title: A mitochondrial ribosomal and RNA decay pathway blocks cell proliferation.
abstract: Proliferating cells require coordinated gene expression between the nucleus and mitochondria in order to divide, ensuring sufficient organelle number in daughter cells [1]. However, the machinery and mechanisms whereby proliferating cells monitor mitochondria and coordinate organelle biosynthesis remain poorly understood. Antibiotics inhibiting mitochondrial translation have emerged as therapeutics for human cancers because they block cell proliferation [2, 3]. These proliferative defects were attributable to modest decreases in mitochondrial respiration [3, 4], even though tumors are mainly glycolytic [5] and mitochondrial respiratory chain function appears to play a minor role in cell proliferation in vivo [6]. Here we challenge this interpretation by demonstrating that one class of antiproliferative antibiotic induces stalled mitochondrial ribosomes, which triggers a mitochondrial ribosome and RNA decay pathway. Rescue of the stalled mitochondrial ribosomes initiates a retrograde signaling response to block cell proliferation and occurs prior to any loss of mitochondrial respiration. The loss of respiratory chain function is simply a downstream effect of impaired mitochondrial translation and not the antiproliferative signal. This mitochondrial ribosome quality-control pathway is actively monitored in cells and constitutes an important organelle checkpoint for cell division.
authors: Research Programs Unit - Molecular Neurology and Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.
authors: Uwe
authors: U
authors: Richter
authors: Taina
authors: T
authors: Lahtinen
authors: Paula
authors: P
authors: Marttinen
authors: Maarit
authors: M
authors: Myöhänen
authors: Dario
authors: D
authors: Greco
authors: Giuseppe
authors: G
authors: Cannino
authors: Howard T
authors: HT
authors: Jacobs
authors: Niina
authors: N
authors: Lietzén
authors: Tuula A
authors: TA
authors: Nyman
authors: Brendan J
authors: BJ
authors: Battersby
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D049109:Cell Proliferation; D019069:Cell Respiration; D002701:Chloramphenicol / Q000494:pharmacology; D004579:Electron Transport; D004926:Escherichia coli / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D024101:Mitochondrial Proteins / Q000378:metabolism*; D020871:RNA Stability; D012269:Ribosomal Proteins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D000900:Anti-Bacterial Agents; D006877:Hydroxamic Acids; D024101:Mitochondrial Proteins; D012269:Ribosomal Proteins; D002701:Chloramphenicol; D000581:Amidohydrolases; C084507:peptide deformylase; C010531:actinonin