Starvation has been shown to cause cell remodeling

The body’s cells burn fat stores when the supply of nutrients from food ceases. A team led by Professor Volker Haucke and Dr. Wonyul Jang from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) has now discovered a previously unknown mechanism for how this “starvation response” is triggered and what can inhibit it. The results have been published in the journal Sciences.

For the body to function, cells need a constant supply of energy. During starvation phases, when nutrients are not taken in from food, cellular metabolism must adapt to ensure a sustained supply of energy.

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.

The genetic defect present in this disease affects the lipid phosphatase MTM1. 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 starvation; 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, an amino acid deficiency occurs. As a result, the researchers found that the ER undergoes shape changes 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,” said 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 demonstrate in a second study, published in Proceedings of the National Academy of Sciences, 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.