{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n CISD2, also known as NAF‐1 or Miner1, encodes a redox‐active 2Fe–2S protein that localizes to the mitochondria, endoplasmic reticulum, and mitochondria‐associated membranes. Its unique “NEET” fold and labile 2Fe–2S cluster enable CISD2 to participate in redox signaling and facilitate iron–sulfur cluster transfer (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " CISD2 is essential for maintaining mitochondrial integrity and proper calcium homeostasis. Loss of CISD2 function leads to mitochondrial breakdown, increased reactive oxygen species production, and aberrant intracellular Ca²⁺ levels that trigger autophagic cell death; these molecular disturbances are closely linked to premature aging and neurodegenerative manifestations, as exemplified in Wolfram syndrome type 2."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition, CISD2 interacts with key regulators of cell survival pathways. For example, its association with BCL-2 and partners such as Gimap5 modulates endoplasmic reticulum Ca²⁺ stores and influences autophagy, which is critical for processes such as adipocyte differentiation and energy metabolism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Dysregulation of CISD2 has also been implicated in oncogenesis, with aberrantly high expression linked to enhanced cell proliferation, metastasis, and poorer clinical outcomes in cancers including hepatocellular, gastric, cervical, and lung carcinomas."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Furthermore, in cardiac and neural tissues, reduced CISD2 expression disrupts Ca²⁺ handling and mitochondrial performance, contributing to age‐related cardiac dysfunction and exacerbating neuroinflammatory responses and neurodegeneration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "12"}]}, {"type": "t", "text": " \n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore the multifaceted role of CISD2 in regulating mitochondrial bioenergetics, redox balance, and intracellular Ca²⁺ dynamics to maintain cellular homeostasis, influence lifespan, and modulate disease processes.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sagi Tamir, Mark L Paddock, Merav Darash-Yahana-Baram, et al. 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