Abstract
SummaryBackgroundRegulation of cell size requires coordination of growth and proliferation. Conditional loss of cyclin-dependent kinase 1 in mice permits hepatocyte growth without cell division, allowing us to study cell size in vivo using transcriptomics and metabolomics.ResultsLarger 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.ConclusionsWe uncover that large cell-size increase is accompanied by downregulation 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.
Highlights
Cell size can be increased by impeding with cell-cycle progression, increasing the rate of biosynthesis, or both
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 downregulation of mitochondrial gene expression, similar to that observed in diabetic individuals
Summary
Cell size can be increased by impeding with cell-cycle progression, increasing the rate of biosynthesis, or both. Cell size and proliferation are mainly controlled by nutrient levels, whereas regulation through growth and mitogenic and survival signals is important in metazoan cells [1]. Cell size increases with ploidy in many organisms, the mechanism behind this is elusive [2, 3]. Genes affecting cell size have been identified through loss-of-function studies in yeast [5, 6] and Drosophila [7, 8], as well as through geneexpression studies of yeast cell-cycle mutants and strains with variable ploidy [9,10,11]. Mechanisms that affect cell size in vivo have received less attention, apart from the role of mTOR
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