of a Functional Deficiency of Iron in Lysosomal Storage Disorders with Translational Relevance to Alzheimer’s Disease

“…There has been a debate as to whether the lysosomal pH is increased or overly acidified in mucolipidosis type IV cells [62][63][64]. An increased lysosomal pH can be present in some other lysosomal storage diseases [65,66], e.g., in skin fibroblasts from patients with mucolipidosis type II [67], which results from a deficiency in N-acetylglucosamine-(GlcNAc) 1-phosphotransferase activity. Alongside potentially favoring iron retention within the lysosome, thereby contributing to a functional iron deficiency, an elevated lysosomal pH can impair the activity of various lysosomal enzymes and possibly perturb calcium homeostasis, e.g., through TRPML1 disruption [66,68].…”