Supernumerary proteins of the human mitochondrial ribosomal small subunit are integral for assembly and translation
Taru Hilander,
Ryan Awadhpersad,
Geoffray Monteuuis,
Krystyna L. Broda,
Max Pohjanpelto,
Elizabeth Pyman,
Sachin Kumar Singh,
Tuula A. Nyman,
Isabelle Crevel,
Robert W. Taylor,
Ann Saada,
Diego Balboa,
Brendan J. Battersby,
Christopher B. Jackson,
Christopher J. Carroll
Affiliations
Taru Hilander
Genetics Section, Cardiovascular and Genomics Research Institute, St George’s, University of London, London, UK
Ryan Awadhpersad
Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Geoffray Monteuuis
Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Krystyna L. Broda
Genetics Section, Cardiovascular and Genomics Research Institute, St George’s, University of London, London, UK
Max Pohjanpelto
Genetics Section, Cardiovascular and Genomics Research Institute, St George’s, University of London, London, UK; Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
Elizabeth Pyman
Genetics Section, Cardiovascular and Genomics Research Institute, St George’s, University of London, London, UK
Sachin Kumar Singh
Department of Immunology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
Tuula A. Nyman
Department of Immunology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway
Isabelle Crevel
Core Facilities, St George’s, University of London, London, UK
Robert W. Taylor
Mitochondrial Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne NE1 4LP, UK
Ann Saada
Department of Genetics, Hadassah Medical Center & Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001 Israel
Diego Balboa
Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, 00290 Helsinki, Finland
Brendan J. Battersby
Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
Christopher B. Jackson
Department of Biochemistry and Developmental Biology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Corresponding author
Christopher J. Carroll
Genetics Section, Cardiovascular and Genomics Research Institute, St George’s, University of London, London, UK; Corresponding author
Summary: Mitochondrial ribosomes (mitoribosomes) have undergone substantial evolutionary structural remodeling accompanied by loss of ribosomal RNA, while acquiring unique protein subunits located on the periphery. We generated CRISPR-mediated knockouts of all 14 unique (mitochondria-specific/supernumerary) human mitoribosomal proteins (snMRPs) in the small subunit to study the effect on mitoribosome assembly and protein synthesis, each leading to a unique mitoribosome assembly defect with variable impact on mitochondrial protein synthesis. Surprisingly, the stability of mS37 was reduced in all our snMRP knockouts of the small and large ribosomal subunits and patient-derived lines with mitoribosome assembly defects. A redox-regulated CX9C motif in mS37 was essential for protein stability, suggesting a potential mechanism to regulate mitochondrial protein synthesis. Together, our findings support a modular assembly of the human mitochondrial small ribosomal subunit mediated by essential supernumerary subunits and identify a redox regulatory role involving mS37 in mitochondrial protein synthesis in health and disease.
