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Respiratory chain enzyme deficiency induces mitochondrial location of actin-binding gelsolin to modulate the oligomerization of VDAC complexes and cell survival
- Source :
- Repositorio Institucional de la Consejería de Sanidad de la Comunidad de Madrid, Consejería de Sanidad de la Comunidad de Madrid
- Publication Year :
- 2017
- Publisher :
- Oxford University Press (OUP), 2017.
-
Abstract
- Despite considerable knowledge on the genetic basis of mitochondrial disorders, their pathophysiological consequences remain poorly understood. We previously used two-dimensional difference gel electrophoresis analyses to define a protein profile characteristic for respiratory chain complex III-deficiency that included a significant overexpression of cytosolic gelsolin (GSN), a cytoskeletal protein that regulates the severing and capping of the actin filaments. Biochemical and immunofluorescence assays confirmed a specific increase of GSN levels in the mitochondria from patients' fibroblasts and from transmitochondrial cybrids with complex III assembly defects. A similar effect was obtained in control cells upon treatment with antimycin A in a dose-dependent manner, showing that the enzymatic inhibition of complex III is sufficient to promote the mitochondrial localization of GSN. Mitochondrial subfractionation showed the localization of GSN to the mitochondrial outer membrane, where it interacts with the voltage-dependent anion channel protein 1 (VDAC1). In control cells, VDAC1 was present in five stable oligomeric complexes, which showed increased levels and a modified distribution pattern in the complex III-deficient cybrids. Downregulation of GSN expression induced cell death in both cell types, in parallel with the specific accumulation of VDAC1 dimers and the release of mitochondrial cytochrome c into the cytosol, indicating a role for GSN in the oligomerization of VDAC complexes and in the prevention of apoptosis. Our results demonstrate that respiratory chain complex III dysfunction induces the physiological upregulation and mitochondrial location of GSN, probably to promote cell survival responses through the modulation of the oligomeric state of the VDAC complexes.
- Subjects :
- 0301 basic medicine
Mitochondrial Diseases
Voltage-dependent anion channel
Cell Survival
Mitochondrial disease
Respiratory chain
Antimycin A
Apoptosis
Mitochondrion
Electron Transport
Two-Dimensional Difference Gel Electrophoresis
03 medical and health sciences
0302 clinical medicine
Cell Line, Tumor
Genetics
medicine
Humans
Molecular Biology
Gelsolin
Genetics (clinical)
biology
Voltage-Dependent Anion Channel 1
Respiratory chain complex
Cytochromes c
Articles
General Medicine
Fibroblasts
medicine.disease
Actins
Mitochondria
Cell biology
Actin Cytoskeleton
030104 developmental biology
Biochemistry
Coenzyme Q – cytochrome c reductase
Mitochondrial Membranes
biology.protein
VDAC1
030217 neurology & neurosurgery
HeLa Cells
Subjects
Details
- ISSN :
- 14602083 and 09646906
- Volume :
- 26
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....c56c362bdd93ebc932fab0cdbed1bd99