MassIVE MSV000092843

Complete Public PXD045329

Ribosome Profiling and Mass Spectrometry Reveal Widespread Mitochondrial Translation Defects in a Striatal Cell Model of Huntington Disease

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Description

Huntington disease (HD) is caused by an expanded polyglutamine mutation in huntingtin (mHTT) that promotes prominent atrophy in the striatum and subsequent psychiatric, cognitive, and choreiform movements. Multiple lines of evidence point to an association between HD and aberrant striatal mitochondrial functions; however, the present knowledge about whether (or how) mitochondrial mRNA translation is differentially regulated in HD remains unclear. We found that protein synthesis is diminished in HD mitochondria compared to healthy control striatal cell models. We utilized ribosome profiling (Ribo Seq) to analyze detailed snapshots of ribosome occupancy of the mitochondrial mRNA transcripts in control and HD striatal cell models. The Ribo-Seq data revealed almost unaltered ribosome occupancy on the nuclear encoded mitochondrial transcripts involved in oxidative phosphorylation (OXPHOS) (SDHA, Ndufv1, Timm23, Tomm5, Mrps22) in HD cells. By contrast, ribosome occupancy was dramatically increased for mitochondrially encoded OXPHOS mRNAs (mtNd-1, mtNd-2, mtNd-4, mtNd-4l, mtNd-5, mtNd-6, mt-Co1, mtCyt b, and mt-ATP8). We also applied tandem mass tag based mass spectrometry identification of mitochondrial proteins to derive correlations between ribosome occupancy and actual mature mitochondrial protein products. We found many mitochondrial transcripts with comparable or higher ribosome occupancy, but diminished mitochondrial protein products, in HD. Thus, our study provides the first evidence of a widespread dichotomous effect on ribosome occupancy and protein turnover of mitochondria related genes in HD. [doi:10.25345/C5J09WF5W] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Dichotomy ; energy metabolism ; TMT ; brain disease ; vulnerability ; oxidative stress ; mitoribosome ; cytoribosome ; mRNA translation

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Principal Investigators:
(in alphabetical order) 		Srinivasa Subramaniam, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, USA
Submitting User: gcrynen
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