Identification of Transcriptional and Metabolic Programs Related to Mammalian Cell Size

• Published in: Current biology 2014-03, Vol.24 (6), p.598-608
• Main Authors: Miettinen, Teemu P., Pessa, Heli K.J., Caldez, Matias J., Fuhrer, Tobias, Diril, M. Kasim, Sauer, Uwe, Kaldis, Philipp, Björklund, Mikael
• Format: Article
• Language: English
• Subjects: Aerobiosis - physiology; Animals; Cell Proliferation; Cell Size; Cytoskeleton - physiology; Female; Gene Expression Regulation - physiology; Glycolysis - physiology; Lipid Metabolism - physiology; Liver - cytology; Metabolome - physiology; Mice; Mitochondria, Liver - metabolism; Mitochondria, Liver - physiology; Transcription, Genetic - physiology
• ISSN: 0960-9822; 1879-0445
• DOI: 10.1016/j.cub.2014.01.071

Regulation 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. 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 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. •Gene expression and metabolites levels relative to cell size are analyzed in liver•Mitochondrial gene expression is repressed cell-autonomously in larger cells•Cell size can be modulated by targeting mitochondria functions and lipid synthesis•Lipids are negative regulators of cell size because they promote cell proliferation Miettinen et al. use conditional knockout of Cdk1 in mouse liver to explore how cell size impacts transcription and metabolism. They find that large cells are not bioenergetically challenged and that mitochondrial function and lipid biosynthesis are changed in response to cell size, possibly due to the differences in the surface-area-to-volume ratio.