Increased Post-Hypoxic Oxidative Stress and Activation of the PERK Branch of the UPR in <i>Trap1</i>-Deficient <i>Drosophila melanogaster</i> Is Abrogated by Metformin

Hypoxia is known to impair mitochondrial and endoplasmic reticulum (ER) homeostasis. Post-hypoxic perturbations of the ER proteostasis result in the accumulation of misfolded/unfolded proteins leading to the activation of the Unfolded Protein Response (UPR). Mitochondrial chaperone TNF receptor-asso...

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Autores principales:	Alma Kokott-Vuong, Jennifer Jung, Aaron T. Fehr, Nele Kirschfink, Rozina Noristani, Aaron Voigt, Arno Reich, Jörg B. Schulz, Michael Huber, Pardes Habib
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Hsp90 family Hsp75 mitochondrial chaperone ER-stress ROS stroke Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/3cdab83c92fd4d1aa7fe84e7ac3cdbdd
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spelling	oai:doaj.org-article:3cdab83c92fd4d1aa7fe84e7ac3cdbdd2021-11-11T17:06:42ZIncreased Post-Hypoxic Oxidative Stress and Activation of the PERK Branch of the UPR in <i>Trap1</i>-Deficient <i>Drosophila melanogaster</i> Is Abrogated by Metformin10.3390/ijms2221115861422-00671661-6596https://doaj.org/article/3cdab83c92fd4d1aa7fe84e7ac3cdbdd2021-10-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11586https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Hypoxia is known to impair mitochondrial and endoplasmic reticulum (ER) homeostasis. Post-hypoxic perturbations of the ER proteostasis result in the accumulation of misfolded/unfolded proteins leading to the activation of the Unfolded Protein Response (UPR). Mitochondrial chaperone TNF receptor-associated protein 1 (TRAP1) is reported to preserve mitochondrial membrane potential and to impede reactive oxygen species (ROS) production thereby protecting cells from ER stress as well as oxidative stress. The first-line antidiabetic drug Metformin has been attributed a neuroprotective role after hypoxia. Interestingly, Metformin has been reported to rescue mitochondrial deficits in fibroblasts derived from a patient carrying a homozygous TRAP1 loss-of-function mutation. We sought to investigate a putative link between Metformin, TRAP1, and the UPR after hypoxia. We assessed post-hypoxic/reperfusion longevity, mortality, negative geotaxis, ROS production, metabolic activity, gene expression of antioxidant proteins, and activation of the UPR in <i>Trap1</i>-deficient flies. Following hypoxia, <i>Trap1</i> deficiency caused higher mortality and greater impairments in negative geotaxis compared to controls. Similarly, post-hypoxic production of ROS and UPR activation was significantly higher in <i>Trap1</i>-deficient compared to control flies. Metformin counteracted the deleterious effects of hypoxia in <i>Trap1</i>-deficient flies but had no protective effect in wild-type flies. We provide evidence that TRAP1 is crucially involved in the post-hypoxic regulation of mitochondrial/ER stress and the activation of the UPR. Metformin appears to rescue <i>Trap1</i>-deficiency after hypoxia mitigating ROS production and downregulating the pro-apoptotic PERK (protein kinase R-like ER kinase) arm of the UPR.Alma Kokott-VuongJennifer JungAaron T. FehrNele KirschfinkRozina NoristaniAaron VoigtArno ReichJörg B. SchulzMichael HuberPardes HabibMDPI AGarticleHsp90 familyHsp75mitochondrial chaperoneER-stressROSstrokeBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11586, p 11586 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Hsp90 family Hsp75 mitochondrial chaperone ER-stress ROS stroke Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	Hsp90 family Hsp75 mitochondrial chaperone ER-stress ROS stroke Biology (General) QH301-705.5 Chemistry QD1-999 Alma Kokott-Vuong Jennifer Jung Aaron T. Fehr Nele Kirschfink Rozina Noristani Aaron Voigt Arno Reich Jörg B. Schulz Michael Huber Pardes Habib Increased Post-Hypoxic Oxidative Stress and Activation of the PERK Branch of the UPR in <i>Trap1</i>-Deficient <i>Drosophila melanogaster</i> Is Abrogated by Metformin
