Activation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy

Abstract Human corneal endothelial cells (HCEnCs) are terminally differentiated cells that have limited regenerative potential. The large numbers of mitochondria in HCEnCs are critical for pump and barrier function required for corneal hydration and transparency. Fuchs Endothelial Corneal Dystrophy...

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Autores principales:	Anne-Sophie Benischke, Shivakumar Vasanth, Takashi Miyai, Kishore Reddy Katikireddy, Tomas White, Yuming Chen, Adna Halilovic, Marianne Price, Francis Price, Paloma B. Liton, Ula V. Jurkunas
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Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ecc7e19f75dc46359548d6a57c136297
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spelling	oai:doaj.org-article:ecc7e19f75dc46359548d6a57c1362972021-12-02T12:32:08ZActivation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy10.1038/s41598-017-06523-22045-2322https://doaj.org/article/ecc7e19f75dc46359548d6a57c1362972017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06523-2https://doaj.org/toc/2045-2322Abstract Human corneal endothelial cells (HCEnCs) are terminally differentiated cells that have limited regenerative potential. The large numbers of mitochondria in HCEnCs are critical for pump and barrier function required for corneal hydration and transparency. Fuchs Endothelial Corneal Dystrophy (FECD) is a highly prevalent late-onset oxidative stress disorder characterized by progressive loss of HCEnCs. We previously reported increased mitochondrial fragmentation and reduced ATP and mtDNA copy number in FECD. Herein, carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced mitochondrial depolarization decreased mitochondrial mass and Mfn2 levels, which were rescued with mitophagy blocker, bafilomycin, in FECD. Moreover, electron transport chain complex (I, V) decrease in FECD indicated deficient mitochondrial bioenergetics. Transmission electron microscopy of FECD tissues displayed an increased number of autophagic vacuoles containing degenerated and swollen mitochondria with cristolysis. An elevation of LC3-II and LAMP1 and downregulation of Mfn2 in mitochondrial fractions suggested that loss of fusion capacity targets fragmented mitochondria to the pre-autophagic pool and upregulates mitophagy. CCCP-induced mitochondrial fragmentation leads to Mfn2 and LC3 co-localization without activation of proteosome, suggesting a novel Mfn2 degradation pathway via mitophagy. These data indicate constitutive activation of mitophagy results in reduction of mitochondrial mass and abrogates cellular bioenergetics during degeneration of post-mitotic cells of ocular tissue.Anne-Sophie BenischkeShivakumar VasanthTakashi MiyaiKishore Reddy KatikireddyTomas WhiteYuming ChenAdna HalilovicMarianne PriceFrancis PricePaloma B. LitonUla V. JurkunasNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Anne-Sophie Benischke Shivakumar Vasanth Takashi Miyai Kishore Reddy Katikireddy Tomas White Yuming Chen Adna Halilovic Marianne Price Francis Price Paloma B. Liton Ula V. Jurkunas Activation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy
description	Abstract Human corneal endothelial cells (HCEnCs) are terminally differentiated cells that have limited regenerative potential. The large numbers of mitochondria in HCEnCs are critical for pump and barrier function required for corneal hydration and transparency. Fuchs Endothelial Corneal Dystrophy (FECD) is a highly prevalent late-onset oxidative stress disorder characterized by progressive loss of HCEnCs. We previously reported increased mitochondrial fragmentation and reduced ATP and mtDNA copy number in FECD. Herein, carbonyl cyanide m-chlorophenyl hydrazone (CCCP)-induced mitochondrial depolarization decreased mitochondrial mass and Mfn2 levels, which were rescued with mitophagy blocker, bafilomycin, in FECD. Moreover, electron transport chain complex (I, V) decrease in FECD indicated deficient mitochondrial bioenergetics. Transmission electron microscopy of FECD tissues displayed an increased number of autophagic vacuoles containing degenerated and swollen mitochondria with cristolysis. An elevation of LC3-II and LAMP1 and downregulation of Mfn2 in mitochondrial fractions suggested that loss of fusion capacity targets fragmented mitochondria to the pre-autophagic pool and upregulates mitophagy. CCCP-induced mitochondrial fragmentation leads to Mfn2 and LC3 co-localization without activation of proteosome, suggesting a novel Mfn2 degradation pathway via mitophagy. These data indicate constitutive activation of mitophagy results in reduction of mitochondrial mass and abrogates cellular bioenergetics during degeneration of post-mitotic cells of ocular tissue.
format	article
author	Anne-Sophie Benischke Shivakumar Vasanth Takashi Miyai Kishore Reddy Katikireddy Tomas White Yuming Chen Adna Halilovic Marianne Price Francis Price Paloma B. Liton Ula V. Jurkunas
author_facet	Anne-Sophie Benischke Shivakumar Vasanth Takashi Miyai Kishore Reddy Katikireddy Tomas White Yuming Chen Adna Halilovic Marianne Price Francis Price Paloma B. Liton Ula V. Jurkunas
author_sort	Anne-Sophie Benischke
title	Activation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy
title_short	Activation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy
title_full	Activation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy
title_fullStr	Activation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy
title_full_unstemmed	Activation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy
title_sort	activation of mitophagy leads to decline in mfn2 and loss of mitochondrial mass in fuchs endothelial corneal dystrophy
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/ecc7e19f75dc46359548d6a57c136297
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Activation of mitophagy leads to decline in Mfn2 and loss of mitochondrial mass in Fuchs endothelial corneal dystrophy

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