The regulation of mitochondrial DNA copy number in glioblastoma cells

The regulation of mitochondrial DNA copy number in glioblastoma cells


Embryonic stem cells and cancer cells share a number of similarities. Both are highly proliferative (stem cells needing to find a tissue to differentiate at, and cancers are malignant by their nature), glycolytic and have a low copy number of mtDNA. This study compares human neuronal stem cells (hNSCs) and a highly malignant brain cancer called glioblastoma multiforme (GBM). It was shown that hNSCs increase their mtDNA copy number in a cell-specific way during differentiation to a mtDNA "setpoint". When induced to differentiate, GBM fails to match hNSCs expansion in copy number, patterns of gene expression and increased respitatory capacity. However, if mtDNAs are depleted from a GBM and transferred to a mouse, if a tumour manages to form, it is observed that the mtDNA copy number is recovered to in vitro levels, indicating GBM also has an mtDNA setpoint. It is interesting to note that, once mtDNA was depleted from GBM cells and allowed to form a tumour in nude mice, the survival time from largest to smallest was the following: 0.2% (>100 days), 3% (~95 days), 100% (~85 days), 20% (~81 days) and 50% (~78 days), where the percentage indicates the amount of mtDNA remaining in the GBM cells before transfer.

The regulatory role of mitochondria in capacitative calcium entry.

The regulatory role of mitochondria in capacitative calcium entry.

http://www.sciencedirect.com/science/article/pii/S0005272806001137

Mitochondria can uptake calcium by using a uniport in the mitochondrial inner membrane. This uniport is driven by the membrane potential. The uniport has a low affinity for calcium. This implies that mitochondria are not able to take up calcium very efficiently. It is observed, however, that mitochondria do take up calcium and this happens more efficiently than one would expect based on the low affinity of the uniport. This can be explained by the discovery that locally there can be high concentrations of calcium (much higher than the global concentration of calcium in the cytoplasm) which enables the mitochondria to efficiently uptake calcium. Local high concentrations of calcium appear close to calcium channels in the endoplasmic reticulum (ER) and the plasma membrane (PM). 

           The ER is the cell's biggest calcium store and the calcium concentration in the ER can be 3-4 orders of magnitude larger than the concentration in the cytosol. The opening of calcium channels in the ER, which enables calcium to passively flow into the cytosol, depends on the concentration of calcium in the cytosol ([Cacyt]). A higher [Cacyt] induces the opening of the calcium channels in the ER. This positive feedback system is called Calcium-Induced Calcium Release (CICR). If the [Cacyt]  rises above a certain value, however, there is a negative feedback on IP_3-receptor calcium channels (which let calcium flow from the ER into the cytoplasm). This negative feedback inhibits the release of calcium from the ER and consequently decreases the capacitative calcium entry (CCE). This eventually stops the calcium signal in the cell.

       Mitochondria in the vicinity of calcium channels of the ER will take up calcium. This lowers the local [Cacyt] and can prevent the [Cacyt] from reaching the level at which it starts to give negative feedback to calcium channels in the ER. Mitochondria can therefore inhibit negative feedback on IP_3-receptor calcium channels. This stimulates the depletion of calcium stores and also stimulates CCE.
A concentration of calcium in the mitochondrial matrix that is too high can lead to damaged mitochondrial function consequently stops mitochondrial calcium uptake. This will lead to an increase in [Cacyt] and this stimulates negative feedback to the calcium channels. By forming mitochondrial networks, the concentration of calcium inside the mitochondria can be kept at a lower level since the calcium will spread throughout the network. This means that more calcium can be taken up by the mitochondria and less negative feedback will be given to the calcium channels. The formation of mitochondrial networks can therefore lead to a longer effectiveness of the calcium signal.

Novel mechanism of elimination of malfunctioning mitochondria (mitoptosis): Formation of mitoptotic bodies and extrusion of mitochondrial material from the cell

Novel mechanism of elimination of malfunctioning mitochondria (mitoptosis):
Formation of mitoptotic bodies and extrusion of mitochondrial material from the cell

When mitochondria are faulty, what is often observed is mitochondrial autophagy or mitophagy, where a subset of the mitochondrial population are digested by autophagosomes. In this paper, another pathway is observed after damage to the whole mitochondrial population. As a model, highly glycolytic HeLa cells are studied. Respiratory chain inhibitors and uncouplers (which induce ROS production and hydrolyse ATP in mitochondria) were applied. This was observed to cause fission of the mitochondrial network, migration of mitochondria to the perinuclear space, accumulation of mitochondria into a vesicle and then its subsequent expulsion by fusing to the plasma membrane.