IGFBP-3 functions as a molecular switch that mediates mitochondrial and metabolic homeostasis.
IGFBP-3 functions as a molecular switch that mediates mitochondrial and metabolic homeostasis.
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DOI：
10.1096/fj.202100710rr
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发表时间：
2022-01
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线粒体功能障碍或体内平衡丧失是许多人类疾病的核心标志。线粒体稳态由多种质量控制机制介导，包括线粒体自噬，这是一种选择性自噬形式，可回收绝症或功能失调的线粒体，以保持线粒体完整性。我们之前的研究表明，胰岛素样生长因子 (IGF) 家族的成员定位于线粒体，可能在调节角膜上皮线粒体健康方面发挥重要作用，角膜上皮是维持光学透明度和视力所需的完整组织。重要的是，IGF 结合蛋白 3 (IGFBP-3) 是由角膜上皮细胞在应激反应中分泌的，其功能是介导这种细胞类型的细胞内受体运输。在这项研究中，我们通过调节角膜上皮细胞中的短异构体 (s)BNIP3L/NIX 线粒体自噬受体，证明了 IGFBP-3 在线粒体稳态中的新作用，并将这一发现扩展到非眼上皮细胞。我们进一步表明，IGFBP-3 介导的线粒体稳态控制与层状嵴形态和线粒体动力学的改变有关。有趣的是，IGFBP-3 功能的丧失和增强都会导致线粒体呼吸的增加。这种呼吸作用的增加与 IGFBP-3 的核积累有关。总而言之，这些发现支持 IGFBP-3 通过调节线粒体自噬和线粒体形态作为粘膜上皮线粒体健康的关键介质的新作用。
Mitochondrial dysfunction or loss of homeostasis is a central hallmark of many human diseases. Mitochondrial homeostasis is mediated by multiple quality control mechanisms including mitophagy, a form of selective autophagy that recycles terminally ill or dysfunctional mitochondria in order to preserve mitochondrial integrity. Our prior studies have shown that members of the insulin-like growth factor (IGF) family localize to the mitochondria and may play important roles in mediating mitochondrial health in the corneal epithelium, an integral tissue that is required for the maintenance of optical transparency and vision. Importantly, the IGF-binding protein-3, IGFBP-3, is secreted by corneal epithelial cells in response to stress and functions to mediate intracellular receptor trafficking in this cell type. In this study, we demonstrate a novel role for IGFBP-3 in mitochondrial homeostasis through regulation of the short isoform (s)BNIP3L/NIX mitophagy receptor in corneal epithelial cells and extend this finding to non-ocular epithelial cells. We further show that IGFBP-3-mediated control of mitochondrial homeostasis is associated with alterations in lamellar cristae morphology and mitochondrial dynamics. Interestingly, both loss and gain of function of IGFBP-3 drive an increase in mitochondrial respiration. This increase in respiration is associated with nuclear accumulation of IGFBP-3. Taken together, these findings support a novel role for IGFBP-3 as a key mediator of mitochondrial health in mucosal epithelia through the regulation of mitophagy and mitochondrial morphology.