RT Journal Article SR Electronic T1 Mitochondrial stress response triggered by defects in protein synthesis quality control JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e201800219 DO 10.26508/lsa.201800219 VO 2 IS 1 A1 Richter, Uwe A1 Ng, Kah Ying A1 Suomi, Fumi A1 Marttinen, Paula A1 Turunen, Taina A1 Jackson, Christopher A1 Suomalainen, Anu A1 Vihinen, Helena A1 Jokitalo, Eija A1 Nyman, Tuula A A1 Isokallio, Marita A A1 Stewart, James B A1 Mancini, Cecilia A1 Brusco, Alfredo A1 Seneca, Sara A1 Lombès, Anne A1 Taylor, Robert W A1 Battersby, Brendan J YR 2019 UL https://www.life-science-alliance.org/content/2/1/e201800219.abstract AB 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.