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.

Keywords: lysosomal storage disease; lysosome; mitochondria; mitochondrial–lysosomal axis.

Figure 1

Schematic representation of the lysosome and autophagy pathway in normal cells (A) and lysosomal storage disease (LSD) cells (B). (A) Lysosomes fuse with autophagosomes to form autolysosomes. Lysosomes also fuse with endosomes to form highly dynamic membrane structures called endolysosomes. Functional lysosomes require an acidic environment in the lysosomal lumen (pH 4.5 to 5.0) maintained by the V-ATPase proton pump and an adequate level of calcium ions maintained by the TRPML1 transporter. TRPML1: mammalian mucolipin TRP channel subfamily, V-ATPase: a vacuolar ATPase. (B) LSD is a metabolic disorder caused by mutations in genes that encode lysosomal enzymes, consequently leading to accumulation of various substrates. Lysosomes loaded with undigested substances lead to defective lysosomal fusion with autophagosomes or endosomes. Furthermore, lysosomes of LSD exhibit alterations in lysosomal pH and lysosomal Ca²⁺ homeostasis.

Figure 2

Schematic representation of the basic mechanisms of mitochondrial homeostasis in normal cells (A) and LSD-related mitochondrial dysfunction in LSD cells (B). (A) Cytoplasmic Ca²⁺ modulates GTPase activity, which regulates the balance of mitochondrial fusion/fission events. ER: endoplasmic reticulum. (B) Dysregulation of lysosomal Ca²⁺ homeostasis in LSD interferes with the balance of mitochondrial fission and fusion cycles. Lysosomal deficiency deteriorates Ca²⁺ buffering.

Figure 3

Importance of the mitochondrial–lysosomal axis in LSD. (A) Schematic representation of the basic mechanisms describing the effect of lysosomal function on mitochondria, in a contact-independent or dependent manner. MCU: mitochondrial calcium uniporter. (B) Schematic representation of the underlying mechanisms explaining the deletion effect of the mitochondrial transcription factor Tfam on lysosomal function. Tfam: mitochondrial transcription factor A. (C) Schematic representation of the underlying mechanisms explaining the effect of low ATP production due to mitochondrial dysfunction on lysosomal acidification.

Figure 4

Strategies to activate the mitochondrial–lysosomal axis in LSD. (A) The strategy of activating the mitochondrial–lysosomal axis through coenzyme Q10 (CoQ) supplementation improves mitochondrial function to restore lysosome function. Green and pink CoQ indicate low and high CoQ content, respectively. ROS: reactive oxygen species. (B) The strategy of activating the mitochondrial–lysosomal axis through autophagy activation with trehalose improves pathological symptoms associated with LSD. (C) The strategy of activating the mitochondrial–lysosomal axis through lysosomal re-acidification restores the activity of lysosomal enzymes and increases autophagic flux with restoration of mitochondrial function.

Figure 5

Synoptic representation of the mitochondrial–lysosomal axis contributing to the control of LSD. The activation of the mitochondrial–lysosomal axis through mitochondrial functional recovery or lysosomal functional recovery represents a promising and potent strategy to treat LSD.