title: Mitochondrial dynamics, biogenesis, and function are coordinated with the cell cycle by APC/C CDH1.
abstract: Cell proliferation is associated with a high rate of aerobic glycolysis, which has been widely interpreted as a compensatory mechanism for suppressed mitochondrial function, despite reports of high respiration rates. The molecular mechanisms that link cell proliferation with mitochondrial metabolism, dynamics, and biogenesis remain obscure. Here, we show that proliferation is associated with an increase in both glycolysis and respiration, in conjunction with mitochondrial fusion and biogenesis. Changes in mitochondrial morphology and mass are due to accumulation of OPA1, MFN1, and TFAM, silencing any of which hinders cell proliferation. Moreover, the levels of OPA1, MFN1, and TFAM are regulated by the ubiquitin ligase APC/C(CDH1), which also controls proteasomal degradation of key glycolytic, glutaminolytic, and cell-cycle proteins. Thus, we have identified an important component of the molecular mechanism that coordinates cell proliferation with activation of the mitochondrial metabolic machinery that provides the necessary energy and biosynthetic substrates.
authors.affiliation: Wolfson Institute for Biomedical Research, University College London, London, UK. a.garedew@ucl.ac.uk
authors.forename: Assegid
authors.initials: A
authors.lastname: Garedew
authors.forename: Catia
authors.initials: C
authors.lastname: Andreassi
authors.forename: Salvador
authors.initials: S
authors.lastname: Moncada
mesh_terms: D000332:Aerobiosis; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D019069:Cell Respiration; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006019:Glycolysis; D006609:High Mobility Group Proteins / Q000378:metabolism; D056892:Mediator Complex / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; C539582:Med12 protein, mouse; D056892:Mediator Complex; D061988:Proteasome Inhibitors; C081930:Tfam protein, mouse; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D020558:GTP Phosphohydrolases; C488750:Mfn1 protein, mouse