Sunday, 23 October 2016

Cellular Allometry of Mitochondrial Functionality Establishes the Optimal Cell Size

Teemu P. Miettinen and Mikael Björklund

Cells in a population, despite having the same genetic content, are often very different from each other due to the stochastic nature of biological processes. An example is cellular size: some cells are big, some are small and some have an intermediate size. How does the size of a cell affect its functionality? Is there an optimal cell size? This paper focusses on how mitochondrial functionality changes with cell size.

It is known that if a cell is twice as big, it will approximately have twice as many mitochondria, keeping the mitochondrial density roughly constant. However, the expression of mitochondrial genes becomes less than twice as high, meaning that bigger cells express relatively less mitochondrial genes. This may mean that there is a particular cell size corresponding to optimal mitochondrial functionality.

In the paper, they use single cell flow cytometry to measure the size of about 10^5-10^6 cells. Additionally, the mitochondrial membrane potential per unit cell size (ΔΨ) is measured. The relationship between cell size and ΔΨ can then be investigated.

Some of the findings are:
  • Consistent with previous studied, mitochondrial mass increases linearly with cell size
  • ΔΨ first increases as cells get larger, but then decreases again as cells get very large.
  • Mitochondrial respiration is highest in intermediate-sized cells
  • Intermediate-sized cells show the lowest variation in mitochondrial membrane potential
  • A higher ΔΨ variation is correlated with a higher rate of apoptosis (cell death)
  • Intermediate-sized cells showed (on average) the fastest growth

These results strongly indicate that mitochondrial functionality is largest in intermediate-sized cells in a population. Cells also seem to try to maintain the size at which mitochondrial functionality is largest, meaning that this is probably an optimal cell size.

Tuesday, 18 October 2016

Mitochondrial Dysfunction Prevents Repolarization of Inflammatory Macrophages

Jan Van den Bossche, Jeroen Baardman, Natasja A. Otto, Saskia van der Velden, Annette E. Neele, Susan M. van den Berg, Rosario Luque-Martin, Hung-Jen Chen, Marieke C.S. Boshuizen, Mohamed Ahmed, Marten A. Hoeksema, Alex F. de Vos, Menno P.J. de Winther

Macrophages are types of white blood cell. They engulf and digest bodies which do not possess the correct protein markers which mark healthy cells. Whilst these cells play a crucial role in immunity, their dysfunction is associated with a number of auto-immune diseases such as asthma and rheumatoid arthritis. Macrophages exist in a spectrum of states, ranging from pro-inflammatory (M1) to anti-inflammatory (M2). In this study, the authors wished to investigate the mechanisms which prevent the transition from M1 to M2, so that we may better understand the mechanisms of inflammation.

Previous studies have shown that M1 cells are reliant upon glycolysis whereas M2 cells use mitochondrial oxidative phosphorylation (OXPHOS). These modes of energy production have also been associated with promoting the activation of these macrophage states. The authors find here that when macrophages are induced (using LPS + IFN-γ) to become M1 (pro-inflammatory) cells, this process inhibits OXPHOS. The signal (IL-4) which induces M2 (anti-inflammatory) cells cannot reverse this suppression of OXPHOS, and so they remain trapped in the pro-inflammatory state. The authors found that nitric oxide production by M1 cells, which is used as an antimicrobial mechanism and inhibits mitochondrial function, prevents the ability of M1 macrophages to be reprogrammed as non-inflammatory M2 cells.

Tuesday, 11 October 2016

Loss of Dendritic Complexity Precedes Neurodegeneration in a Mouse Model with Disrupted Mitochondrial Distribution in Mature Dendrites

López-Doménech G, Higgs NF, Vaccaro V, Roš H, Arancibia-Cárcamo IL, MacAskill AF, Kittler JT

Miro proteins link mitochondria to motor proteins, allowing them to be trafficked through neurons. In this study, the authors disrupted the expression of Miro proteins in neurons to understand the role of mitochondrial trafficking in neurodegeneration. The authors found that Miro1-KO caused the distribution of mitochondria in dendrites (the branched extensions of nerve cells which receive electrochemical signals from other neurons) to become more accumulated around the soma, and more sparse along dendrites. Miro1-KO cells also appeared smaller and less developed than wild-type neurons; this was also shown to be the case in an inducible Miro1-KO system in mature neurons of the forebrain of mice. The deletion of this gene was associated with neurodegeneration 12 months after induction of Miro1-KO.