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Reactive Oxygen Species Control Protein Degradation at the Mitochondrial Import Gate
Reactive Oxygen Species Control Protein Degradation at the Mitochondrial Import Gate
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202103548
- ISBN
- 9798288863479
- DDC
- 574
- 서명/저자
- Reactive Oxygen Species Control Protein Degradation at the Mitochondrial Import Gate
- 발행사항
- [Sl] : University of California, Berkeley, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 78 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-01, Section: B.
- 주기사항
- Advisor: Rape, Michael.
- 학위논문주기
- Thesis (Ph.D.)--University of California, Berkeley, 2025.
- 초록/해제
- 요약In addition to being key sites of biosynthesis and energy production, mitochondria perform important signaling roles in the cell. These include the control of caspase-dependent cell death through the release of cytochrome c, regulation of innate immunity, regulation of intracellular Ca2+ levels, and the control of stem cell differentiation. Given these diverse and critical functions, it is no surprise that mitochondrial dysfunction has been implicated in aging and a variety of different diseases including cancer, diabetes, and neurodegeneration. Thus, ensuring that mitochondrial activities are accurately regulated is essential to preserve cellular and organismal health.We recently identified a pathway that detects and alleviates persistent inactivity of the mitochondrial electron transport chain (ETC), a condition that depletes cells of physiological reactive oxygen species (ROS) molecules. In this reductive stress response, the E3 ligase, Cullin 2-FEM1 homolog B (CUL2FEM1B), reacts to a drop in ROS levels by ubiquitylating Folliculin Interacting Protein 1 (FNIP1) leading to its turnover by the proteasome. Targeting of FNIP1 by CUL2FEM1B stimulates oxidative phosphorylation, which in turn increases ROS production and corrects reductive stress. FEM1B, recognizes FNIP1 through a short degron that contains three Cys residues. During reductive stress, the Cys residues become reduced, allowing ubiquitylation of FNIP1 through CUL2FEM1B and effectively coupling reductive stress signaling to cellular ROS levels. However, the source of the ROS that serve as second messengers in reductive stress signaling as well as how this pathway modulates oxidative phosphorylation have been unclear.In this work, I show that the central enzyme of the reductive stress response, the ligase CUL2FEM1B, specifically acts at mitochondrial translocase of the outer membrane (TOM) complexes where it senses ROS produced by complex III of the electron transport chain (ETC). ROS depletion during times of low ETC activity triggers the localized degradation of CUL2FEM1B substrates, which sustains mitochondrial import and ensures the biogenesis of the rate-limiting ETC complex IV. As complex III yields most ROS when the ETC outpaces metabolic demands or oxygen availability, basal ROS are sentinels of mitochondrial activity that help cells adjust their ETC to changing environments, as required for cell differentiation and survival.
- 일반주제명
- Cellular biology
- 일반주제명
- Biochemistry
- 일반주제명
- Biology
- 키워드
- Mitochondria
- 키워드
- Tom complex
- 키워드
- Ubiquitin
- 기타저자
- University of California, Berkeley Molecular & Cell Biology
- 기본자료저록
- Dissertations Abstracts International. 87-01B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520260202103548
■006m o d
■007cr#unu||||||||
■020 ▼a9798288863479
■035 ▼a(MiAaPQ)AAI32041545
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aMcMinimy, Rachael Ackerman.
■24510▼aReactive Oxygen Species Control Protein Degradation at the Mitochondrial Import Gate
■260 ▼a[Sl]▼bUniversity of California, Berkeley▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a78 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-01, Section: B.
■500 ▼aAdvisor: Rape, Michael.
■5021 ▼aThesis (Ph.D.)--University of California, Berkeley, 2025.
■520 ▼aIn addition to being key sites of biosynthesis and energy production, mitochondria perform important signaling roles in the cell. These include the control of caspase-dependent cell death through the release of cytochrome c, regulation of innate immunity, regulation of intracellular Ca2+ levels, and the control of stem cell differentiation. Given these diverse and critical functions, it is no surprise that mitochondrial dysfunction has been implicated in aging and a variety of different diseases including cancer, diabetes, and neurodegeneration. Thus, ensuring that mitochondrial activities are accurately regulated is essential to preserve cellular and organismal health.We recently identified a pathway that detects and alleviates persistent inactivity of the mitochondrial electron transport chain (ETC), a condition that depletes cells of physiological reactive oxygen species (ROS) molecules. In this reductive stress response, the E3 ligase, Cullin 2-FEM1 homolog B (CUL2FEM1B), reacts to a drop in ROS levels by ubiquitylating Folliculin Interacting Protein 1 (FNIP1) leading to its turnover by the proteasome. Targeting of FNIP1 by CUL2FEM1B stimulates oxidative phosphorylation, which in turn increases ROS production and corrects reductive stress. FEM1B, recognizes FNIP1 through a short degron that contains three Cys residues. During reductive stress, the Cys residues become reduced, allowing ubiquitylation of FNIP1 through CUL2FEM1B and effectively coupling reductive stress signaling to cellular ROS levels. However, the source of the ROS that serve as second messengers in reductive stress signaling as well as how this pathway modulates oxidative phosphorylation have been unclear.In this work, I show that the central enzyme of the reductive stress response, the ligase CUL2FEM1B, specifically acts at mitochondrial translocase of the outer membrane (TOM) complexes where it senses ROS produced by complex III of the electron transport chain (ETC). ROS depletion during times of low ETC activity triggers the localized degradation of CUL2FEM1B substrates, which sustains mitochondrial import and ensures the biogenesis of the rate-limiting ETC complex IV. As complex III yields most ROS when the ETC outpaces metabolic demands or oxygen availability, basal ROS are sentinels of mitochondrial activity that help cells adjust their ETC to changing environments, as required for cell differentiation and survival.
■590 ▼aSchool code: 0028.
■650 4▼aCellular biology
■650 4▼aBiochemistry
■650 4▼aBiology
■653 ▼aCytochrome c oxidase
■653 ▼aMitochondria
■653 ▼aMitochondrial protein import
■653 ▼aTom complex
■653 ▼aUbiquitin
■690 ▼a0379
■690 ▼a0487
■690 ▼a0306
■71020▼aUniversity of California, Berkeley▼bMolecular & Cell Biology.
■7730 ▼tDissertations Abstracts International▼g87-01B.
■790 ▼a0028
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17357699▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
