Tongji University investigators reveal that overexpressing the mitochondrial calcium uniporter (MCU) or silencing its gatekeeper MICU1 in Drosophila intestinal stem cells restores mitochondrial calcium levels, re-establishing ER–mitochondria contact sites (MERCs) via IP3R activation. This calcium oscillation-driven autophagy rejuvenates aged stem cells, rebalancing metabolic profiles and preserving gut homeostasis, highlighting a potential avenue to mitigate age-associated tissue degeneration.
Key points
Enhancing mitochondrial Ca²⁺ uptake via MCU overexpression or MICU1 knockdown restores MitoCa²⁺ levels and reduces cytosolic Ca²⁺ overload in aged Drosophila intestinal stem cells.
Reactivated MitoCa²⁺ triggers IP₃R-mediated ER Ca²⁺ release at MERCs, initiating Atg1/Atg13 and Class III PI3K-dependent autophagosome formation independent of AMPK.
Restored MERC integrity and autophagy reverse DNA damage, metabolic dysregulation, and mis-differentiation, preserving gut pH homeostasis and stem cell function.
Why it matters:
This discovery reveals a MERC calcium-autophagy axis as a therapeutic lever to rejuvenate aged stem cells and halt tissue decline.
Q&A
What are MERCs?
How does mitochondrial calcium uptake stimulate autophagy?
What genetic tools were used to manipulate mitochondrial calcium levels?
Why is this finding relevant for studying aging in mammals?
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Academy
Mitochondria–Endoplasmic Reticulum Contact Sites (MERCs)
Definition and Structure
Mitochondria–endoplasmic reticulum contact sites, or MERCs, are stable contact regions where the outer mitochondrial membrane comes within 10–30 nanometers of the ER membrane. This close proximity is maintained by tethering proteins—such as Mitofusin 2 (MFN2), the IP₃R–Grp75–VDAC complex, VAPB–PTPIP51, and members of the ERMES complex in yeast—that span the inter-organelle gap.
Functions of MERCs
MERCs serve as dynamic hubs for various essential cellular processes:
- Calcium Signaling: MERCs facilitate rapid, localized transfer of Ca²⁺ from the ER lumen into mitochondria through IP₃ receptors (IP₃Rs) and voltage-dependent anion channels (VDACs). This Ca²⁺ influx activates key mitochondrial enzymes and regulates ATP production.
- Lipid Metabolism: Many enzymes involved in phospholipid synthesis and exchange—such as phosphatidylserine synthase and phosphatidylethanolamine N-methyltransferase—are enriched at MERCs, allowing direct lipid trafficking.
- Autophagy Initiation: MERCs provide membrane platforms for autophagosome nucleation. Key autophagy machinery (Atg1/ULK1 complex, PI3K complex Atg6/Vps34) and omegasome markers (DFCP1/ZFYVE1) are recruited to MERCs upon induction of autophagy.
- Stress and Quality Control: MERCs coordinate mitochondrial fission and mitophagy. Proteins such as Drp1 localize to MERCs, marking sites for mitochondrial division.
Mechanisms of Calcium Transfer
Calcium stored in the ER is released through IP₃Rs on the ER membrane. A subdomain of the ER called the mitochondria-associated membrane (MAM) concentrates IP₃Rs and tethering complexes to efficiently hand off Ca²⁺ to VDACs on mitochondria. The calcium concentration spike in the mitochondrial intermembrane space is sensed by the mitochondrial calcium uniporter (MCU) on the inner membrane, driving Ca²⁺ into the matrix.
Role in Autophagy
At MERCs, local Ca²⁺ oscillations triggered by alternating release from the ER and uptake by mitochondria activate the Atg1/ULK1 kinase complex. This phosphorylation event initiates the nucleation of the isolation membrane. MERCs also supply membrane lipids and recruit PI3P-producing complexes to form phagophores.
MERCs Dysfunction and Aging
With age, MERC number and stability decline. Reduced output of Ca²⁺ to mitochondria impairs metabolic enzyme activity, lowers ATP levels, and blunts autophagy. Accumulation of damaged proteins and organelles accelerates cellular senescence, particularly in long-lived stem cell populations.
Therapeutic Potential in Longevity Science
Preserving or restoring MERC integrity can rejuvenate aged stem cells by re-establishing the Ca²⁺ oscillation–autophagy axis. Strategies include overexpressing MCU, modulating MICU1, or stabilizing tether complexes (Grp75, VAPB–PTPIP51). By boosting cellular cleanup and metabolic resilience, MERC-targeted therapies hold promise to delay tissue decline and extend health span.
Key Takeaways for Longevity Enthusiasts
- MERCs are vital for calcium signaling and autophagy initiation.
- Age-related MERC loss undermines stem cell function and accelerates tissue aging.
- Genetic or pharmacological approaches that restore ER–mitochondria contacts can rejuvenate aged cells, offering new longevity interventions.
