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 Uwe Richter
A1 Kah Ying Ng
A1 Fumi Suomi
A1 Paula Marttinen
A1 Taina Turunen
A1 Christopher Jackson
A1 Anu Suomalainen
A1 Helena Vihinen
A1 Eija Jokitalo
A1 Tuula A Nyman
A1 Marita A Isokallio
A1 James B Stewart
A1 Cecilia Mancini
A1 Alfredo Brusco
A1 Sara Seneca
A1 Anne Lombès
A1 Robert W Taylor
A1 Brendan J Battersby
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.