description	Hypoxia is known to impair mitochondrial and endoplasmic reticulum (ER) homeostasis. Post-hypoxic perturbations of the ER proteostasis result in the accumulation of misfolded/unfolded proteins leading to the activation of the Unfolded Protein Response (UPR). Mitochondrial chaperone TNF receptor-associated protein 1 (TRAP1) is reported to preserve mitochondrial membrane potential and to impede reactive oxygen species (ROS) production thereby protecting cells from ER stress as well as oxidative stress. The first-line antidiabetic drug Metformin has been attributed a neuroprotective role after hypoxia. Interestingly, Metformin has been reported to rescue mitochondrial deficits in fibroblasts derived from a patient carrying a homozygous TRAP1 loss-of-function mutation. We sought to investigate a putative link between Metformin, TRAP1, and the UPR after hypoxia. We assessed post-hypoxic/reperfusion longevity, mortality, negative geotaxis, ROS production, metabolic activity, gene expression of antioxidant proteins, and activation of the UPR in <i>Trap1</i>-deficient flies. Following hypoxia, <i>Trap1</i> deficiency caused higher mortality and greater impairments in negative geotaxis compared to controls. Similarly, post-hypoxic production of ROS and UPR activation was significantly higher in <i>Trap1</i>-deficient compared to control flies. Metformin counteracted the deleterious effects of hypoxia in <i>Trap1</i>-deficient flies but had no protective effect in wild-type flies. We provide evidence that TRAP1 is crucially involved in the post-hypoxic regulation of mitochondrial/ER stress and the activation of the UPR. Metformin appears to rescue <i>Trap1</i>-deficiency after hypoxia mitigating ROS production and downregulating the pro-apoptotic PERK (protein kinase R-like ER kinase) arm of the UPR.
format	article
author	Alma Kokott-Vuong Jennifer Jung Aaron T. Fehr Nele Kirschfink Rozina Noristani Aaron Voigt Arno Reich Jörg B. Schulz Michael Huber Pardes Habib
author_facet	Alma Kokott-Vuong Jennifer Jung Aaron T. Fehr Nele Kirschfink Rozina Noristani Aaron Voigt Arno Reich Jörg B. Schulz Michael Huber Pardes Habib
author_sort	Alma Kokott-Vuong
title	Increased Post-Hypoxic Oxidative Stress and Activation of the PERK Branch of the UPR in <i>Trap1</i>-Deficient <i>Drosophila melanogaster</i> Is Abrogated by Metformin
title_short	Increased Post-Hypoxic Oxidative Stress and Activation of the PERK Branch of the UPR in <i>Trap1</i>-Deficient <i>Drosophila melanogaster</i> Is Abrogated by Metformin
title_full	Increased Post-Hypoxic Oxidative Stress and Activation of the PERK Branch of the UPR in <i>Trap1</i>-Deficient <i>Drosophila melanogaster</i> Is Abrogated by Metformin
title_fullStr	Increased Post-Hypoxic Oxidative Stress and Activation of the PERK Branch of the UPR in <i>Trap1</i>-Deficient <i>Drosophila melanogaster</i> Is Abrogated by Metformin
title_full_unstemmed	Increased Post-Hypoxic Oxidative Stress and Activation of the PERK Branch of the UPR in <i>Trap1</i>-Deficient <i>Drosophila melanogaster</i> Is Abrogated by Metformin
title_sort	increased post-hypoxic oxidative stress and activation of the perk branch of the upr in <i>trap1</i>-deficient <i>drosophila melanogaster</i> is abrogated by metformin
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/3cdab83c92fd4d1aa7fe84e7ac3cdbdd
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Increased Post-Hypoxic Oxidative Stress and Activation of the PERK Branch of the UPR in <i>Trap1</i>-Deficient <i>Drosophila melanogaster</i> Is Abrogated by Metformin

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