Gravity Activates Mitochondrial Translation: Space Station Study Reveals Molecular Pathway Linking Mechanical Forces to Cellular Energy Production

A landmark study published in Nature Communications on June 30 has unraveled a fundamental biological mechanism: how cells sense gravity and translate that physical force into mitochondrial protein production. The international collaborative research, led by Shintaro Iwasaki at the RIKEN (search)Search company Iwasaki RNA Systems Biochemistry Laboratory, demonstrates that microgravity aboard the International Space Station (ISS) causes a dramatic reduction in mitochondrial translation — the process by which specialized ribosomes within mitochondria synthesize proteins critical for energy production.

The findings represent the first comprehensive analysis of how gravitational forces shape translation at the protein level, moving beyond prior work that focused primarily on gene transcription. "It is well known that microgravity reduces or alters gene expression," said Thomas Corydon, a space biologist at Aarhus University in Denmark. This analysis, he added, provides evidence of how microgravity affects cells "directly on the protein level."

Space-Based Experiments Reveal Translation Deficits

With the cooperation of the Japan Aerospace Exploration AgencyView company profile (JAXA), the research team cultured human cells in the Japanese Experiment Module "Kibo" aboard the ISS for either 24 or 48 hours under microgravity conditions, with control samples maintained in an onboard centrifuge simulating standard Earth gravity at 1 g. Astronaut Soichi Noguchi conducted the cell culture experiments on the ISS.

After the samples returned to Earth, the team employed ribosome profiling — a technique that captures comprehensive, quantitative information about which messenger RNAs (mRNAs) are being translated by ribosomes and to what extent. The analysis revealed that cells exposed to microgravity for 24 hours had fewer mitochondrial mRNAs than controls, and their mitochondrial ribosomes synthesized fewer proteins.

To test whether the phenomenon was reproducible across species, the researchers performed ribosome profiling on Caenorhabditis elegans nematodes cultured under microgravity conditions on the ISS for four days. Again, a decrease in mitochondrial translation was observed, though the effect was less pronounced than in human cells.

Simulated Microgravity Confirms and Extends Findings

Earth-based replication experiments using a 3D clinostat — a device that rotates culture vessels in three dimensions to average gravitational acceleration to near zero — confirmed the space-based observations. After 24 hours in the clinostat, human cell mitochondria showed reduced production of 13 proteins. Extending the rotation to 48 and 72 hours further decreased mitochondrial protein synthesis.

The team then investigated the molecular mechanism underlying this phenomenon, focusing on cell adhesion. Past space experiments had shown that cell adhesion weakens under microgravity. Using the mito-FUNCAT method, which labels newly synthesized proteins for detection, the researchers demonstrated that mitochondrial translation increases with higher concentrations of laminin, a basement membrane molecule of the extracellular matrix. When laminin was increased under simulated microgravity conditions, it counteracted the effects and mitigated the decrease in mitochondrial translation.

A Signaling Pathway from Cell Surface to Mitochondria

Through a series of knockdown experiments and small-scale chemical screening, the researchers mapped the signal transduction pathway linking cell adhesion to mitochondrial translation. The pathway proceeds from integrins — cell membrane proteins that bind laminin — through the phosphorylation enzyme FAK (search)Search target, then downstream through PAK1 (search)Search target, RAC1 (search)Search target, BAD (search)Search target, and Bcl2 (search)Search target family proteins, which reside on the outer mitochondrial membrane.

Inside the mitochondria, the team discovered that the fatty acid synthesis pathway plays a critical regulatory role. When cell adhesion is strong, fatty acid synthesis proceeds using malonyl-CoA as a substrate. When cell adhesion weakens, fatty acid synthesis declines, causing malonyl-CoA to accumulate. This accumulation leads to malonylation — the enzyme-independent binding of malonyl-CoA to lysine residues — of the mitochondrial translation machinery, further suppressing protein synthesis.

Mechanical Stress and Broader Physiological Relevance

The researchers hypothesized that this pathway has physiological significance beyond the artificial condition of microgravity. Since the laminin-integrin (search)Search target cell adhesion pathway is known to be activated by mechanical stress such as exercise, they proposed that cells possess a system that enhances mitochondrial translation in response to physical activity. Ribosome profiling using a mouse skeletal muscle model in which mechanical stress was minimized confirmed a decrease in mitochondrial translation, supporting this hypothesis.

"This could be used to understand how we should better prepare astronauts going into space," said Corydon. Afshin Beheshti, a space biomedicine researcher at the University of Pittsburgh, noted that earlier work had provided "the general overview of how mitochondrial dysregulation was happening," but the molecular mechanisms through which gravity affects mitochondrial biology had remained poorly understood.

The study's implications extend beyond space medicine. The findings are expected to contribute to elucidating the pathogenesis of diseases related to aging, muscle atrophy, and mechanical stress in everyday life. The research team anticipates that these results will inform drug discovery research targeting mitochondrial translation, potentially leading to therapies that counteract mitochondrial decline associated with both spaceflight and terrestrial aging.