Starvation Causes Cellular Remodeling: Research | Health

Cells require a constant flow of energy to function properly. Cellular metabolism must adjust during periods of hungerwhen nutrients are not absorbed from food, to ensure a constant supply of energy.

The study findings published in the journal Science.

FMP researchers have gained new insights into this fundamental mechanism in human cells while investigating a rare genetic muscle disorder: X-linked centronuclear myopathy (XLCNM). This disease, which usually affects boys, involves a faulty gene on the X chromosome, resulting in a disorder of skeletal muscle development. This muscle weakness is so severe that, in many cases, affected children require ventilatory support and are wheelchair bound. Affected individuals do not survive beyond the age of 10 to 12 years; in severe cases, they die shortly after birth.

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The genetic defect present in this disease affects MTM1 lipid phosphatase. This enzyme controls the turnover of a signaling lipid in endosomes, vesicle-like structures in cells involved in sorting nutrient receptors. It was while studying the structure of the patients’ mutant human muscle cells that the researchers discovered changes in the endoplasmic reticulum (ER), a network of membranes that spans the entire cell. In healthy cells, the ER forms a large interconnected network of “flattened” membrane-enclosed sacs near the cell’s nucleus and narrow tubules at the cell’s periphery. In diseased cells, this balance shifts towards the tubules and, in addition, the membranous sacs appear perforated. The researchers found a very similar accumulation of narrow ER tubules and enclosed sacs in perforated membranes in starved cells, in which MTM1 was genetically inactivated.

Muscles are very sensitive to hunger.; their energy reserves are soon depleted. We therefore began to suspect that the defect in cells from XLCNM patients might be related to an incorrect response to starvation,” reported Volker Haucke. When cells starve, a deficiency of amino acids forms in healthy cells: the narrow outer tubules recede and become flat, membrane-enclosed sacs.

This altered structure of the ER allows mitochondria, spherical organelles that supply the cell with energy (adenosine triphosphate, ATP) and are in contact with the ER, to fuse together. “These vastly enlarged ‘giant mitochondria’ are much better able to metabolize fat,” explained Dr. Wonyul Jang, lead author of the study.

However, fats cannot be efficiently transported or burned in MTM1-deficient cells. The MTM1-controlled endosome plays a key role in this process. In healthy cells, starvation reduces the contact points between the endosomes and the ER, allowing the latter to remodel itself as a result. In cells from XLCNM patients, however, no contact site reduction occurs: the endosome exerts a “tractive force” on the ER, resulting in stabilization of the peripheral tubules and fenestration of the sacs. enclosed by the membrane. Since the peripheral ER tubules are responsible for mitochondrial fission, mitochondria remain small in the absence of MTM1. In this form, they are much less able to burn stored fats, resulting in a severe deficiency of energy in the cell.

“We have found a completely new mechanism for how the different compartments of the cell communicate with each other, so that the cellular metabolism adapts in response to the food supply,” summarized Volker Haucke. In light of this, the current study shows that starvation is totally damaging to the muscle cells of XLCNM patients. They need a constant intake of food to prevent muscle proteins from breaking down into amino acids. The FMP researchers were able to show in a second study (2) that defects due to loss of MTM1 lipid phosphatase can be essentially repaired by inactivating the ‘opposite’ enzyme, PI3KC2B lipid kinase.

Only time will tell if this will work in XLCNM patients. The team led by Volker Haucke is currently working to find a suitable inhibitor that can suppress the activity of PI3KC2B. They have already shown in cell culture that this is possible in principle.

This story is published from a news agency source with no text changes. Only the title has been changed.

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