Cellular Allometry of Mitochondrial Functionality Establishes the Optimal Cell Size

Teemu P Miettinen,Mikael Björklund

doi:10.1016/j.devcel.2016.09.004

Teemu P Miettinen, Mikael Björklund

Open Access

https://doi.org/10.1016/j.devcel.2016.09.004

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Abstract

SummaryEukaryotic 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.

Highlights

For every cell type there is a typical cell size, possibly reflecting the size for optimal cellular functions (Ginzberg et al, 2015)
We show that cells within a single population exhibit an optimal cell size, whereby mitochondrial functionality and fitness are maximized
Mitochondrial Functionality Scales Nonlinearly with Cell Size We recently reported that the relative expression of many mitochondrial genes declines in cells larger than normal size in cultured Drosophila cells and in mouse hepatocytes in vivo, the mitochondrial content per volume unit did not

Summary

Introduction

For every cell type there is a typical cell size, possibly reflecting the size for optimal cellular functions (Ginzberg et al, 2015). Cellular protein as well as organelle content typically scales linearly with cell size (Reber and Goehring, 2015; Schmoller and Skotheim, 2015), and it is commonly assumed that functionality increases linearly with total protein and organelle content. It is difficult to reconcile how linear size scaling of mitochondrial functionality, which reflects the metabolic activity of the cell, could help in establishing an optimal cell size (Figure 1A). The presence of cell sizedependent changes in functionality and/or feedback to metabolic and growth processes have been considered critical for cell size homeostasis (Ginzberg et al, 2015; Schmoller and Skotheim, 2015)

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