(ORDO NEWS) — Studies of cells from patients with X-linked centronuclear myopathy, a rare inherited muscle disease, have shed light on the normal and abnormal cell response to starvation.
It turned out that the lack of nutrition changes the shape of the intracellular membrane system (endoplasmic reticulum) and causes the mitochondria to merge together.
Cells require an uninterrupted supply of energy to function properly. However, during starvation, when the supply of nutrients is cut off, the cell’s metabolism must change in such a way as to continue to support itself through alternative mechanisms.
The authors of a new article in Science have found out exactly how human cells adapt to a lack of nutrition. Curiously, in order to do this, they had to look at a rare genetic muscle disorder, X-linked centronuclear myopathy (XLCNM).
This hereditary myopathy usually affects boys. The disease is caused by mutations in one of the geneslocated on the X sex chromosome.
As a result, the development of skeletal muscles is disrupted, and they become so weak that the child may need ventilation or a wheelchair.
Affected children usually live no more than 10-12 years, and in the most severe cases die shortly after birth.
In X-linked centronuclear myopathy, mutations occur in the gene encoding lipid phosphatase MTM1. This is an enzyme that is responsible for the metabolism of signaling lipids of endosomes (vesicles involved in sorting and targeted transport within the cell ).
Previous studies of mutant human muscle cells (obtained from patients) described changes in their intracellular membranes – more precisely, the endoplasmic reticulum (EPR).
In a normal cell, the ER is a complex intertwined network of closed membranes – in the form of bags where it is adjacent to the nucleus or in the form of thin strands on the periphery.
This polymorphism of the intracellular membrane system has a functional significance and changes with a genetic defect.
The fact is that mutations shift the dynamic balance of the EPR towards thin and long strands. There are more of them, and the membrane “bags” in the center of the cell look perforated.
It turned out that exactly the same rearrangement of the EPR system occurs in cells with the “turned off” MTM1 gene under starvation conditions.
“Muscles are extremely sensitive to starvation, while their energy reserves will soon run out. That is why we suspected that cell defects in XLCNM patients may be due to a pathological response to starvation, ” explained Volker Haucke.
The authors of the new article found that this is what triggers pathological changes in the shape of cells: the outer elongated strands of the EPR degrade and turn into large flattened sacs.
Following EPR, mitochondria change – organelles that are the “power plants” of the cell. The fact is that the pathological process in the neighboring ER causes individual mitochondria to merge together, forming huge “supermitochondria”.
Oddly enough, such abnormal “fused” mitochondria are much better at processing fats. However, in the case of patients with XLCNM (that is, without the MTM1 enzyme), this is not to be rejoiced at: efficient processing, as well as transport of fats and similar compounds, is impossible.
In healthy cells, starvation reduces the number of contacts between the ER and endosomes, causing them to change shape.
But this does not happen in people with XLCNM: endosomes overcome the “pull” of the ER. Because of this, the membrane strands at the cell periphery become more stable, while the central part of the ER becomes fenestrated, that is, it becomes “leaky”.
Since the strands of the external EPR are involved in the division of mitochondria (capable, like whole cells, of “dividing in two”), these organelles become very small. As a result, they process fats much worse, and this is caused precisely by a deficiency of MTM1.
“We were able to describe a completely new mechanism for how different compartments (membrane-separated “compartments” of the cell interact with each other so that the cellular metabolism adapts to the mode of food intake,” summed up Hauke.
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