Cells must respond adequately to nutritional signals. Defects in the rewiring of metabolism in response to changes in nutrient supply have been linked to human diseases ranging from diabetes to muscle atrophy. Starvation suppresses anabolic pathways and facilitates catabolic ones, such as the breakdown of macromolecules by autophagy and endolysosomes. It also causes changes in metabolism that are coordinated by the cell and its organelles.
A team led by Professor Volker Haucke and Dr. Wonyul Jang of the Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP) has discovered the mechanism behind triggering this ‘starvation response’. The study provided detailed insights into this fundamental mechanism in human cells while investigating a rare genetic muscle disorder – X-linked centronuclear myopathy (XLCNM).
The faulty gene of the X chromosome causes this condition, which usually affects boys and causes an abnormality in skeletal muscle development. Children with acute muscle weakness often require ventilator support and are wheelchair bound. Affected people do not live past 10 to 12 years; in extreme situations they die shortly after birth.
Lipid phosphatase MTM1 is affected by the genetic defect that causes this disease. On endosomes, vesicle-like cell structures involved in the classification of nutritional receptors, this enzyme regulates the conversion of a signaling lipid. Scientists discovered changes in the endoplasmic reticulum (ER), a membrane network that spans the entire cell, when analyzing the structure of mutated human muscle cells from patients.
In healthy cells, the ER forms an extensive interconnected network of “flattened” membrane-enclosed sacs near the cell nucleus and narrow tubes at the cell periphery. In diseased cells, this equilibrium is shifted to 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 very sensitive to starvation; their energy reserves are quickly depleted. We therefore began to suspect that the defect in cells from XLCNM patients might be related to an inappropriate response to starvation. When cells are starved, amino acid deficiency occurs. As a result, we found, the ER undergoes shape changes in healthy cells – the outer narrow tubules recede and become flat, membrane-enclosed sacs.
Dr. Wonyul Jang, lead author of the study, said: “This altered ER structure allows the mitochondria – globular organelles that provide 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 effectively transport or burn lipids. The key player in this process is the endosome that regulates MTM1. Starvation reduces the interaction points between endosomes and the ER in healthy cells, allowing the latter to change shape as a result. However, there is no reduction in the contact site 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 form they are much less able to burn stored fats, resulting in a serious energy shortage 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 found a completely new mechanism for how different compartments in the cell communicate with each other so that cell metabolism adapts in response to food supply.”
“In light of this, the current study shows that starvation is detrimental to the muscle cells of XLCNM patients. They need constant food to prevent muscle proteins from being broken down into amino acids. In a second study, FMP researchers showed that defects resulting from a loss of the lipid phosphatase MTM1 could essentially be repaired by inactivating the “opposite” 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 on a suitable inhibitor that can suppress the activity of PI3KC2B. They have already shown in cell culture that this is possible in principle.”
- Jang, W., Puchkov, D., Samso, P., Liang, YT, Nadler-Holly, M., Sigrist, SJ, 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, PA*, Posor, Y., Lo, WT, 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