Tuesday, 29 April 2014

The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter


In this paper, mice lacking the calcium uniporter are investigated to see what consequences this has on mitochondrial calcium uptake, bioenergetics and cell death.

Mice lacking the calcium uniporter could not take up calcium rapidly. The basal mitochondrial matrix calcium concentration (from skeletal muscle cells) was reduced by 75% compared to that of wild type cells. Despite this, the uniporter-lacking cells showed no change in basal oxygen consumption and also the maximal maximal oxidative capacity was the same in wilde-type and uniporter-lacking mice.

Because of the lower calcium levels in uniporter-lacking mice, phosphorylation levels of the pyruvate dehydrogenase were increased which reduces its activity. This difference in phosphorylation levels was only seen in starved conditions, but dissapeared once the mice were fed. Because there were hardly any defects in basal metabolism of uniporter-lacking cells, the in vivo effects of altering matrix calcium may be most important under certain stress conditions.

When mice were placed on a treadmill, the uniporter-lacking mice were less able to exercise than the control group.

The mitochondrial permeability transition pore (PTP) opens if extramitochondrial calcium concentrations rise above a certain value. This behaviour was not seen in cells lacking the uniporter.

Effects on apoptosis
Cells were exposed to agents that induce cell death (such as tunicamycin,   doxorubicin and  thapsigargin). There was no change in the kinetics or magnitude of cell death in MEFs with or without the uniporter. Levels of cytosolic calcium and the release of cytochrome c were also the same in control and uniporter-lacking cells during cell death.

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