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

Dagar, Sunayana; Sharma, Manish; Tsaprailis, George; Tapia, Catherina Scharager; Crynen, Gogce; Joshi, Preksha Sandipkumar; Shahani, Neelam; Subramaniam, Srinivasa

Dagar, Sunayana; Sharma, Manish; Tsaprailis, George; Tapia, Catherina Scharager; Crynen, Gogce; Joshi, Preksha Sandipkumar; Shahani, Neelam; Subramaniam, Srinivasa.

Afiliación

Dagar S; Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida, USA.
Sharma M; Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida, USA.
Tsaprailis G; Proteomics Core, The Wertheim UF Scripps Institute, Jupiter, Florida, USA.
Tapia CS; Proteomics Core, The Wertheim UF Scripps Institute, Jupiter, Florida, USA.
Crynen G; Bioinformatics and Statistics Core, The Wertheim UF Scripps Institute, Jupiter, Florida, USA.
Joshi PS; Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida, USA.
Shahani N; Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida, USA.
Subramaniam S; Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida, USA; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, La Jolla, California, USA; Norman Fixel Institute for Neurological

Mol Cell Proteomics ; 23(4): 100746, 2024 Apr.

Article en En | MEDLINE | ID: mdl-38447791

ABSTRACT

ABSTRACT

Huntington disease (HD) is caused by an expanded polyglutamine mutation in huntingtin (mHTT) that promotes prominent atrophy in the striatum and subsequent psychiatric, cognitive deficits, 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 (SDHA, Ndufv1, Timm23, Tomm5, Mrps22) in HD cells. By contrast, ribosome occupancy was dramatically increased for mitochondrially encoded oxidative phosphorylation mRNAs (mt-Nd1, mt-Nd2, mt-Nd4, mt-Nd4l, mt-Nd5, mt-Nd6, mt-Co1, mt-Cytb, 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 abundance of mitochondria-related genes in HD.

Asunto(s)

Enfermedad de Huntington; Mitocondrias; Biosíntesis de Proteínas; Perfilado de Ribosomas; Humanos; Línea Celular; Cuerpo Estriado/metabolismo; Cuerpo Estriado/patología; Enfermedad de Huntington/metabolismo; Enfermedad de Huntington/genética; Enfermedad de Huntington/patología; Espectrometría de Masas; Mitocondrias/metabolismo; Proteínas Mitocondriales/metabolismo; Proteínas Mitocondriales/genética; Fosforilación Oxidativa; ARN Mensajero/metabolismo; ARN Mensajero/genética; ARN Mitocondrial/metabolismo; ARN Mitocondrial/genética

Palabras clave

abnormality; brain disease; cytoribosome; dichotomy; energy metabolism; mRNA translation; mitoribosome; oxidative stress; vulnerability

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Biosíntesis de Proteínas / Enfermedad de Huntington / Perfilado de Ribosomas / Mitocondrias Límite: Humans Idioma: En Revista: Mol Cell Proteomics Asunto de la revista: BIOLOGIA MOLECULAR / BIOQUIMICA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos

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