PMID- 37983591 OWN - NLM STAT- MEDLINE DCOM- 20240127 LR - 20240127 IS - 2198-3844 (Electronic) IS - 2198-3844 (Linking) VI - 11 IP - 2 DP - 2024 Jan TI - Targeting the Mitochondrial Chaperone TRAP1 Alleviates Vascular Pathologies in Ischemic Retinopathy. PG - e2302776 LID - 10.1002/advs.202302776 [doi] LID - 2302776 AB - Activation of hypoxia-inducible factor 1alpha (HIF1alpha) contributes to blood-retinal barrier (BRB) breakdown and pathological neovascularization responsible for vision loss in ischemic retinal diseases. During disease progression, mitochondrial biology is altered to adapt to the ischemic environment created by initial vascular dysfunction, but the mitochondrial adaptive mechanisms, which ultimately contribute to the pathogenesis of ischemic retinopathy, remain incompletely understood. In the present study, it is identified that expression of mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) is essential for BRB breakdown and pathologic retinal neovascularization in mouse models mimicking ischemic retinopathies. Genetic Trap1 ablation or treatment with small molecule TRAP1 inhibitors, such as mitoquinone (MitoQ) and SB-U015, alleviate retinal pathologies via proteolytic HIF1alpha degradation, which is mediated by opening of the mitochondrial permeability transition pore and activation of calcium-dependent protease calpain-1. These findings suggest that TRAP1 can be a promising target for the development of new treatments against ischemic retinopathy, such as retinopathy of prematurity and proliferative diabetic retinopathy. CI - (c) 2023 The Authors. Advanced Science published by Wiley-VCH GmbH. FAU - Kim, So-Yeon AU - Kim SY AD - Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea. FAU - Yoon, Nam Gu AU - Yoon NG AD - Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea. FAU - Im, Jin Young AU - Im JY AD - SmartinBio Inc., Cheongju, 28160, Republic of Korea. FAU - Lee, Ji Hye AU - Lee JH AD - Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea. FAU - Kim, Juhee AU - Kim J AD - Department of Ophthalmology, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea. AD - Cell & Matrix Research Institute, Kyungpook National University, Daegu, 41944, Republic of Korea. FAU - Jeon, Yujin AU - Jeon Y AD - Department of Ophthalmology, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea. AD - Cell & Matrix Research Institute, Kyungpook National University, Daegu, 41944, Republic of Korea. FAU - Choi, Young Jae AU - Choi YJ AD - Bioanalysis and Pharmacokinetics Research Group, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea. FAU - Lee, Jong-Hwa AU - Lee JH AD - Bioanalysis and Pharmacokinetics Research Group, Korea Institute of Toxicology, Daejeon, 34114, Republic of Korea. AD - Department of Human and Environment Toxicology, University of Science & Technology, Daejeon, 34113, Republic of Korea. FAU - Uemura, Akiyoshi AU - Uemura A AD - Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601, Japan. FAU - Park, Dong Ho AU - Park DH AUID- ORCID: 0000-0001-6911-3765 AD - Department of Ophthalmology, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea. AD - Cell & Matrix Research Institute, Kyungpook National University, Daegu, 41944, Republic of Korea. FAU - Kang, Byoung Heon AU - Kang BH AUID- ORCID: 0000-0001-5902-0549 AD - Department of Biological Sciences, Ulsan National Institutes of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea. AD - SmartinBio Inc., Cheongju, 28160, Republic of Korea. LA - eng GR - 2022R1C1C2010406/National Research Foundation of Korea/ GR - 2019R1A2C1084371/National Research Foundation of Korea/ GR - 2019R1A2C2086618/National Research Foundation of Korea/ GR - 2018R1A5A1024340/National Research Foundation of Korea/ GR - 2019M3A9A8065669/National Research Foundation of Korea/ GR - 2022M3E5F2017408/National Research Foundation of Korea/ GR - RS-2021-DD120784(HN21C0923000021)/Korea Drug Development Fund/ GR - RS-2021-DD120712(HN21C0882)/Korea Drug Development Fund/ GR - HR22C1832/Ministry of Health and Welfare/ GR - IITP-2023-2020-0-01808/Institute for Information and communications Technology Promotion/ PT - Journal Article DEP - 20231120 PL - Germany TA - Adv Sci (Weinh) JT - Advanced science (Weinheim, Baden-Wurttemberg, Germany) JID - 101664569 RN - 0 (TRAP-1 protein, mouse) SB - IM MH - Animals MH - Mice MH - Blood-Retinal Barrier MH - *Diabetic Retinopathy/metabolism/pathology MH - Ischemia MH - Neovascularization, Pathologic/metabolism MH - Retina/pathology MH - *Retinal Diseases/metabolism/pathology MH - *Retinal Neovascularization/metabolism/pathology PMC - PMC10787068 OTO - NOTNLM OT - calcium OT - calpain-1 OT - hypoxia-inducible factor 1alpha (HIF1alpha) OT - ischemic retinopathy OT - mitochondrial permeability transition pore (mPTP) OT - tumor necrosis factor receptor-associated protein 1 (TRAP1) COIS- B.H.K. is the founder of SmartinBio. Inc. Other authors declare that they have no competing interests. EDAT- 2023/11/20 18:44 MHDA- 2024/01/15 12:42 PMCR- 2023/11/20 CRDT- 2023/11/20 16:03 PHST- 2023/10/06 00:00 [revised] PHST- 2023/05/02 00:00 [received] PHST- 2024/01/15 12:42 [medline] PHST- 2023/11/20 18:44 [pubmed] PHST- 2023/11/20 16:03 [entrez] PHST- 2023/11/20 00:00 [pmc-release] AID - ADVS6878 [pii] AID - 10.1002/advs.202302776 [doi] PST - ppublish SO - Adv Sci (Weinh). 2024 Jan;11(2):e2302776. doi: 10.1002/advs.202302776. Epub 2023 Nov 20.