Calcium plays a central role in how cells function, but scientists are still uncovering how it helps maintain the quality of proteins inside the endoplasmic reticulum, the cellular factory responsible for producing and transporting proteins. New research has now shed light on this process, offering fresh insight into diseases linked to protein misfolding, including Type 2 diabetes, Alzheimer’s disease and amyotrophic lateral sclerosis.
In a large international study led by Distinguished Associate Professor Masaki Okumura of Tohoku University in Japan, researchers examined how calcium ions regulate proteostasis, the system that ensures proteins are correctly folded and functional inside cells. The study involved 17 research teams from Japan, South Korea and the United Kingdom and was published in Nature Cell Biology on November 11, 2025.
The researchers focused on PDIA6, a gene that produces a protein within the endoplasmic reticulum that helps other proteins fold properly. They discovered that calcium can trigger a process known as phase separation in PDIA6. This causes the protein to form liquid-like droplets rather than remaining evenly distributed in the cell.
According to the findings, this calcium-driven phase separation plays a protective role. The droplets act as controlled environments that help correct errors during protein folding. One key target is proinsulin, the precursor of insulin. When proinsulin is improperly folded or accumulates in excess, it can disrupt insulin production and increase the risk of Type 2 diabetes.
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The study showed that without this calcium-regulated mechanism, proteins are more likely to form rigid aggregates instead of flexible droplets. These aggregates can interfere with normal cellular pathways and contribute to disease development.
Professor Okumura explained that maintaining this droplet-based system is essential for keeping proteins functional and preventing harmful buildup inside cells. Beyond diabetes, the findings also improve understanding of calcium-dependent processes linked to neurodegenerative conditions such as Alzheimer’s disease and ALS.
Researchers say the discovery could guide future drug development aimed at restoring or enhancing protein quality control in cells. By targeting calcium-driven proteostasis, new therapies may eventually help slow or prevent diseases caused by protein misfolding.
