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CYB5R1 and Coenzyme Q Forge a Redox Relay to Mitigate Ferroptosis
CYB5R1 and Coenzyme Q Forge a Redox Relay to Mitigate Ferroptosis
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202103634
- ISBN
- 9798290992495
- DDC
- 615
- 서명/저자
- CYB5R1 and Coenzyme Q Forge a Redox Relay to Mitigate Ferroptosis
- 발행사항
- [Sl] : University of Pittsburgh, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 169 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-02, Section: B.
- 주기사항
- Advisor: Straub, Adam.
- 학위논문주기
- Thesis (Ph.D.)--University of Pittsburgh, 2025.
- 초록/해제
- 요약Reduction-oxidation (redox) switches dynamically regulate cell signaling by modulating substrate oxidation states needed to maintain organismal homeostasis. Here, we identify cytochrome b5 reductase 1 (CYB5R1) as a critical outer mitochondrial membrane enzyme in endothelial cells that functions as a CoQ-dependent redox cycler, uniquely conferring resistance to lipid peroxidation - an ability not shared by other CYB5R family members. Mechanistically, CYB5R1 facilitates CoQ redox cycling, mitigating lipid hydroperoxide accumulation and preventing iron-dependent cell death, known as ferroptosis. Conversely, disruption of CYB5R1- CoQ coupling promotes hydrogen peroxide generation, initiating a pro-ferroptotic cascade. In a murine model of atherosclerosis (AS), both global and endothelial cell-specific CYB5R1 knockout mice exhibited significantly increased atherosclerotic plaque burden compared to wild-type controls. Furthermore, through a rationally designed screening approach, we developed a novel quinone-nitroalkene hybrid that reduces atherosclerotic plaque burden in mice and enhanced redox coupling, conferring anti-ferroptotic activity by suppressing lipid peroxidation and upregulating CYB5R1 expression. These findings uncover a previously unrecognized CoQ-mediated redox mechanism by which CYB5R1 serves as a "redox rheostat" governing ferroptosis, offering mechanistic insights for therapeutic strategies targeting cardiovascular, cancer, neurodegenerative, renal, and hemoglobinopathy-associated diseases.
- 일반주제명
- Pharmacology
- 일반주제명
- Oncology
- 일반주제명
- Immunology
- 키워드
- Atherosclerosis
- 키워드
- Ferroptosis
- 키워드
- Redox
- 키워드
- Hemoglobinopathy
- 키워드
- Cancer
- 기타저자
- University of Pittsburgh Molecular Pharmacology
- 기본자료저록
- Dissertations Abstracts International. 87-02B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■006m o d
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■020 ▼a9798290992495
■035 ▼a(MiAaPQ)AAI32047410
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a615
■1001 ▼aHall, Robert Joseph.▼0(orcid)0000-0001-8564-8364
■24510▼aCYB5R1 and Coenzyme Q Forge a Redox Relay to Mitigate Ferroptosis
■260 ▼a[Sl]▼bUniversity of Pittsburgh▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a169 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-02, Section: B.
■500 ▼aAdvisor: Straub, Adam.
■5021 ▼aThesis (Ph.D.)--University of Pittsburgh, 2025.
■520 ▼aReduction-oxidation (redox) switches dynamically regulate cell signaling by modulating substrate oxidation states needed to maintain organismal homeostasis. Here, we identify cytochrome b5 reductase 1 (CYB5R1) as a critical outer mitochondrial membrane enzyme in endothelial cells that functions as a CoQ-dependent redox cycler, uniquely conferring resistance to lipid peroxidation - an ability not shared by other CYB5R family members. Mechanistically, CYB5R1 facilitates CoQ redox cycling, mitigating lipid hydroperoxide accumulation and preventing iron-dependent cell death, known as ferroptosis. Conversely, disruption of CYB5R1- CoQ coupling promotes hydrogen peroxide generation, initiating a pro-ferroptotic cascade. In a murine model of atherosclerosis (AS), both global and endothelial cell-specific CYB5R1 knockout mice exhibited significantly increased atherosclerotic plaque burden compared to wild-type controls. Furthermore, through a rationally designed screening approach, we developed a novel quinone-nitroalkene hybrid that reduces atherosclerotic plaque burden in mice and enhanced redox coupling, conferring anti-ferroptotic activity by suppressing lipid peroxidation and upregulating CYB5R1 expression. These findings uncover a previously unrecognized CoQ-mediated redox mechanism by which CYB5R1 serves as a "redox rheostat" governing ferroptosis, offering mechanistic insights for therapeutic strategies targeting cardiovascular, cancer, neurodegenerative, renal, and hemoglobinopathy-associated diseases.
■590 ▼aSchool code: 0178.
■650 4▼aPharmacology
■650 4▼aOncology
■650 4▼aImmunology
■653 ▼aAtherosclerosis
■653 ▼aFerroptosis
■653 ▼aRedox
■653 ▼aHemoglobinopathy
■653 ▼aCancer
■690 ▼a0419
■690 ▼a0992
■690 ▼a0982
■71020▼aUniversity of Pittsburgh▼bMolecular Pharmacology.
■7730 ▼tDissertations Abstracts International▼g87-02B.
■790 ▼a0178
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17358036▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
