A mitochondria-specific isoform of FASTK is present in mitochondrial RNA granules and regulates gene expression and function

Alexis A Jourdain; Mirko Koppen; Christopher D Rodley; Kinsey Maundrell; Naïg Gueguen; Pascal Reynier; Adela M Guaras; José A Enriquez; Paul Anderson; Maria Simarro; Jean-Claude Martinou

doi:10.1016/j.celrep.2015.01.063

A mitochondria-specific isoform of FASTK is present in mitochondrial RNA granules and regulates gene expression and function

Cell Rep. 2015 Feb 24;10(7):1110-21. doi: 10.1016/j.celrep.2015.01.063. Epub 2015 Feb 19.

Affiliations

¹ Department of Cell Biology, University of Geneva, 30 quai Ernest-Ansermet, 1211 Genève 4, Switzerland.
² UMR CNRS 6214 - INSERM 1083, Département de Biochimie et Génétique, CHU d'Angers, 4 rue Larrey, 49933 Angers Cedex, France.
³ Centro Nacional de Investigaciones Cardiovasculares Carlos III, Melchor Fernández Almagro 3, 28029 Madrid, Spain.
⁴ Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, One Jimmy Fund Way, Smith 652, Boston, MA 02115, USA.
⁵ Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, One Jimmy Fund Way, Smith 652, Boston, MA 02115, USA; Departamento de Microbiologia, Facultad de Medicina, Edificio de Ciencias de la Salud, Avda ramon y Cajal 7, Valladolid 47005, Spain.
⁶ Department of Cell Biology, University of Geneva, 30 quai Ernest-Ansermet, 1211 Genève 4, Switzerland. Electronic address: jean-claude.martinou@unige.ch.

PMID: 25704814
DOI: 10.1016/j.celrep.2015.01.063

Abstract

The mitochondrial genome relies heavily on post-transcriptional events for its proper expression, and misregulation of this process can cause mitochondrial genetic diseases in humans. Here, we report that a novel translational variant of Fas-activated serine/threonine kinase (FASTK) co-localizes with mitochondrial RNA granules and is required for the biogenesis of ND6 mRNA, a mitochondrial-encoded subunit of the NADH dehydrogenase complex (complex I). We show that ablating FASTK expression in cultured cells and mice results specifically in loss of ND6 mRNA and reduced complex I activity in vivo. FASTK binds at multiple sites along the ND6 mRNA and its precursors and cooperates with the mitochondrial degradosome to ensure regulated ND6 mRNA biogenesis. These data provide insights into the mechanism and control of mitochondrial RNA processing within mitochondrial RNA granules.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
Animals
Cell Line
Electron Transport Complex I / metabolism
Endoribonucleases / metabolism
Gene Expression Regulation
Humans
Mice
Microscopy, Confocal
Mitochondria / metabolism*
Multienzyme Complexes / metabolism
Myocardium / metabolism
NADH Dehydrogenase / genetics
NADH Dehydrogenase / metabolism
Polyribonucleotide Nucleotidyltransferase / metabolism
Protein Serine-Threonine Kinases / antagonists & inhibitors
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Protein Structure, Tertiary
RNA / metabolism*
RNA Helicases / metabolism
RNA Interference
RNA, Messenger / metabolism
RNA, Mitochondrial
RNA, Small Interfering / metabolism
Signal Transduction

Substances

3' Untranslated Regions
Multienzyme Complexes
RNA, Messenger
RNA, Mitochondrial
RNA, Small Interfering
degradosome
RNA
MT-ND6 protein, human
NADH Dehydrogenase
FASTK protein, human
Protein Serine-Threonine Kinases
Polyribonucleotide Nucleotidyltransferase
Endoribonucleases
RNA Helicases
Electron Transport Complex I