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.

Why translation counts for mitochondria – retrograde signalling links mitochondrial protein synthesis to mitochondrial biogenesis and cell proliferation

“…However, this interpretation is at odds with data from a vast scientific literature that demonstrate that glycolysis fuels the metabolic demands of cellular proliferation (reviewed by Hanahan and Weinberg, 2011). Moreover, these proliferation defects persist even when the culture medium is supplemented with uridine (Richter et al, 2013), which can bypass the dependency of the mitochondrial respiratory chain function on dihydroorotate dehydrogenase, which is required for de novo pyrimidine biosynthesis (Rawls et al, 2000). Therefore, loss of the respiratory chain is simply a downstream consequence of mitochondrial dysfunction and not the biological driver that activates the checkpoint in this model system.…”

“…Third, chloramphenicol is a well-known antibiotic that inhibits both prokaryotic and mitochondrial function by occupying the A site of the ribosome (Bulkley et al, 2010;Koc et al, 2010), which systematically blocks all translation elongation. We found that after 48 hours of administration, there was no proliferation defect in glucose, even though we could not detect any translation or mitochondrially encoded subunits (Richter et al, 2013). It has been shown previously that only much longer incubations with chloramphenicol (greater than 10 days) result in impaired proliferation (Bunn et al, 1974).…”

“…We recently addressed this question and demonstrated that mitochondrial translational stress impaired cell proliferation, and not the loss of respiratory chain complexes (Richter et al, 2013). In this study, we showed that treatment with the antibiotic actinonin induced stalling of mitochondrial translation elongation, which, in turn, activated a pathway to rescue dysfunctional mitochondrial ribosomes.…”

“…The proliferation of cultured mammalian cells can be impaired following disruption of mitochondrial function Escobar-Alvarez et al, 2010;Richter et al, 2010;Richter et al, 2013;Rorbach et al, 2008;Skrtić et al, 2011;Soleimanpour-Lichaei et al, 2007;Uchiumi et al, 2010). In some cases, these proliferation defects were attributed to dysfunctional mitochondrial respiration (Escobar-Alvarez et al, 2010;Skrtić et al, 2011).…”

“…It has been shown previously that only much longer incubations with chloramphenicol (greater than 10 days) result in impaired proliferation (Bunn et al, 1974). Finally, treatment with actinonin, which binds to mitochondrial peptide deformylase (PDF) (Box 1) (Fieulaine et al, 2011) and traps it on mitochondrial ribosomes, stalls translation elongation and impairs cell proliferation in as little as 12 hours (Richter et al, 2013). These examples demonstrate that the reduction in the rate of translation elongation in itself, at least as measured in a 1-hour pulse radiolabelling experiment, cannot account for the acute proliferation defects and emphasise that more in-depth studies into the complexity of ribosomal function are required to elucidate the molecular basis of these phenotypes.…”