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M607982200v1
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Papers In Press, published online ahead of print October 20, 2006
J. Biol. Chem, 10.1074/jbc.M607982200
Submitted on August 21, 2006
Revised on October 6, 2006
Accepted on October 20, 2006

Mitochondrial aberrations in mucolipidosis type IV

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

Dept Biological Sciences, University of Pittsburgh, Pittsburgh, PA 15260

Corresponding Author: kiselyov{at}pitt.edu

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 mucolpidoses. Mitochondria accumulate that can not 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.


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