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LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury
The brain undergoes oxidative stress and mitochondrial dysfunction following physiological insults such as Traumatic brain injury (TBI), ischemia-reperfusion, and stroke. Pharmacotherapeutics targeting mitochondria (mitoceuticals) against oxidative stress include antioxidants, mild uncouplers, and e...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10217498/ https://www.ncbi.nlm.nih.gov/pubmed/37408279 http://dx.doi.org/10.3390/cells12101445 |
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author | Velmurugan, Gopal V. Hubbard, W. Brad Prajapati, Paresh Vekaria, Hemendra J. Patel, Samir P. Rabchevsky, Alexander G. Sullivan, Patrick G. |
author_facet | Velmurugan, Gopal V. Hubbard, W. Brad Prajapati, Paresh Vekaria, Hemendra J. Patel, Samir P. Rabchevsky, Alexander G. Sullivan, Patrick G. |
author_sort | Velmurugan, Gopal V. |
collection | PubMed |
description | The brain undergoes oxidative stress and mitochondrial dysfunction following physiological insults such as Traumatic brain injury (TBI), ischemia-reperfusion, and stroke. Pharmacotherapeutics targeting mitochondria (mitoceuticals) against oxidative stress include antioxidants, mild uncouplers, and enhancers of mitochondrial biogenesis, which have been shown to improve pathophysiological outcomes after TBI. However, to date, there is no effective treatment for TBI. Studies have suggested that the deletion of LDL receptor-related protein 1 (LRP1) in adult neurons or glial cells could be beneficial and promote neuronal health. In this study, we used WT and LRP1 knockout (LKO) mouse embryonic fibroblast cells to examine mitochondrial outcomes following exogenous oxidative stress. Furthermore, we developed a novel technique to measure mitochondrial morphometric dynamics using transgenic mitochondrial reporter mice mtD2g (mitochondrial-specific Dendra2 green) in a TBI model. We found that oxidative stress increased the quantity of fragmented and spherical-shaped mitochondria in the injury core of the ipsilateral cortex following TBI, whereas rod-like elongated mitochondria were seen in the corresponding contralateral cortex. Critically, LRP1 deficiency significantly decreased mitochondrial fragmentation, preserving mitochondrial function and cell growth following exogenous oxidative stress. Collectively, our results show that targeting LRP1 to improve mitochondrial function is a potential pharmacotherapeutic strategy against oxidative damage in TBI and other neurodegenerative diseases. |
format | Online Article Text |
id | pubmed-10217498 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-102174982023-05-27 LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury Velmurugan, Gopal V. Hubbard, W. Brad Prajapati, Paresh Vekaria, Hemendra J. Patel, Samir P. Rabchevsky, Alexander G. Sullivan, Patrick G. Cells Article The brain undergoes oxidative stress and mitochondrial dysfunction following physiological insults such as Traumatic brain injury (TBI), ischemia-reperfusion, and stroke. Pharmacotherapeutics targeting mitochondria (mitoceuticals) against oxidative stress include antioxidants, mild uncouplers, and enhancers of mitochondrial biogenesis, which have been shown to improve pathophysiological outcomes after TBI. However, to date, there is no effective treatment for TBI. Studies have suggested that the deletion of LDL receptor-related protein 1 (LRP1) in adult neurons or glial cells could be beneficial and promote neuronal health. In this study, we used WT and LRP1 knockout (LKO) mouse embryonic fibroblast cells to examine mitochondrial outcomes following exogenous oxidative stress. Furthermore, we developed a novel technique to measure mitochondrial morphometric dynamics using transgenic mitochondrial reporter mice mtD2g (mitochondrial-specific Dendra2 green) in a TBI model. We found that oxidative stress increased the quantity of fragmented and spherical-shaped mitochondria in the injury core of the ipsilateral cortex following TBI, whereas rod-like elongated mitochondria were seen in the corresponding contralateral cortex. Critically, LRP1 deficiency significantly decreased mitochondrial fragmentation, preserving mitochondrial function and cell growth following exogenous oxidative stress. Collectively, our results show that targeting LRP1 to improve mitochondrial function is a potential pharmacotherapeutic strategy against oxidative damage in TBI and other neurodegenerative diseases. MDPI 2023-05-22 /pmc/articles/PMC10217498/ /pubmed/37408279 http://dx.doi.org/10.3390/cells12101445 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Velmurugan, Gopal V. Hubbard, W. Brad Prajapati, Paresh Vekaria, Hemendra J. Patel, Samir P. Rabchevsky, Alexander G. Sullivan, Patrick G. LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury |
title | LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury |
title_full | LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury |
title_fullStr | LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury |
title_full_unstemmed | LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury |
title_short | LRP1 Deficiency Promotes Mitostasis in Response to Oxidative Stress: Implications for Mitochondrial Targeting after Traumatic Brain Injury |
title_sort | lrp1 deficiency promotes mitostasis in response to oxidative stress: implications for mitochondrial targeting after traumatic brain injury |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10217498/ https://www.ncbi.nlm.nih.gov/pubmed/37408279 http://dx.doi.org/10.3390/cells12101445 |
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