Restoring calcium crosstalk between ER and mitochondria promotes intestinal stem cell rejuvenation through autophagy in aged Drosophila

Breakdown of calcium network is closely associated with cellular aging. Previously, we found that cytosolic calcium (CytoCa²⁺) levels were elevated while mitochondrial calcium (MitoCa²⁺) levels were decreased and associated with metabolic shift in aged intestinal stem cells (ISCs) of Drosophila. How MitoCa²⁺ was decoupled from the intracellular calcium network and whether the reduction of MitoCa²⁺ drives ISC aging, however, remains unresolved. Here, we show that genetically restoring MitoCa²⁺ can reverse ISC functional decline and promote intestinal homeostasis by activating autophagy in aged flies. Further studies indicate that MitoCa²⁺ and Mitochondria-ER contacts (MERCs) form a positive feedback loop via IP3R to regulate autophagy independent of AMPK. Breakdown of this loop is responsible for MitoCa²⁺ reduction and ISC dysfunction in aged flies. Our results identify a regulatory module for autophagy initiation involving calcium crosstalk between the ER and mitochondria, providing a strategy to treat aging and age-related diseases.