Starvation has been shown to cause cell remodeling

Body cells burn fat reserves when the supply of nutrients from food is cut off. Professor Volker Haucke from the Leibniz-Forschungsinstitut für Moleculare Pharmakologie (FMP) and Dr. A team led by Wonyul Jang has discovered a previously unknown mechanism for how this “hunger response” is triggered and what can inhibit it. The results were published in the journal Science.

In order for the body to function, cells need a constant source of energy. During starvation phases, when no nutrients are taken from food, cellular metabolism must adapt to provide a continuous source of energy.

Researchers from FMP gained new insights into this fundamental mechanism in human cells while investigating X-linked centronuclear myopathy (XLCNM), a rare genetic muscle disorder. This disease, which usually affects boys, contains a defective gene on the X chromosome and results in a developmental disorder of skeletal muscles.

This muscle weakness is so severe that, in most cases, affected children require respiratory support and are confined to a wheelchair. Affected individuals do not survive beyond 10 to 12 years of age; In severe cases, they die soon after birth.

The genetic defect found in this disease affects the lipid phosphatase MTM1. This enzyme controls the conversion of a signal lipid on endosomes, which are vesicle-like structures in cells involved in the classification of food receptors.

When examining the structure of mutant human muscle cells from patients, 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-bound sacs near the cell nucleus and narrow tubules around the cell. In diseased cells, this balance shifts towards the tubules, and also membrane-enclosed sacs appear perforated.

The researchers found a very similar accumulation of narrow ER tubules and perforated membrane-enclosed sacs in starved cells where MTM1 was genetically inactivated.

“Muscles are very sensitive to hunger; their energy reserves are quickly depleted. So we began to suspect that the defect in the cells of XLCNM patients might be related to the wrong response to hunger,” said Volker Haucke.

Amino acid deficiency occurs when cells starve. As a result, the researchers found that the ER undergoes shape changes in healthy cells—the outer narrow tubules regress and turn into smooth membrane-enclosed sacs. This modified structure of the ER allows the fusion of mitochondria (spherical organelles) that provide energy (adenosine triphosphate, ATP) to the cell and are in contact with the ER.

Lead author of the study, Dr. “Such enlarged ‘giant mitochondria’ are able to metabolize fat much better,” said Wonyul Jang.

However, in cells deficient in MTM1, fats cannot be transported or burned efficiently. The endosome, controlled by MTM1, plays a key role in this process. In healthy cells, starvation reduces the contact points between endosomes and the ER, ultimately allowing the latter to remodel. However, contact site reduction does not occur in the cells of XLCNM patients: the endosome exerts a “pulling force” on the ER, causing stabilization of peripheral tubules and window opening of membrane-enclosed sacs.

Since peripheral ER tubules are responsible for mitochondrial fission, mitochondria remain small in the absence of MTM1. In this form, they can burn their storage fat much less, which causes a severe lack of energy in the cell.

“We found an entirely new mechanism for how different compartments in the cell communicate with each other, such that cell metabolism adapts in response to food supply,” said Volker Haucke. In light of this, the current study shows that starvation is completely detrimental to the muscle cells of XLCNM patients. They need constant food intake to prevent the breakdown of muscle proteins into amino acids.

FMP researchers were able to demonstrate in a second published study. Proceedings of the National Academy of Sciences, that defects resulting from the loss of the lipid phosphatase MTM1 can be repaired mainly by inactivation of the “opponent” enzyme, the lipid kinase PI3KC2B. Only time will tell if this will work for XLCNM patients.

The team led by Volker Haucke is currently working to find a suitable inhibitor that can suppress PI3KC2B activity. They have already shown in cell culture that this is possible in principle.