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<p>Breakdown of calcium network is closely associated with cellular aging. Previously, we found that cytosolic calcium (CytoCa<sup>2+</sup>) levels were elevated while mitochondrial calcium (MitoCa<sup>2+</sup>) levels were decreased and associated with metabolic shift in aged intestinal stem cells (ISCs) of <i>Drosophila</i>. How MitoCa<sup>2+</sup> was decoupled from the intracellular calcium network and whether the reduction of MitoCa<sup>2+</sup> drives ISC aging, however, remains unresolved. Here, we show that genetically restoring MitoCa<sup>2+</sup> can reverse ISC functional decline and promote intestinal homeostasis by activating autophagy in aged flies. Further studies indicate that MitoCa<sup>2+</sup> and Mitochondria–ER contacts (MERCs) form a positive feedback loop via <i>IP3R</i> to regulate autophagy independent of <i>AMPK</i>. Breakdown of this loop is responsible for MitoCa<sup>2+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月27日

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  • Yao Zhang,
  • Peng Ma,
  • Saifei Wang,
  • Shuxin Chen,
  • Hansong Deng

摘要

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.