Miettinen TP1, Pessa HK1, Caldez MJ2, Fuhrer T3, Diril MK4, Sauer U3, Kaldis P2, Björklund M5.
1 Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee, UK.
2 Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research); Department of Biochemistry, National University of Singapore (NUS), Singapore.
3 Institute of Molecular Systems Biology, Eidgenössische Technische Hochschule Zürich (ETH), Zürich, Switzerland.
4 Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore.
5 Division of Cell and Developmental Biology, College of Life Sciences, University of Dundee, Dundee, UK.
Published in Current Biology on 17 March 2014.
Regulation of cell size requires coordination of growth and proliferation. Conditional loss of cyclin-dependent kinase 1 (Cdk1) in mice permits hepatocyte growth without cell division, allowing us to study cell size in vivo using transcriptomics and metabolomics. Larger cells displayed increased expression of cytoskeletal genes but unexpectedly repressed expression of many genes involved in mitochondrial functions. This effect appears to be cell autonomous because cultured Drosophila cells induced to increase cell size displayed a similar gene expression pattern. Larger hepatocytes also displayed a reduction in the expression of lipogenic transcription factors, especially sterol-regulatory element binding proteins. Inhibition of mitochondrial functions and lipid biosynthesis, which is dependent on mitochondrial metabolism, increased the cell size with reciprocal effects on cell proliferation in several cell lines. We uncover that large cell-size increase is accompanied by down regulation of mitochondrial gene expression, similar to that observed in diabetic individuals. Mitochondrial metabolism and lipid synthesis are used to couple cell size and cell proliferation. This regulatory mechanism may provide a possible mechanism for sensing metazoan cell size.
Figure Legend: Glycolysis increases with cell size.
(A) Representative electron microscopy images of Cdk1Flox/Flox and Cdk1Liv-/- liver before and after hepatectomy. Arrows and ‘‘M’’ indicate glycogen and mitochondria, respectively. All scale bars represent 500 nm. (B) mRNA expression (red line) and protein levels (blue bars) of selected OxPhos proteins. Western blot shows the measured OxPhos complex components, phospho-Thr172-AMPK (pAMPK) levels, and GAPDH (loading control). (C) Relative ATP and AMP levels in liver samples, as measured by mass spectrometry. Statistical significance was measured by ANOVA. (D) Proportional expression of key glycolytic genes based on liver RNAseq data. (E) Glutamate metabolite levels (orange) and Idh expression levels (blue and gray) correlate with cell size. (F) Inhibition of glycolysis and glutaminolysis by 2-DG and DON rescue U2OS cell size increase by 1 mM sodium azide (p < 0.001 in both; t test, mean 6 SD, n = 3).
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