Mitochondrial stress response triggered by defects in protein synthesis quality control

  • Life Sci Alliance. 2019 Jan 25;2(1):e201800219. doi: 10.26508/lsa.201800219.
Uwe Richter  1 ,  Kah Ying Ng  1 ,  Fumi Suomi  1 ,  Paula Marttinen  1 ,  Taina Turunen  1 ,  Christopher Jackson  2 ,  Anu Suomalainen  2 ,  Helena Vihinen  1 ,  Eija Jokitalo  1 ,  Tuula A Nyman  3 ,  Marita A Isokallio  4 ,  James B Stewart  4 ,  Cecilia Mancini  5 ,  Alfredo Brusco  5 ,  Sara Seneca  6 ,  Anne Lombès  7 ,  Robert W Taylor  8 ,  Brendan J Battersby  9
Affiliations
  • 1. Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • 2. Research Programs Unit-Molecular Neurology, University of Helsinki, Helsinki, Finland.
  • 3. Department of Immunology, Institute of Clinical Medicine, University of Oslo and Oslo University Hospital, Oslo, Norway.
  • 4. Max Planck Institute for Biology of Ageing, Cologne, Germany.
  • 5. Department of Medical Sciences, University of Torino, Torino, Italy.
  • 6. Center for Medical Genetics/Research Center Reproduction and Genetics, Universitair Ziekenhuis Brussel, Brussels, Belgium.
  • 7. Faculté de médecine Cochin, Institut Cochin Institut national de la santé et de la recherche médicale U1016, Centre national de la recherche scientifique Unités Mixtes de Recherche 8104, Université Paris 5, Paris, France.
  • 8. Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK.
  • 9. Institute of Biotechnology, University of Helsinki, Helsinki, Finland [email protected].
PMID: 30683687 DOI: 10.26508/lsa.201800219
Abstract

Mitochondria have a compartmentalized gene expression system dedicated to the synthesis of membrane proteins essential for Oxidative Phosphorylation. Responsive quality control mechanisms are needed to ensure that aberrant protein synthesis does not disrupt mitochondrial function. Pathogenic mutations that impede the function of the mitochondrial matrix quality control protease complex composed of AFG3L2 and paraplegin cause a multifaceted clinical syndrome. At the cell and molecular level, defects to this quality control complex are defined by impairment to mitochondrial form and function. Here, we establish the etiology of these phenotypes. We show how disruptions to the quality control of mitochondrial protein synthesis trigger a sequential stress response characterized first by OMA1 activation followed by loss of mitochondrial ribosomes and by remodelling of mitochondrial inner membrane ultrastructure. Inhibiting mitochondrial protein synthesis with chloramphenicol completely blocks this stress response. Together, our data establish a mechanism linking major cell biological phenotypes of AFG3L2 pathogenesis and show how modulation of mitochondrial protein synthesis can exert a beneficial effect on organelle homeostasis.