Identification of Transcriptional and Metabolic Programs Related to Mammalian Cell Size

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.

Mitochondrial Function and Cell Size: An Allometric Relationship

“…Lipid biosynthesis pathways and their transcriptional controllers, including the sterol regulatory element binding proteins (SREBPs), are downregulated at the mRNA level in vivo when proliferation 25 is prevented and cells increase in size [13]. Conceptually, these observations are consistent with the reasoning that larger cells have a reduced SV ratio and, consequently reduced need for plasma membrane lipids.…”

“…We found that the rate at which mitochondrial activity was reduced with 25 increasing cell size also reacted to temperature as predicted by these mathematical models of allometric scaling [34]. Consistently, we have previously observed that mitochondria associated genes display a relative reduction in mRNA levels in response to increases in hepatocyte size in vivo [13]. This downregulation of mitochondria-related gene expression likely reflects the reduced demand for mitochondrial function in larger cells.…”

“…While mitochondria are clearly important for setting the overall metabolic activity of the cell, there is some controversy in which way mitochondrial perturbations affect animal cell size [13][14][15]. Inhibition of oxidative phosphorylation, induction of mitochondrial ROS and mild uncoupling of mitochondrial membrane potential increase cell size and reduce cell proliferation [13]. Yet, at least in yeast, deletions of mitochondrial genes can 10 reduce cell size.…”

“…Some of the metabolic pathways downstream of mitochondria can also decrease cellular catabolism more than 5 they reduce protein synthesis, causing an increase in cell size [12]. While mitochondria are clearly important for setting the overall metabolic activity of the cell, there is some controversy in which way mitochondrial perturbations affect animal cell size [13][14][15]. Inhibition of oxidative phosphorylation, induction of mitochondrial ROS and mild uncoupling of mitochondrial membrane potential increase cell size and reduce cell proliferation [13].…”

“…Mitochondrial metabolism is also a main source for cytosolic acetyl-CoA, a metabolite critical for histone acetylation and lipid synthesis. Acetyl-CoA promotes cell proliferation [23] and inhibition of lipid biosynthesis limits proliferation and resulting in larger cell size [12,13].…”