When hungry, the cell remodels

Human cell structure (Image: depositphotos)
Human cell structure (Image: depositphotos)

Body cells burn fat reserves when the supply of nutrients from food is interrupted. A team led by Volker Haucke of Freie Universität Berlin and the Leibniz Research Institute for Molecular Pharmacology (FMP) and Wonyul Jang of the FMP has now discovered a previously unknown mechanism for how this "starvation metabolism" gets going - and what can inhibit it.

For our body to function, cells need energy - at all times. In periods of hunger, during which no nutrients are consumed, the cellular metabolism must therefore change in order to ensure the supply of energy.

Researchers at the FMP gained new insights into this fundamental mechanism in the human cell when they studied a rare, hereditary muscle disorder, X-linked myotubular myopathy (XLCNM). In this disorder, which mostly affects boys, a gene on the X chromosome is defective, resulting in a developmental disorder of the skeletal muscles. This muscle weakness is so severe that affected children are often ventilated and have to sit in wheelchairs. They reach a maximum age of about 10 to 12 years, in severe cases they die already after birth.

The gene defect present in this disease affects the lipid phosphatase MTM1. This enzyme controls the turnover of a signal lipid of the endosome, a vesicle-like structure in the cell involved in sorting nutrient receptors. When the researchers studied the structure of mutant human muscle cells from patients, they discovered changes in the endoplasmic reticulum (ER), a membrane network that extends throughout the cell. In healthy cells, the ER represents a mixture of interconnected extended, "flattened" membrane sacs near the nucleus and thin tubes in the cell periphery. In diseased cells, this equilibrium is shifted toward the thin tubes and the membrane sacs are also perforated. The researchers found a very similar enrichment of thin ER tubes and perforated membrane sacks in cells in the starvation state, in which MTM1 was genetically inactivated.

Muscles are very sensitive to hunger and their energy reserves do not last long. That’s why we began to suspect that the defect in cells of XLCNM patients might have to do with an incorrect response to hunger," Volker Haucke reports. Starvation causes a lack of amino acids in cells. As a result, the researchers found, the ER in healthy cells changes its shape, the outer thin tubes regress and are converted into flat membrane sacs. This altered structure of the ER enables the mitochondria - roundish organelles that supply the cell with energy (adenosine triphosphate, ATP) and are in constant contact with the ER - to fuse together. "Such ’giant mitochondria’, enlarged about tenfold, are much better able to metabolize fats," explains Dr. Wonyul Jang, first author of the study.

However, both the transport and the combustion of fats do not function in cells in which MTM1 is defective. The key role here is played by the endosome controlled by MTM1. In the presence of starvation, the contact sites between the endosome and the ER dissolve in the healthy cell, which can subsequently deform. In cells of XLCNM patients, however, contact detachment is absent: The endosome "pulls" on the ER, forming peripheral tubes and fenestrating the membrane sacs. Since peripheral ER tubes are responsible for mitochondrial division, they remain small in the absence of MTM1. In this form, they are much less able to burn storage lipids, leading to a massive energy deficiency in the cell (1).

We have found a completely new mechanism for how different compartments in the cell communicate with each other in such a way that the cell metabolism is reorganized depending on the food supply," summarizes Volker Haucke. The current work shows that starvation is absolutely harmful for the muscle cells of XLCNM patients. They need a steady supply of food to prevent the breakdown of muscle proteins into amino acids. In a second paper (2), researchers at the FMP were able to show that defects resulting from the loss of the lipid phosphatase MTM1 can in principle be repaired by inactivating the "opposite" enzyme, the lipid kinase PI3KC2B. Whether this could work in XLCNM patients remains to be seen. A team led by Volker Haucke is currently working on finding a suitable inhibitor that can switch off PI3KC2B. They have already demonstrated in cell culture that this is possible in principle.

The results were published in the prestigious international journal ’Science’.