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J. Biol. Chem., Vol. 281, Issue 51, 39041-39050, December 22, 2006

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Mitochondrial Aberrations in Mucolipidosis Type IV^*

John J. Jennings, Jr.¹, Jian-hui Zhu¹, Youssef Rbaibi, Xiang Luo^¶, Charleen T. Chu^||, and Kirill Kiselyov²

From the Departments of Biological Science and Pathology and the ^||Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15260 and the ^¶Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390

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.

Received for publication, August 21, 2006 , and in revised form, October 6, 2006.

^* This work was supported by the Pittsburgh Life Science Greenhouse start-up fund, a Winters Foundation grant, and the University of Pittsburgh Small Grant Development Fund and by a Mucolipidosis IV Foundation grant (to K. K.), National Institutes of Health Grant NS40817, and a pilot grant from the University of Pittsburgh Center for the Environmental Basis of Human Disease (to C. T. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biological Sciences, University of Pittsburgh, 4249 Fifth Ave., Pittsburgh, PA 15260. Tel.: 412-624-4317; E-mail: Kiselyov{at}pitt.edu.

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