title: Cellular Allometry of Mitochondrial Functionality Establishes the Optimal Cell Size.
abstract: Eukaryotic cells attempt to maintain an optimal size, resulting in size homeostasis. While cellular content scales isometrically with cell size, allometric laws indicate that metabolism per mass unit should decline with increasing size. Here we use elutriation and single-cell flow cytometry to analyze mitochondrial scaling with cell size. While mitochondrial content increases linearly, mitochondrial membrane potential and oxidative phosphorylation are highest at intermediate cell sizes. Thus, mitochondrial content and functional scaling are uncoupled. The nonlinearity of mitochondrial functionality is cell size, not cell cycle, dependent, and it results in an optimal cell size whereby cellular fitness and proliferative capacity are maximized. While optimal cell size is controlled by growth factor signaling, its establishment and maintenance requires mitochondrial dynamics, which can be controlled by the mevalonate pathway. Thus, optimization of cellular fitness and functionality through mitochondria can explain the requirement for size control, as well as provide means for its maintenance.
authors.affiliation: Division of Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK; MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Teemu P
authors.initials: TP
authors.lastname: Miettinen
authors.affiliation: Division of Cell and Developmental Biology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK. Electronic address: mikael.bjorklund.lab@gmail.com.
authors.forename: Mikael
authors.initials: M
authors.lastname: Björklund
mesh_terms: D000818:Animals; D002453:Cell Cycle; D019069:Cell Respiration; D048429:Cell Size; D004330:Drosophila / Q000166:cytology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D019169:Jurkat Cells; D053078:Membrane Potential, Mitochondrial; D053858:Metabolic Networks and Pathways; D008798:Mevalonic Acid / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism*; D063154:Mitochondrial Dynamics; D017711:Nonlinear Dynamics; D017368:Protein Prenylation; D015398:Signal Transduction; D013696:Temperature
chemical_list: D007328:Insulin; D008798:Mevalonic Acid
keywords: Drp1; allometry; cell size; fitness; growth; metabolism; mevalonate pathway; mitochondria; mitochondrial dynamics; organelle scaling