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FMRpolyG alters mitochondrial transcripts level and respiratory chain complex assembly in Fragile X associated tremor/ataxia syndrome [FXTAS]
- Source :
- Biochimica et Biophysica Acta-Molecular Basis of Disease, Biochimica et Biophysica Acta-Molecular Basis of Disease, Elsevier, 2019, 1865 (6), pp.1379-1388. ⟨10.1016/j.bbadis.2019.02.010⟩
- Publication Year :
- 2019
- Publisher :
- Elsevier BV, 2019.
-
Abstract
- Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inherited neurodegenerative disorder caused by an expansion of 55 to 200 CGG repeats (premutation) in FMR1. These CGG repeats are Repeat Associated non-ATG (RAN) translated into a small and pathogenic protein, FMRpolyG. The cellular and molecular mechanisms of FMRpolyG toxicity are unclear. Various mitochondrial dysfunctions have been observed in FXTAS patients and animal models. However, the causes of these mitochondrial alterations are not well understood. In the current study, we investigated interaction of FMRpolyG with mitochondria and its role in modulating mitochondrial functions. Beside nuclear inclusions, FMRpolyG also formed small cytosolic aggregates that interact with mitochondria both in cell and mouse model of FXTAS. Importantly, expression of FMRpolyG reduces ATP levels, mitochondrial transmembrane potential, mitochondrial supercomplexes assemblies and activities and expression of mitochondrial DNA encoded transcripts in cell and animal model of FXTAS, as well as in FXTAS patient brain tissues. Overall, these results suggest that FMRpolyG alters mitochondrial functions, bioenergetics and initiates cell death. The further study in this direction will help to establish the role of mitochondria in FXTAS conditions.
- Subjects :
- 0301 basic medicine
Mitochondrial DNA
Programmed cell death
Ataxia
[SDV]Life Sciences [q-bio]
Gene Expression
Mice, Transgenic
Mitochondrion
Biology
DNA, Mitochondrial
Fragile X Mental Retardation Protein
Mice
Protein Aggregates
03 medical and health sciences
Adenosine Triphosphate
0302 clinical medicine
Cell Line, Tumor
Cerebellum
Tremor
medicine
Animals
Humans
RNA, Messenger
Molecular Biology
ComputingMilieux_MISCELLANEOUS
Aged
Aged, 80 and over
Membrane Potential, Mitochondrial
Neurons
Respiratory chain complex
medicine.disease
FMR1
Mitochondria
3. Good health
Cell biology
Disease Models, Animal
Cytosol
HEK293 Cells
030104 developmental biology
Electron Transport Chain Complex Proteins
Fragile X Syndrome
Molecular Medicine
medicine.symptom
Energy Metabolism
Trinucleotide Repeat Expansion
030217 neurology & neurosurgery
Fragile X-associated tremor/ataxia syndrome
Subjects
Details
- ISSN :
- 09254439
- Volume :
- 1865
- Database :
- OpenAIRE
- Journal :
- Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
- Accession number :
- edsair.doi.dedup.....27b8384c654cb58b4da5af3b51fec5c7