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Lisa A Brennan, Rebecca McGreal, Caitlin Logan, Ales Cvekl, A Sue Menko, Marc Kantorow; Elimination of Mitochondria, Endoplasmic Reticulum and Golgi during lens cell differentiation to form the lens organelle-free zone requires the mitophagy protein BNIP3L and is regulated by the transcription factor HIF1a.. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1212.
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© ARVO (1962-2015); The Authors (2016-present)
A key feature of lens cell differentiation is elimination of mitochondria and other organelles to form the transparent lens organelle-free zone (OFZ). The purpose of this study was to establish the proteins required for elimination of lens mitochondria during OFZ formation and the mechanisms regulating their function.
RNA sequencing and bioinformatic analysis was used to identify that the mitophagy protein BNIP3L/Nix and the transcription factor HIF1a exhibited increased expression patterns that coincided with OFZ formation. P1 and P14 lenses of BNIP3L knock-out mice were analyzed for elimination of mitochondria and other organelles by multicolor confocal immunohistochemistry and western analysis. Ex vivo cultured Day 10 embryonic chick lenses were exposed to a HIF1a stabilizer and analyzed for levels of HIF1a, BNIP3L and specific organelles markers by western analysis and multicolor confocal immunohistochemistry.
BNIP3L and HIF1a exhibited their highest expression levels in fiber cells just prior to organelle loss, consistent with their involvement in the elimination of mitochondria and other organelles during lens cell differentiation. Deletion of BNIP3L resulted in retention of mitochondria, endoplasmic reticulum (ER) and Golgi during lens cell differentiation. Stabilization of HIF1a by cobalt chloride resulted in increased levels of HIF1a and increased BNIP3L expression in cultured embryonic chick lenses.
These data provide evidence for a novel pathway for elimination of mitochondria, ER and Golgi to form the lens OFZ that requires BNIP3L and that BNIP3L transcription is regulated by HIF1a in the lens. Since HIF1a has been previously shown to regulate transcription of BNIP3L and is negatively regulated by oxygen levels that are known to decrease from the outer to inner lens, the data suggest that decreased oxygen levels during lens differentiation regulate the transcriptional activation of BNIP3L by HIF1a that in turn mediates the degradation of mitochondria and other organelles to form the lens OFZ.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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