NRF2 Alters Mitochondrial Gene Expression in Neonate Mice Exposed to Hyperoxia
Approximately 1 in 10 newborns are born preterm and require supplemental oxygen (O<sub>2</sub>) in an extrauterine environment following birth. Supplemental O<sub>2</sub> can induce oxidative stress that can impair mitochondrial function, resulting in lung injury and increase...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-04-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/11/4/760 |
| _version_ | 1797437076423049216 |
|---|---|
| author | Heather L. Vellers Hye-Youn Cho Wesley Gladwell Kevin Gerrish Janine H. Santos Gaston Ofman Laura Miller-DeGraff T. Beth Mahler Steven R. Kleeberger |
| author_facet | Heather L. Vellers Hye-Youn Cho Wesley Gladwell Kevin Gerrish Janine H. Santos Gaston Ofman Laura Miller-DeGraff T. Beth Mahler Steven R. Kleeberger |
| author_sort | Heather L. Vellers |
| collection | DOAJ |
| description | Approximately 1 in 10 newborns are born preterm and require supplemental oxygen (O<sub>2</sub>) in an extrauterine environment following birth. Supplemental O<sub>2</sub> can induce oxidative stress that can impair mitochondrial function, resulting in lung injury and increased risk in early life pulmonary diseases. The nuclear factor-erythroid 2 related factor 2 (NRF2) protects the cells from oxidative stress by regulating the expression of genes containing antioxidant response elements and many mitochondrial-associated genes. In this study, we compared <i>Nrf2</i>-deficient (<i>Nrf2<sup>−/−</sup></i>) and wild-type (<i>Nrf2<sup>+/+</sup></i>) mice to define the role of NRF2 in lung mitochondrial genomic features in late embryonic development in mice (embryonic days, E13.5 and E18.5) versus birth (postnatal day 0, PND0). We also determined whether NRF2 protects lung mitochondrial genome parameters in postnatal mice exposed to a 72 h hyperoxia environment. We found <i>Nrf2<sup>−/−</sup></i> embryonic lungs were characterized by decreases in mtDNA copies from E13.5 to E18.5. Interestingly, <i>Nrf2<sup>−/−</sup></i> heteroplasmy frequency was significantly higher than <i>Nrf2<sup>+/+</sup></i> at E18.5, though this effect reversed at PND0. In postnatal mice exposed to hyperoxia, we identified three- to four-fold increases in mitochondria-encoded mitochondrial genes, which regulate oxidative phosphorylation. Overall, our findings demonstrate a potentially critical role of NRF2 in mediating long-term effects of hyperoxia on mitochondrial function. |
| first_indexed | 2024-03-09T11:13:47Z |
| format | Article |
| id | doaj.art-37b95ba35a3d4e7dad2fc02c2e9396ef |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T11:13:47Z |
| publishDate | 2022-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-37b95ba35a3d4e7dad2fc02c2e9396ef2023-12-01T00:36:27ZengMDPI AGAntioxidants2076-39212022-04-0111476010.3390/antiox11040760NRF2 Alters Mitochondrial Gene Expression in Neonate Mice Exposed to HyperoxiaHeather L. Vellers0Hye-Youn Cho1Wesley Gladwell2Kevin Gerrish3Janine H. Santos4Gaston Ofman5Laura Miller-DeGraff6T. Beth Mahler7Steven R. Kleeberger8Health and Exercise Science Department, University of Oklahoma, Norman, OK 73019, USAImmunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USAMolecular Genomics Core Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USAMolecular Genomics Core Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USADivision of the National Toxicology Program, Mechanistic Toxicology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USADepartment of Pediatrics, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USAImmunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USADivision of the National Toxicology Program, Comparative and