Mitochondrial Aberrations in Mucolipidosis Type IV

John J Jennings,Jian-Hui Zhu,Youssef Rbaibi,Xiang Luo,Charleen T Chu,Kirill Kiselyov

doi:10.1074/jbc.m607982200

Abstract

Mucolipidosis type IV is a genetic lysosomal storage disease associated with degenerative processes in the brain, eye, and other tissues. Mucolipidosis type IV results from mutations in the gene MCOLN1, which codes for the TRP family ion channel, mucolipin 1. The connection between lysosomal dysfunction and degenerative processes in mucolipidosis type IV is unclear. Here we report that mucolipidosis type IV and several unrelated lysosomal storage diseases are associated with significant mitochondrial fragmentation and decreased mitochondrial Ca2+ buffering efficiency. The mitochondrial alterations observed in these lysosomal storage diseases are reproduced in control cells by treatment with lysosomal inhibitors and with the autophagy inhibitor 3-methyladenine. This suggests that inefficient autophagolysosomal recycling of mitochondria generates fragmented, effete mitochondria in mucolipidosis. Mitochondria accumulate that cannot properly buffer calcium fluxes in the cell. A decrease in mitochondrial Ca2+ buffering capacity in cells affected by these lysosomal storage diseases is associated with increased sensitivity to apoptosis induced by Ca2+-mobilizing agonists and executed via a caspase-8-dependent pathway. Deficient Ca2+ homeostasis may represent a common mechanism of degenerative cell death in several lysosomal storage diseases.

Highlights

Mucolipidosis (ML)3 is the collective name for a group of autosomal recessive diseases characterized by accumulation of membranous lipid inclusions in patients’ cells [1, 2]
We believe that our results provide a mechanistic explanation that links suppression of lysosomal function in MLIV, and perhaps other lysosomal storage diseases (LSDs), with cell death
In MLIV-control fibroblasts, mitochondria are organized as extended threads with average lengths of 73.8 Ϯ 4.5 ␮m (n ϭ 25 cells and all results are the means Ϯ S.E.) (Fig. 1, A and B)

Summary

Introduction

Mucolipidosis (ML)3 is the collective name for a group of autosomal recessive diseases characterized by accumulation of membranous lipid inclusions in patients’ cells [1, 2]. A decrease in mitochondrial Ca2؉ buffering capacity in cells affected by these lysosomal storage diseases is associated with increased sensitivity to apoptosis induced by Ca2؉-mobilizing agonists and executed via a caspase-8-dependent pathway.

Results

Conclusion