Calcium ions (Ca 2+ ) play a crucial role in numerous cellular functions, yet their specific influence on protein quality control in the endoplasmic reticulum (ER) has remained largely unclear. A collaborative research effort involving 17 teams from Japan, Korea, and the UK, led by Masaki Okumura at the Tohoku University Frontier Research Institute for Interdisciplinary Sciences, has provided significant insights into this process. The findings, published in Nature Cell Biology on November 11, 2025, may have implications for understanding conditions like Type 2 diabetes, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS).
The researchers focused on the concept of proteostasis, the regulation of protein folding and stability within the ER. Their study found that Ca 2+ ions can induce a phase separation in a protein known as PDIA6. This gene is responsible for producing an ER-localized protein essential for proper protein folding. If PDIA6 functions improperly, it can lead to protein misfolding, which has serious health consequences, including diabetes.
Importantly, the research uncovered that calcium-driven phase separation creates liquid-like droplets within the ER. These droplets play a pivotal role in correcting proinsulin, the precursor to insulin. Excessive proinsulin levels can signal an increased risk for Type 2 diabetes. According to Okumura, “To keep everything running smoothly, we need these condensation-like droplets to ensure proinsulin is properly folded – as opposed to forming large, aggregate clumps that can disrupt the normal pathways and cause negative health outcomes.”
This discovery not only enhances our understanding of calcium’s role in cellular processes but also opens avenues for potential drug development targeting challenging diseases such as ALS, Alzheimer’s, and Type 2 diabetes. The collaborative nature of the study underscores the importance of interdisciplinary approaches in tackling complex biological questions.
The research team included a diverse array of scientists, highlighting the global effort in advancing our understanding of cellular mechanisms. The detailed findings of this study contribute meaningfully to the ongoing exploration of proteostasis and its implications for health and disease management, providing a foundation for future research initiatives.
With ongoing advancements in this field, it is hoped that such insights can lead to effective strategies for preventing and treating debilitating conditions linked to protein misfolding.
