Ribosome Profiling Reveals a Dichotomy Between Ribosome Occupancy of Nuclear-Encoded and Mitochondrial-Encoded OXPHOS mRNA Transcripts in a Striatal Cell Model of Huntington Disease

Abstract

Huntington disease (HD) is caused by an expanded polyglutamine mutation in huntingtin (mHTT), which promotes a 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, present knowledge about whether (or how) mitochondrial mRNA translation is differentially regulated in HD remains unclear. We have recently applied ribosome profiling (Ribo-Seq), a technique based on the high-throughput sequencing of ribosome-protected mRNA fragments, to analyze detailed snapshots of ribosome occupancy of the mitochondrial mRNA transcripts in control and HD striatal cells. Ribo-seq data revealed almost unaltered ribosome occupancy on the nuclear-encoded mitochondrial transcripts involved in oxidative phosphorylation (OXPHOS) and only a mild reduction in ribosome occupancy on a few selected transcripts (SHDA, Ndufv1, Timm23, Tomm5, and Mrps22) in HD cells. By contrast, ribosome occupancy of mitochondrially encoded OXPHOS mRNAs (mtNd-1, mtNd-2, mtNd-4, mtNd-4l, mtNd-5, mtNd-6, mt-Co1, mtCyt b, and mt-ATP8) was dramatically increased, implying widespread dichotomous effects on ribosome occupancy and OXPHOS mRNA translation in HD. Thus, mHTT may command signals that specifically regulate translation of the mitochondrial OXPHOS transcripts and influence HD pathogenesis.