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

Abstract

SummaryOrganelle biosynthesis is a key requirement for cell growth and division. The regulation of mitochondrial biosynthesis exhibits additional layers of complexity compared with that of other organelles because they contain their own genome and dedicated ribosomes. Maintaining these components requires gene expression to be coordinated between the nucleo-cytoplasmic compartment and mitochondria in order to monitor organelle homeostasis and to integrate the responses to the physiological and developmental demands of the cell. Surprisingly, the parameters that are used to monitor or count mitochondrial abundance are not known, nor are the signalling pathways. Inhibiting the translation on mito-ribosomes genetically or with antibiotics can impair cell proliferation and has been attributed to defects in aerobic energy metabolism, even though proliferating cells rely primarily on glycolysis to fuel their metabolic demands. However, a recent study indicates that mitochondrial translational stress and the rescue mechanisms that relieve this stress cause the defect in cell proliferation and occur before any impairment of oxidative phosphorylation. Therefore, the process of mitochondrial translation in itself appears to be an important checkpoint for the monitoring of mitochondrial homeostasis and might have a role in establishing mitochondrial abundance within a cell. This hypothesis article will explore the evidence supporting a role for mito-ribosomes and translation in a mitochondria-counting mechanism.

Mitohormesis

“…Through yet undefined mechanisms, peptide release from the mitochondria triggers a transcriptional response that involves several proteins including the ubiquitin-like protein UBL-5, the homeobox containing transcription factor DVE-1 and ATFS-1(Haynes et al, 2007; Haynes et al, 2010). While much remains to be learned, the use of released peptides from the mitochondrial matrix to trigger a response is vaguely reminiscent of another biological phenomenon, namely quorum sensing in gram-positive bacteria(Battersby and Richter, 2013). In this situation, oligopeptides are released into the environment through an ABC transporter located on the surface of the bacteria (Henke and Bassler, 2004).…”

Mitochondrial ribosomes in cancer

“…Actinonin treatment induces a time-dependent loss of mitoribosomal proteins with different degrees of severity [156, 157]. This might be the effect of the peptidyl deformylase activity of Actinonin.…”

Tim29 is required for stem cell activity during regeneration in the flatwormMacrostomum lignano

“…Our findings demonstrate that healthy mitochondria are essential for proper neoblast function, and add to the increasing recognition of mitochondrial signaling as a key component to mediate stem cell activity. The emerging picture is that mitochondria continuously integrate cellular and environmental cues to influence stem cell fate and activity, which enables organisms to adapt to the environmental changes (Battersby and Richter, 2013;Lisowski et al, 2018;Zhang et al, 2018). Many questions remain, however, as the majority of published mitochondrial research focused on postmitotic tissues, and the role of mitochondria in the context of stem cells has been largely neglected until recently for several reasons (Zhang et al, 2018).…”