TY - JOUR T1 - Mitochondrial stress response triggered by defects in protein synthesis quality control JF - Life Science Alliance JO - Life Sci. Alliance DO - 10.26508/lsa.201800219 VL - 2 IS - 1 SP - e201800219 AU - Uwe Richter AU - Kah Ying Ng AU - Fumi Suomi AU - Paula Marttinen AU - Taina Turunen AU - Christopher Jackson AU - Anu Suomalainen AU - Helena Vihinen AU - Eija Jokitalo AU - Tuula A Nyman AU - Marita A Isokallio AU - James B Stewart AU - Cecilia Mancini AU - Alfredo Brusco AU - Sara Seneca AU - Anne Lombès AU - Robert W Taylor AU - Brendan J Battersby Y1 - 2019/02/01 UR - https://www.life-science-alliance.org/content/2/1/e201800219.abstract N2 - 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. ER -