Inhibition of mitoNEET attenuates LPS-induced inflammation and oxidative stress
Abstract MitoNEET (mitochondrial protein containing Asn–Glu–Glu–Thr (NEET) sequence) is a 2Fe–2S cluster-containing integral membrane protein that resides in the mitochondrial outer membrane and participates in a redox-sensitive signaling and Fe–S cluster transfer. Thus, mitoNEET is a key regulator...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-022-04586-2 |
| _version_ | 1818973795668459520 |
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| author | Seunghee Lee Byeong Geun Seok Seon-Jin Lee Su Wol Chung |
| author_facet | Seunghee Lee Byeong Geun Seok Seon-Jin Lee Su Wol Chung |
| author_sort | Seunghee Lee |
| collection | DOAJ |
| description | Abstract MitoNEET (mitochondrial protein containing Asn–Glu–Glu–Thr (NEET) sequence) is a 2Fe–2S cluster-containing integral membrane protein that resides in the mitochondrial outer membrane and participates in a redox-sensitive signaling and Fe–S cluster transfer. Thus, mitoNEET is a key regulator of mitochondrial oxidative capacity and iron homeostasis. Moreover, mitochondrial dysfunction and oxidative stress play critical roles in inflammatory diseases such as sepsis. Increased iron levels mediated by mitochondrial dysfunction lead to oxidative damage and generation of reactive oxygen species (ROS). Increasing evidence suggests that targeting mitoNEET to reverse mitochondrial dysfunction deserves further investigation. However, the role of mitoNEET in inflammatory diseases is unknown. Here, we investigated the mechanism of action and function of mitoNEET during lipopolysaccharide (LPS)-induced inflammatory responses in vitro and in vivo. Levels of mitoNEET protein increased during microbial or LPS-induced sepsis. Pharmacological inhibition of mitoNEET using mitoNEET ligand-1 (NL-1) decreased the levels of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in animal models of sepsis, as well as LPS-induced inflammatory responses by macrophages in vitro. Inhibition of mitoNEET using NL-1 or mitoNEET shRNA abrogated LPS-induced ROS formation and mitochondrial dysfunction. Furthermore, mitochondrial iron accumulation led to generation of LPS-induced ROS, a process blocked by NL-1 or shRNA. Taken together, these data suggest that mitoNEET could be a key therapeutic molecule that targets mitochondrial dysfunction during inflammatory diseases and sepsis. |
| first_indexed | 2024-12-20T15:29:51Z |
| format | Article |
| id | doaj.art-a2d997ce9e574d8d9487af57a93e99b5 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-20T15:29:51Z |
| publishDate | 2022-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-a2d997ce9e574d8d9487af57a93e99b52022-12-21T19:35:39ZengNature Publishing GroupCell Death and Disease2041-48892022-02-011321910.1038/s41419-022-04586-2Inhibition of mitoNEET attenuates LPS-induced inflammation and oxidative stressSeunghee Lee0Byeong Geun Seok1Seon-Jin Lee2Su Wol Chung3School of Biological Sciences, College of Natural Sciences, University of Ulsan, 93 Daehak-ro, Nam-guSchool of Biological Sciences, College of Natural Sciences, University of Ulsan, 93 Daehak-ro, Nam-guGenome Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong-guSchool of Biological Sciences, College of Natural Sciences, University of Ulsan, 93 Daehak-ro, Nam-guAbstract MitoNEET (mitochondrial protein containing Asn–Glu–Glu–Thr (NEET) sequence) is a 2Fe–2S cluster-containing integral membrane protein that resides in the mitochondrial outer membrane and participates in a redox-sensitive signaling and Fe–S cluster transfer. Thus, mitoNEET is a key regulator of mitochondrial oxidative capacity and iron homeostasis. Moreover, mitochondrial dysfunction and oxidative stress play critical roles in inflammatory diseases such as sepsis. Increased iron levels mediated by mitochondrial dysfunction lead to oxidative damage and generation of reactive oxygen species (ROS). Increasing evidence suggests that targeting mitoNEET to reverse mitochondrial dysfunction deserves further investigation. However, the role of mitoNEET in inflammatory diseases is unknown. Here, we investigated the mechanism of action and function of mitoNEET during lipopolysaccharide (LPS)-induced inflammatory responses in vitro and in vivo. Levels of mitoNEET protein increased during microbial or LPS-induced sepsis. Pharmacological inhibition of mitoNEET using mitoNEET ligand-1 (NL-1) decreased the levels of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α in animal models of sepsis, as well as LPS-induced inflammatory responses by macrophages in vitro. Inhibition of mitoNEET using NL-1 or mitoNEET shRNA abrogated LPS-induced ROS formation and mitochondrial dysfunction. Furthermore, mitochondrial iron accumulation led to generation of LPS-induced ROS, a process blocked by NL-1 or shRNA. Taken together, these data suggest that mitoNEET could be a key therapeutic molecule that targets mitochondrial dysfunction during inflammatory diseases and sepsis.https://doi.org/10.1038/s41419-022-04586-2 |
| spellingShingle | Seunghee Lee Byeong Geun Seok Seon-Jin Lee Su Wol Chung Inhibition of mitoNEET attenuates LPS-induced inflammation and oxidative stress Cell Death and Disease |
| title | Inhibition of mitoNEET attenuates LPS-induced inflammation and oxidative stress |
| title_full | Inhibition of mitoNEET attenuates LPS-induced inflammation and oxidative stress |
| title_fullStr | Inhibition of mitoNEET attenuates LPS-induced inflammation and oxidative stress |
| title_full_unstemmed | Inhibition of mitoNEET attenuates LPS-induced inflammation and oxidative stress |
| title_short | Inhibition of mitoNEET attenuates LPS-induced inflammation and oxidative stress |
| title_sort | inhibition of mitoneet attenuates lps induced inflammation and oxidative stress |
| url | https://doi.org/10.1038/s41419-022-04586-2 |
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