In November 2025, a team led by Dr. Yuting Guo at the University of Chinese Academy of Sciences revealed how mitochondria-ER contact sites (MERCS) decode proteotoxic stress via calcium nanodomain regulation, activating adaptive mitochondrial responses. Published in Protein & Cell, the work proposes new therapeutic avenues for neurodegenerative diseases.
Mitochondrial proteostasis disruption contributes critically to aging and disease. The mitochondrial unfolded protein response (UPRmt), a conserved pathway from C. elegans to primates, restores proteostasis by inducing chaperones and proteases. However, its complex regulation and technical limitations in live-cell imaging have left mammalian UPRmt activation mechanisms poorly understood. Moreover, while mitochondrial calcium dynamics is central to mitochondrial homeostasis, its spatiotemporal link to UPRmt remain unclear.
To address these questions, the team employed their home-made high-resolution GI/3D-SIM imaging technology and constructed MERCS-enhanced (REDMAP) and -deficient models. They found that enhanced MERCS restrict mitochondrial calcium efflux, delay mPTP opening, and subsequently activate UPRmt.
Mechanistically, MERCS-mediated calcium retention triggers UPRmt via two pathways: 1) Impaired calcium efflux reduces ATF5 mitochondrial import, promoting its nuclear translocation and stress gene expression; and 2) Calcium-sensitive kinase CAMK4 drives H3K27 acetylation, increasing chromatin accessibility and UPRmt transcription.
In an Alzheimer’s model, this “calcium-transcription-epigenetics” axis conferred neuroprotection. Inhibiting mPTP pharmacologically (CsA) or genetically (CypD-KD) activated UPRmt, alleviating Aβ-induced mitochondrial dysfunction and apoptosis.
This study systematically elucidates how MERCS-regulated nanocalcium signals integrate transcriptional and epigenetic mechanisms to preserve proteostasis, advancing inter-organelle communication understanding and identifying new targets for diseases like AD.
The research was conducted at the University of Chinese Academy of Sciences. Co-first authors are Dr. Lv Yanan, MSc Zhao Xuejing, and Prof. Li Di. Corresponding author is Prof. Guo Yuting.
DOI:10.1093/procel/pwaf097