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PMID: 12864925 Published · epublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes.

BMC neuroscience ·Vol. 4 ·2003-07-15 ·Pages 16

Higgins CM, Jung C, Xu Z

Abstract

Amyotrophic lateral sclerosis (ALS) is an age-dependent neurodegenerative disease that causes motor neuron degeneration, paralysis and death. Mutations in Cu, Zn superoxide dismutase (SOD1) are one cause for the familial form of this disease. Transgenic mice expressing mutant SOD1 develop age-dependent motor neuron degeneration, skeletal muscle weakness, paralysis and death similar to humans. The mechanism whereby mutant SOD1 induces motor neuron degeneration is not understood but widespread mitochondrial vacuolation has been observed during early phases of motor neuron degeneration. How this vacuolation develops is not clear, but could involve autophagic vacuolation, mitochondrial permeability transition (MPT) or uncharacterized mechanisms. To determine which of these possibilities are true, we examined the vacuolar patterns in detail in transgenic mice expressing mutant SOD1G93A. Vacuolar patterns revealed by electron microscopy (EM) suggest that vacuoles originate from the expansion of the mitochondrial intermembrane space and extension of the outer mitochondrial membrane. Immunofluorescence microscopy and immuno-gold electron microscopy reveal that vacuoles are bounded by SOD1 and mitochondrial outer membrane markers, but the inner mitochondrial membrane marker is located in focal areas inside the vacuoles. Small vacuoles contain cytochrome c while large vacuoles are porous and lack cytochrome c. Vacuoles lack lysosomal signal but contain abundant peroxisomes and SOD1 aggregates. These findings demonstrate that mutant SOD1, possibly by toxicity associated with its aggregation, causes mitochondrial degeneration by inducing extension and leakage of the outer mitochondrial membrane, and expansion of the intermembrane space. This could release the pro-cell death molecules normally residing in the intermembrane space and initiate motor neuron degeneration. This Mitochondrial Vacuolation by Intermembrane Space Expansion (MVISE) fits neither MPT nor autophagic vacuolation mechanisms, and thus, is a previously uncharacterized mechanism of mitochondrial degeneration in mammalian CNS.

MeSH Terms
Amyotrophic Lateral Sclerosis/enzymology,pathology Animals Disease Models, Animal Humans Intracellular Membranes/enzymology,pathology,ultrastructure Macromolecular Substances Mice Mice, Transgenic Microscopy, Immunoelectron Mitochondria/enzymology,pathology,ultrastructure Peroxisomes/enzymology,pathology Superoxide Dismutase/genetics,metabolism Vacuoles/pathology,ultrastructure
Chemicals
Macromolecular Substances SOD1 G93A protein Superoxide Dismutase
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Higgins Cynthia M J
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, 364 Plantation St, Worcester, MA 01655, USA. cynthia.higgins@umassmed.edu
Jung Cheolwha
Xu Zuoshang
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Article Info
Journal
BMC neuroscience
Abbr.
BMC Neurosci
ISSN
1471-2202
DOI
10.1186/1471-2202-4-16
Email
cynthia.higgins@umassmed.edu
Published
2003-07-15
Epub
2003-00-15
Pages
16
Language
English
Region
England
NLM ID
100966986
PMCID
PMC169170
Subset
IM
Grants
NINDS NIH HHS · 5 T32 NS07366-05 · United States
NINDS NIH HHS · R01 NS41739 · United States
NINDS NIH HHS · R01 NS041739 · United States
NINDS NIH HHS · T32 NS007366 · United States
NINDS NIH HHS · NS35750 · United States
External Links
PubMed source DOI: 10.1186/1471-2202-4-16 PMC Full Text View journal details
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