Cells need to react appropriately to nutritional cues. Defects in the rewiring of metabolism in response to alterations in nutrient supply have been linked to human diseases ranging from diabetes to muscle atrophy. Starvation represses anabolic pathways and facilitates catabolic ones, such as the degradation of macromolecules by autophagy and endolysosomes. It also triggers changes in metabolism that are coordinated across the cell and its organelles.
A team led by Professor Volker Haucke and Dr. Wonyul Jang from the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) has discovered the mechanism behind the triggering of this “starvation response.” The study offered detailed insights into this fundamental mechanism in human cells while investigating a rare genetic muscular disorder – X-linked centronuclear myopathy (XLCNM).
The X chromosome’s faulty gene causes this condition, which typically affects boys and causes a skeletal muscle developmental abnormality. Children with acute muscle weakness frequently need ventilator support and are wheelchair-bound. Affected people do not live above the ages of 10 to 12; in extreme situations, they pass away shortly after birth.
Lipid phosphatase MTM1 is impacted by the genetic defect that causes this illness. On endosomes, vesicle-like cell structures involved in the classification of nutrient receptors, this enzyme regulates the turnover of a signaling lipid. Scientists discovered changes to the endoplasmic reticulum (ER), a membrane network that spans the entire cell, when analyzing the structure of mutant human muscle cells from patients.
In healthy cells, the ER forms an extensive interconnected network of “flattened” membrane-enclosed sacs near the cell’s nucleus and narrow tubules in the cell periphery. In diseased cells, this equilibrium is shifted towards the tubules, and the membrane-enclosed sacs appear perforated.
Scientists found a similar accumulation of narrow ER tubules and perforated membrane-enclosed sacs in starved cells, in which MTM1 was genetically inactivated.
Volker Haucke said, “Muscles are highly 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. When cells are starved, amino acid deficiency occurs. As a result, the we found, the ER undergoes changes in shape in healthy cells – the outer narrow tubules regress and are converted into flat membrane-enclosed sacs.”
Dr. Wonyul Jang, lead author of the study, said, “This altered ER structure enables the mitochondria – spherical organelles that supply the cell with energy (adenosine triphosphate, ATP) and are in contact with the ER – to fuse. Such greatly enlarged ‘giant mitochondria’ are much better able to metabolize fats.”
However, MTM1-deficient cells are unable to transport or burn lipids effectively. The major player in this process is the endosome that MTM1 regulates. Starvation decreases the points of interaction between endosomes and the ER in healthy cells, allowing the latter to change form as a result. However, there is no contact site reduction in the cells of XLCNM patients because the endosome pulls on the ER, stabilizing the peripheral tubules and fenestrating the membrane-enclosed sacs.
Since peripheral ER tubules are responsible for mitochondrial fission, mitochondria remain small without MTM1. In this shape, they are much less able to burn stored fats, resulting in severe energy deficiency in the cell.
Volker Haucke. In light of this, the current study shows that starvation is harmful to the muscle cells of XLCNM patients said: “We have found a completely new mechanism for how different compartments in the cell communicate with each other such that cell metabolism adapts in response to the food supply.”
“In light of this, the current study shows that starvation is harmful to the muscle cells of XLCNM patients. They need constant food intake to prevent muscle proteins from being broken down into amino acids. FMP researchers showed in a second study that defects due to a loss of the lipid phosphatase MTM1 could essentially be repaired by inactivating the “opposing” enzyme, the lipid kinase PI3KC2B. 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 PI3KC2B activity. They have already demonstrated in cell culture that this is possible in principle.”
- Jang, W., Puchkov, D., Samso, P., Liang, Y.T., Nadler-Holly, M., Sigrist, S.J., Kintscher, U., Liu, F., Mamchaoui, K., Mouly, V., Haucke, V. (2022) Endosomal lipid signaling reshapes the endoplasmic reticulum to control mitochondrial function. Science; DOI: 10.1126/science.abq5209
- Samso, P.*, Koch, P.A.*, Posor, Y., Lo, W.T., Belabed, H., Nazare, M., Laporte, J., Haucke, V. (2022) Antagonistic control of active surface integrins by myotubularin and phosphatidylinositol 3-kinase C2b in a myotubular myopathy model. Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2202236119