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Roles of mitochondria morphodynamic changes in the DNA damage signaling and cellular stresses
- Alternative Title
- 미토콘드리아 형태 변화에 의한 DNA 손상신호 조절에 관한연구
- Author(s)
- NGUYEN THI KIM OANH
- Advisor
- Hyeseong Cho
- Department
- 일반대학원 의생명과학과
- Publisher
- The Graduate School, Ajou University
- Publication Year
- 2018-02
- Language
- eng
- Keyword
- DNA damage signaling; Mitochondria fission; Nuclear; JNK; Jun N-terminal Kinase; SIRT1; Sirtuin 1; ATM; ataxia-telangiectasia mutated
- Alternative Abstract
- Mitochondria are dynamic organelles essential for the life and death of the cells. The dynamic nature of mitochondria allows them to organize a network of organelles that dynamically fuse and divide. Mitochondrial morphology determined by the equilibrium betIen fusion and fission processes, is controlled by a family of “mitochondrial shaping” proteins, including hFis1, Drp1, Mfn1/2 and Opa1. In response to cellular stress, signaling cascades require tight coordination between the nucleus and mitochondria to adapt the ever-changing cellular milieu. Despite our increasing knowledge on the core components of the mitochondria-shaping machinery, knowledge regarding to the mitochondrial dynamics and nuclear communication signaling is still scare. Therefore, the aim of this research is to study the role of mitochondria morphodynamic changes in response to DNA damage and cellular stress. It was reported that ablation of mitochondria elongation by hFis1 inhibition (a mitochondria fission factor) triggered nuclear accumulation of γ-H2AX. This was accompanied with a significant reduction in cell cycle regulators that induced cellular senescence. In the first part of this study, I show how mitochondria dynamics communicate with nuclear genome in DNA damage response. Here, I found that mitochondria fragmentation induced by MFN1 depletion significantly decreased γ-H2AX accumulation under DNA damage whereas re-expression of MFN1 restored the γ-H2AX, suggesting that mitochondria dynamics affect DNA damage response signaling. Notably, targeted cytosolic irradiation using micro-irradiation laser promotes γ-H2AX accumulation in nucleus. Mechanistically, I found that the JNK activation was significantly reduced in MFN1 knockout cells and γ-H2AX accumulation can be mediated by JNK activation associated ATM phosphorylation under DNA damage response. Accordingly, mitochondrial fission induced by MFN1 depletion or hFis1 overexpression attenuates the homologous recombination and NHEJ of DNA repair mechanisms. In the second part of this research, the mitochondrial elongation mechanism under hypoxic condition was studied. I revealed that mitochondria elongation under hypoxic condition is regulated through SIRT1-mediated MFN1 deacetylation and accumulation. I further observed MFN1 as a direct target of SIRT1 and TIP60. MFN1 is hyper-acetylated by TIP60 and this modification promotes the degradation of MFN1 through a proteasome dependent pathway. Moreover, upon hypoxic condition, SIRT1 de-acetylates MFN1 and this de-acetylation modulates its stabilization. Thus, these findings provide a novel function of how mitonuclear communication safeguards cellular and organismal fitness and regulates lifespan.
- Fulltext
- Appears in Collections:
- Graduate School of Ajou University > Department of Biomedical Sciences > 4. Theses(Ph.D)
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