Two studies in Science found that starvation leads to cell remodeling

In order for the body to function properly, cells need a constant supply
of energy.
During the starvation phase, when nutrients are not ingested from food, cellular metabolism must adapt to ensure a continuous supply
of energy.

Researchers from FMP have gained new insights
into this fundamental mechanism in human cells while studying a rare inherited muscle disease, X-linked central ribomyopathy (XLCNM).
The disease, which usually occurs in boys, involves a defective gene on the X chromosome, leading to skeletal muscle development disorders
.
This muscle weakness is so severe that in many cases affected children require respiratory support and are strapped in
wheelchairs.
Affected individuals do not survive to be 10 to 12 years old; 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 signaling lipids on endosomes, vesicles-like structures
in cells involved in the sorting of trophic receptors.
It was while studying the structure of mutated human muscle cells from patients that the researchers discovered changes in the endoplasmic reticulum (ER), a membrane network
that spans the entire cell.
In healthy cells, the endoplasmic reticulum forms a large interconnected network
of "flat" membrane-wrapped sacs and narrow tubules around the cell periphery near the nucleus.
In diseased cells, this balance shifts to the tubules, and perforation
of the membrane-wrapped sac.
The researchers found very similar accumulation of narrow ER tubules and perforated membrane envelopes in starving cells, in which the MTM1 gene is inactivated
.

"Muscles are highly sensitive to hunger; Their energy reserves are quickly depleted
.
As a result, we began to suspect that defects in XLCNM patients' cells might be related to a misresponse to starvation," Volker Haucke reports
.
Amino acid deficiency
occurs when cells are hungry.
As a result, the researchers found that in healthy cells, the shape of the endoplasmic reticulum changed—the narrow tubules in the outer layer degenerated and transformed into flat, membrane-wrapped sacs.

Changes in the structure of the endoplasmic reticulum allow mitochondria—spherical organelles that supply energy to cells (adenosine triphosphate, ATP) and come into contact with the endoplasmic reticulum—fuse together
.
Dr Wonyul Jang, lead author of the study, explains: "This vastly enlarged 'giant mitochondria' are more capable of metabolizing fat
.
"

However, in cells lacking MTM1, fat cannot be transported or burned
efficiently.
The endosomes controlled by MTM1 play a key role
in this process.
In healthy cells, starvation reduces the point of contact between the endosome and the endoplasmic reticulum, allowing the latter to be reshaped
.
However, in the cells of XLCNM patients, no reduction in the site of contact occurs: the endosomes exert a "pull" on the endoplasmic reticulum, resulting in stabilization of the peripheral tubules and fenestration
of the membrane-wrapped capsule.
Since the peripheral ER tubules are responsible for mitochondrial fission, mitochondria remain small
in the absence of MTM1.
In this shape, their ability to burn stored fat is much lower, resulting in a severe lack of energy in the cells
.

Volker Haucke concludes: "We have discovered a completely new mechanism that explains how different regions in the cell communicate with each other, allowing cellular metabolism to adapt to the food supply
.
" In light of this, the current study shows that starvation is completely harmful to muscle cells in XLCNM patients
.
They require a sustained food intake to prevent muscle protein from being broken down into amino acids
.
The FMP researchers were able to demonstrate in the second study that defects due to the deletion of the lipid phosphatase MTM1 could essentially be repaired
by inactivating the "opposite" enzyme, the lipid kinase PI3KC2B.
Only time will tell if this is effective
for XLCNM patients.
The team, led by Volker Haucke, is currently looking for a suitable inhibitor that can inhibit the activity
of PI3KC2B.
They have shown in cell culture that this is possible
in principle.

(1) 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 signalling reshapes the endoplasmic reticulum to control mitochondrial function.
 Science [advance online]

(2) 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.
 Proc Natl Acad Sci USA 119, e2202236119