{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T03:07:27Z","timestamp":1784689647801,"version":"3.55.0"},"reference-count":64,"publisher":"MDPI AG","issue":"21","license":[{"start":{"date-parts":[[2021,10,28]],"date-time":"2021-10-28T00:00:00Z","timestamp":1635379200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009398","name":"Medizinische Fakult\u00e4t, RWTH Aachen University","doi-asserted-by":"publisher","award":["START 111\/17 PH"],"award-info":[{"award-number":["START 111\/17 PH"]}],"id":[{"id":"10.13039\/501100009398","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 Trap1-deficient flies. Following hypoxia, Trap1 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 Trap1-deficient compared to control flies. Metformin counteracted the deleterious effects of hypoxia in Trap1-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 Trap1-deficiency after hypoxia mitigating ROS production and downregulating the pro-apoptotic PERK (protein kinase R-like ER kinase) arm of the UPR.<\/jats:p>","DOI":"10.3390\/ijms222111586","type":"journal-article","created":{"date-parts":[[2021,10,27]],"date-time":"2021-10-27T22:00:23Z","timestamp":1635372023000},"page":"11586","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Increased Post-Hypoxic Oxidative Stress and Activation of the PERK Branch of the UPR in Trap1-Deficient Drosophila melanogaster Is Abrogated by Metformin"],"prefix":"10.3390","volume":"22","author":[{"given":"Alma","family":"Kokott-Vuong","sequence":"first","affiliation":[{"name":"Department of Neurology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4870-6059","authenticated-orcid":false,"given":"Jennifer","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron T.","family":"Fehr","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nele","family":"Kirschfink","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rozina","family":"Noristani","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0428-7462","authenticated-orcid":false,"given":"Aaron","family":"Voigt","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany"},{"name":"JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum J\u00fclich GmbH and RWTH Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arno","family":"Reich","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8903-0593","authenticated-orcid":false,"given":"J\u00f6rg B.","family":"Schulz","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany"},{"name":"JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum J\u00fclich GmbH and RWTH Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7222-8686","authenticated-orcid":false,"given":"Michael","family":"Huber","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Molecular Immunology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5771-216X","authenticated-orcid":false,"given":"Pardes","family":"Habib","sequence":"additional","affiliation":[{"name":"Department of Neurology, Medical Faculty, RWTH Aachen University, 52074 Aachen, Germany"},{"name":"JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum J\u00fclich GmbH and RWTH Aachen University, 52074 Aachen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1136\/bmj.300.6727.763","article-title":"Pulmonary hypertension due to chronic hypoxia","volume":"300","author":"Peacock","year":"1990","journal-title":"BMJ Clin. 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