Molecular Pathogenesis Branch, Research Triangle Park, NC 27709, USAImmunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USAApproximately 1 in 10 newborns are born preterm and require supplemental oxygen (O<sub>2</sub>) in an extrauterine environment following birth. Supplemental O<sub>2</sub> can induce oxidative stress that can impair mitochondrial function, resulting in lung injury and increased risk in early life pulmonary diseases. The nuclear factor-erythroid 2 related factor 2 (NRF2) protects the cells from oxidative stress by regulating the expression of genes containing antioxidant response elements and many mitochondrial-associated genes. In this study, we compared <i>Nrf2</i>-deficient (<i>Nrf2<sup>−/−</sup></i>) and wild-type (<i>Nrf2<sup>+/+</sup></i>) mice to define the role of NRF2 in lung mitochondrial genomic features in late embryonic development in mice (embryonic days, E13.5 and E18.5) versus birth (postnatal day 0, PND0). We also determined whether NRF2 protects lung mitochondrial genome parameters in postnatal mice exposed to a 72 h hyperoxia environment. We found <i>Nrf2<sup>−/−</sup></i> embryonic lungs were characterized by decreases in mtDNA copies from E13.5 to E18.5. Interestingly, <i>Nrf2<sup>−/−</sup></i> heteroplasmy frequency was significantly higher than <i>Nrf2<sup>+/+</sup></i> at E18.5, though this effect reversed at PND0. In postnatal mice exposed to hyperoxia, we identified three- to four-fold increases in mitochondria-encoded mitochondrial genes, which regulate oxidative phosphorylation. Overall, our findings demonstrate a potentially critical role of NRF2 in mediating long-term effects of hyperoxia on mitochondrial function.https://www.mdpi.com/2076-3921/11/4/760mitochondrial sequencingmtDNA copy numberheteroplasmymitochondrial functionNRF2DNA lesions |
| spellingShingle | Heather L. Vellers Hye-Youn Cho Wesley Gladwell Kevin Gerrish Janine H. Santos Gaston Ofman Laura Miller-DeGraff T. Beth Mahler Steven R. Kleeberger NRF2 Alters Mitochondrial Gene Expression in Neonate Mice Exposed to Hyperoxia Antioxidants mitochondrial sequencing mtDNA copy number heteroplasmy mitochondrial function NRF2 DNA lesions |
| title | NRF2 Alters Mitochondrial Gene Expression in Neonate Mice Exposed to Hyperoxia |
| title_full | NRF2 Alters Mitochondrial Gene Expression in Neonate Mice Exposed to Hyperoxia |
| title_fullStr | NRF2 Alters Mitochondrial Gene Expression in Neonate Mice Exposed to Hyperoxia |
| title_full_unstemmed | NRF2 Alters Mitochondrial Gene Expression in Neonate Mice Exposed to Hyperoxia |
| title_short | NRF2 Alters Mitochondrial Gene Expression in Neonate Mice Exposed to Hyperoxia |
| title_sort | nrf2 alters mitochondrial gene expression in neonate mice exposed to hyperoxia |
| topic | mitochondrial sequencing mtDNA copy number heteroplasmy mitochondrial function NRF2 DNA lesions |
| url | https://www.mdpi.com/2076-3921/11/4/760 |
| work_keys_str_mv | AT heatherlvellers nrf2altersmitochondrialgeneexpressioninneonatemiceexposedtohyperoxia AT hyeyouncho nrf2altersmitochondrialgeneexpressioninneonatemiceexposedtohyperoxia AT wesleygladwell nrf2altersmitochondrialgeneexpressioninneonatemiceexposedtohyperoxia AT kevingerrish nrf2altersmitochondrialgeneexpressioninneonatemiceexposedtohyperoxia AT janinehsantos nrf2altersmitochondrialgeneexpressioninneonatemiceexposedtohyperoxia AT gastonofman nrf2altersmitochondrialgeneexpressioninneonatemiceexposedtohyperoxia AT lauramillerdegraff nrf2altersmitochondrialgeneexpressioninneonatemiceexposedtohyperoxia AT tbethmahler nrf2altersmitochondrialgeneexpressioninneonatemiceexposedtohyperoxia AT stevenrkleeberger nrf2altersmitochondrialgeneexpressioninneonatemiceexposedtohyperoxia |