期刊
FASEB JOURNAL
卷 36, 期 1, 页码 -出版社
WILEY
DOI: 10.1096/fj.202100710RR
关键词
autophagy; insulin-like growth factor type 1 receptor; metabolism; mitochondria; mTOR
资金
- NEI [R0I EY029258, R0I EY024546, F30 EY031559, P30 EY030413]
- Lions Foundation for Sight
- Eye Bank Association of America
- Research to Prevent Blindness, New York, NY
- NHL [151000021685]
This study reveals a novel role for IGFBP-3 in regulating mitochondrial homeostasis through the regulation of mitophagy receptors in corneal epithelial cells. Additionally, IGFBP-3 affects mitochondrial morphology and respiration.
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.
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