Spatiotemporal Ca2+ nanodomain remodeling at MERCS regulates mitochondrial proteostasis

Area of Science:

• Cell Biology
• Neuroscience
• Mitochondrial Biology

Background:

• Mitochondrial calcium (Ca2+) fluxes are crucial for cell function and survival.
• The precise regulation of Ca2+ transients at mitochondria-ER contact sites (MERCS) and their role in stress signaling are not fully understood.

Purpose of the Study:

• To investigate the spatiotemporal regulation of Ca2+ transients at MERCS.
• To elucidate the mechanisms by which MERCS integrate Ca2+ signals into adaptive mitochondrial stress responses.
• To explore the therapeutic potential of targeting MERCS for neurodegenerative diseases.

Main Methods:

• Utilized custom-built high temporal-spatial resolution GI/3D-SIM imaging for nanoscale Ca2+ transient visualization.
• Performed quantitative protein expression and transcriptome analyses.
• Investigated the effects of Cyclosporin A (CsA) on neuronal cells challenged with Aβ1-42.

Main Results:

• Identified MERCS-localized Ca2+ oscillations as key regulators of retrograde stress signaling.
• Demonstrated that increased mitochondria-associated ER membrane (MAMs) connectivity attenuates global mitochondrial Ca2+ efflux.
• Showed that CsA-mediated calcium retention mimics MAMs induction, preserving mitochondrial integrity and activating UPRmt in Aβ1-42-challenged neurons, thereby protecting against apoptosis.

Conclusions:

• MERCS decode proteotoxic stress into transcriptional and epigenetic adaptations via retrograde signaling.
• MERCS-mediated signaling pathways, including ATF5 shuttling and epigenetic reprogramming, enhance cellular stress resilience.
• Targeting MERCS and associated calcium dynamics offers a potential therapeutic strategy for neurodegenerative diseases.