Microgravity weakens cell attachment to tissue and slows protein synthesis in mitochondria
Microgravity weakens cell attachment to tissue and slows protein synthesis in mitochondria
On June 30, Nature Communications published a study of cells grown on the ISS. Under microgravity, mitochondrial ribosomes synthesized proteins more slowly. The authors traced the pathway from cell attachment to the surrounding tissue through to the chemical regulation of this protein synthesis machinery. Unloading and immobilizing the hindlimbs of mice produced the same signature in the soleus muscle.
Mitochondria make some of their own proteins. Their genome encodes 13 components of the respiratory chain, the machinery that converts energy from food into АТФ. Mitochondrial translation is therefore important for muscle cells. It determines how quickly mitochondrial ribosomes read RNA and assemble these proteins.
Taisei Wakigawa, Yusuke Kimura, and their colleagues grew human cells on the ISS for 24 and 48 hours. A centrifuge aboard the station provided the control condition by generating normal Earth gravity, 1g. After 24 hours in microgravity, fewer ribosomes were working on mitochondrial RNAs. The amount of RNA itself remained almost unchanged at that point, which showed that protein synthesis had specifically slowed. Worms that spent four days aboard the station showed a decrease in the same aggregate measure of translation efficiency.
The authors reproduced the effect on Earth using a three-dimensional clinostat, a device that continuously changes the orientation of cells to simulate the absence of a constant gravity vector. The signal decreased within one hour, returned to baseline under normal gravity, and increased under tenfold hypergravity.
The mechanism began outside the cell. Laminin is a protein in the supporting tissue, and integrins act as molecular anchors that attach cells to it. The more firmly a cell attached to laminin, the faster its mitochondria synthesized proteins. Blocking integrins had the opposite effect and reduced mitochondrial oxygen consumption.
Contact with laminin activates a protein pathway. It begins with FAK, an enzyme located at the site of cell attachment, and continues through RAC1 and PAK1. This pathway changes the activity of BAD at the outer mitochondrial membrane and initiates fatty acid synthesis inside the mitochondrion. The process consumes malonyl-CoA. This leaves fewer inhibitory malonyl marks on the translation machinery, allowing ribosomes to initiate translation sooner and elongate the protein chain more rapidly.
The authors unloaded and immobilized the hindlimbs of eight-week-old mice for 14 days. In the soleus muscle, both muscle mass and mitochondrial translation decreased. The authors tested the pathway in cells, worms, and young mice. They have not yet studied aged muscle or the recovery of muscle strength.