Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1865, Issue 6, Pages 1379-1388Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2019.02.010
Keywords
FXTAS; RAN translation; FMRpoIyG; Mitochondria; Mitochondrial supercomplexes (mSCs)
Funding
- Department of Science and Technology, Government of India, Indo-French grant [DST/ANR2014/Neuro-1/FXTAS]
- University Grant Commission (UGC), Government of India
- DBT Govt. of India
- DST, Govt of India
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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, FMRpoIyG. The cellular and molecular mechanisms of FMRpoIyG 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 FMRpoIyG with mitochondria and its role in modulating mitochondrial functions. Beside nuclear inclusions, FMRpoIyG also formed small cytosolic aggregates that interact with mitochondria both in cell and mouse model of FXTAS. Importantly, expression of FMRpoIyG 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.
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