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

Myeong Uk Kuk,Su Young Hwang,Yun Haeng Lee,Sang Chul Park,Joon Tae Park,Jae Won Kim

doi:10.3390/cells10020420

Myeong Uk Kuk, Su Young Hwang + Show 4 more

Open Access

https://doi.org/10.3390/cells10020420

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Journal: Cells	Publication Date: Feb 17, 2021
Citations: 8	License type: CC BY 4.0

Affiliation: Incheon National University, Chonnam National University

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.

Highlights

Ment for lysosomal enzymes, benefits in situations of lysosomal treatment enhances activity,providing reducingtherapeutic substrate accumulation in lysosomes. These findings suggest that a strategy to activate the mitochondrial–lysosomal axis through restoration of mitochondrial function might be effective in treating Lysosomal storage disease (LSD)
The importance of reciprocal crosstalk was discussed but was limited to its role in neurodegeneration [53]. This limitation of relevance was improved by another review addressing the potential role of mitochondrial dysfunction in the pathophysiology of LSD [42]
A review paper has been published focusing on mitochondrial dysfunction as an important contributing factor in the pathophysiology of LSD [78]

Summary

Introduction

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Enzyme replacement therapy has been suggested as a treatment for LSD as it can alleviate symptoms [11,12,13]. This treatment has not been effective in restoring pathologic phenotypes to normal levels [11,12,13]. A functional role of the mitochondrial–lysosomal axis in senescence alleviation has been proposed [14,17]. Based on the previous and recent findings that have been processed and analyzed (Supplementary Figure S1), we will highlight the role of the mitochondrial–lysosomal axis in LSD and propose a crucial role for this axis as a regulator of LSD treatment

Lysosomal Dysfunction in LSD

Mitochondrial Dysfunction in LSD

Importance of the Mitochondrial–Lysosomal Axis in LSD

Strategies to Activate the Mitochondrial–Lysosomal Axis in LSD

Conclusions and Perspectives