EXD2 governs germ stem cell homeostasis and lifespan by promoting mitoribosome integrity and translation

Nat Cell Biol. 2018 Feb;20(2):162-174. doi: 10.1038/s41556-017-0016-9.

Joana Silva ¹, Suvi Aivio ¹ ², Philip A Knobel ¹ ³, Laura J Bailey ⁴, Andreu Casali ¹, Maria Vinaixa ⁵ ⁶, Isabel Garcia-Cao ¹, Étienne Coyaud ⁷ ⁸, Alexis A Jourdain ⁹ ¹⁰ ¹¹, Pablo Pérez-Ferreros ¹ ¹², Ana M Rojas ¹³, Albert Antolin-Fontes ¹, Sara Samino-Gené ⁵ ⁶, Brian Raught ⁷ ⁸, Acaimo González-Reyes ¹⁴, Lluís Ribas de Pouplana ¹ ¹⁵, Aidan J Doherty ⁴, Oscar Yanes ⁵ ⁶, Travis H Stracker ¹⁶

Affiliations

1 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain.
2 Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
3 Department for Radiation Oncology, University Hospital Zurich, Zurich, Switzerland.
4 Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Brighton, UK.
5 Metabolomics Platform, Department of Electronic Engineering (DEEEA), Universitat Rovira i Virgili, Tarragona, Spain.
6 Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Madrid, Spain.
7 Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
8 Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
9 Department of Molecular Biology, Howard Hughes Medical Institute, Massachusetts General Hospital, Boston, MA, USA.
10 Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
11 Broad Institute of MIT and Harvard, Cambridge, MA, USA.
12 EMBL Australia, University of New South Wales, Lowy Cancer Research Center, Single Molecule Science Node, Sydney and Arc Center of Excellence in Advance Molecular Imaging, Sydney, New South Wales, Australia.
13 Computational Biology and Bioinformatics Group, Institute of Biomedicine of Seville (IBIS/CSIC/US/JA), Campus Hospital Universitario Virgen del Rocio, Seville, Spain.
14 Centro Andaluz de Biología del Desarrollo, Universidad Pablo de Olavide/CSIC/JA, Seville, Spain.
15 Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain.
16 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain. [email protected].

PMID: 29335528 DOI: 10.1038/s41556-017-0016-9

Abstract

Mitochondria are subcellular organelles that are critical for meeting the bioenergetic and biosynthetic needs of the cell. Mitochondrial function relies on genes and RNA species encoded both in the nucleus and mitochondria, and on their coordinated translation, import and respiratory complex assembly. Here, we characterize EXD2 (exonuclease 3'-5' domain-containing 2), a nuclear-encoded gene, and show that it is targeted to the mitochondria and prevents the aberrant association of messenger RNAs with the mitochondrial ribosome. Loss of EXD2 results in defective mitochondrial translation, impaired respiration, reduced ATP production, increased Reactive Oxygen Species and widespread metabolic abnormalities. Depletion of the Drosophila melanogaster EXD2 orthologue (CG6744) causes developmental delays and premature female germline stem cell attrition, reduced fecundity and a dramatic extension of lifespan that is reversed with an antioxidant diet. Our results define a conserved role for EXD2 in mitochondrial translation that influences development and ageing.

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