Mitochondrial Ca2+ homeostasis in lysosomal storage diseases

Abstract

Lysosomal storage diseases (LSDs) are a class of genetic disorders in which proteins responsible for digestion or absorption of endocytosed material do not function or do not localize properly. The resulting cellular "indigestion" causes buildup of intracellular storage inclusions that contain unprocessed lipids and proteins that form macromolecular complexes. The buildup of storage material is associated with degenerative processes that are observed in all LSDs, albeit the correlation between the amount of storage inclusions and the severity of the degenerative processes is not always evident. The latter suggests that a specific mechanism set in motion by aberrant lysosomal function drives the degenerative processes in LSDs. It is becoming increasingly clear that in addition to their function in degrading endocytosed material, lysosomes are essential housekeeping organelles responsible for maintaining healthy population of intracellular organelles, in particular mitochondria. The present review surveys the current knowledge on the lysosomal-mitochondrial axis and its possible role as a contributing factor to mitochondrial Ca(2+) homeostasis and to cell death in LSDs.

Fig 1. The endocytic pathway, lysosomes and autophagy

Endocytosed material first enters endocytic vesicles, which then consolidate into early endosomes. After sorting, the material destined to be degraded is delivered to late endosomes, with which lysosomes fuse in a transient manner to pick up the material for final digestion and absorption. Lysosomes also drive autophagy and eventually fuse with the autophagic vacuole.

Fig 2. Common dysfunctions that lead to lysosomal storage diseases

1: miss-sorting of enzymes may lead to their secretion instead of targeting to lysosomes (e.g. mucolipidosis II). 2: Non-functional enzymes or supporting proteins do not break down the endocytosed material (e.g. galactosialidosis, Batten (?), Niemann-Pick (?); question marks indicate that the exact mechanism of lysosomal dysfunctions in these disease has not been completely settled). 3: Defective excretion of hydrolyzed products out of the lysosomes (e.g. sialidosis). 4: Defective regulation of lysosomal pH (Mucolipidosis IV, mutations in ClC and CLN3 (?)).

Fig 3. The lysosome-mitochondria axis

In normal cells, the fragmented aged or damaged mitochondria are delivered by autophagy to the lysosomes for degradation. Aberrant autophagy in LSDs compromise degradation of effete mitochondria.

Fig 4. Possible consequences of the loss of Ca²⁺ buffering in lysosomal storage diseases

Red arrows represent Ca²⁺ influx, red “blasts” show the “hotspots” of abnormal Ca²⁺ regulation in cells with affected mitochondrial function. 1, 2: Inefficient Ca²⁺ buffering underneath the plasma membrane or in proximity of the mitochondria at the endoplasmic reticulum/mitochondria boundaries. 3: Inhibition of Ca²⁺ dependent processes in the mitochondria with ensuing lack of ATP production. 4: Activation of perimitochondrial Ca²⁺ dependent proteases.