Mitochondrial respiration reduces exposure of the nucleus to oxygen.
Mitochondrial respiration reduces exposure of the nucleus to oxygen.
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DOI：
10.1016/j.jbc.2023.103018
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发表时间：
2023-03
影响因子：
4.8
通讯作者：
Hwang, Paul M.
中科院分区：
文献类型：
--
作者：
Mori, Mateus Prates;Penjweini, Rozhin;Ma, Jin;Alspaugh, Greg;Andreoni, Alessio;Kim, Young-Chae;Wang, Ping-yuan;Knutson, Jay R.;Hwang, Paul M.
内共生理论认为，古代真核细胞吞没了消耗O2的原核生物，从而保护它们免受O2毒性的侵害。先前的研究表明，缺乏呼吸所需的细胞色素c氧化酶（COX）的细胞会增加DNA损伤并减少增殖，这可以通过减少氧气暴露来改善。最近开发的基于荧光寿命显微镜的探针显示，线粒体的[O2]含量低于细胞质，我们假设细胞中线粒体的核周分布可能为O2进入细胞核制造了屏障，可能影响细胞生理和维持基因组完整性。为了验证这一假设，我们使用了myogloin - mcherry荧光寿命显微镜O2传感器，没有亚细胞靶向（“细胞质”）或靶向线粒体或细胞核，以测量其局部O2稳态。我们的研究结果表明，与线粒体类似，在施加的O2水平为~ 0.5至18.6%时，核[O2]与细胞质相比减少了~ 20%至40%。药理学上抑制呼吸增加了核氧水平，而通过COX重建氧消耗逆转了这种增加。同样，通过删除对COX组装至关重要的SCO2基因来破坏呼吸，或通过用SCO2 cDNA转导SCO2 - / -细胞恢复COX活性来复制核氧水平的这些变化。已知受细胞氧可用性影响的基因表达进一步支持了这一结果。我们的研究揭示了线粒体呼吸活动对核氧水平的动态调节的潜力，这反过来可能影响氧化应激和细胞过程，如神经变性和衰老。
The endosymbiotic theory posits that ancient eukaryotic cells engulfed O2-consuming prokaryotes, which protected them against O2 toxicity. Previous studies have shown that cells lacking cytochrome c oxidase (COX), required for respiration, have increased DNA damage and reduced proliferation, which could be improved by reducing O2 exposure. With recently developed fluorescence lifetime microscopy–based probes demonstrating that the mitochondrion has lower [O2] than the cytosol, we hypothesized that the perinuclear distribution of mitochondria in cells may create a barrier for O2 to access the nuclear core, potentially affecting cellular physiology and maintaining genomic integrity. To test this hypothesis, we utilized myoglobin-mCherry fluorescence lifetime microscopy O2 sensors without subcellular targeting (“cytosol”) or with targeting to the mitochondrion or nucleus for measuring their localized O2 homeostasis. Our results showed that, similar to the mitochondria, the nuclear [O2] was reduced by ∼20 to 40% compared with the cytosol under imposed O2 levels of ∼0.5 to 18.6%. Pharmacologically inhibiting respiration increased nuclear O2 levels, and reconstituting O2 consumption by COX reversed this increase. Similarly, genetic disruption of respiration by deleting SCO2, a gene essential for COX assembly, or restoring COX activity in SCO2−/− cells by transducing with SCO2 cDNA replicated these changes in nuclear O2 levels. The results were further supported by the expression of genes known to be affected by cellular O2 availability. Our study reveals the potential for dynamic regulation of nuclear O2 levels by mitochondrial respiratory activity, which in turn could affect oxidative stress and cellular processes such as neurodegeneration and aging.
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影响因子：
14.9
作者：
Lee S;Lee J;Chae S;Moon Y;Lee HY;Park B;Yang EG;Hwang D;Park H
通讯作者：
Park H
影响因子：
8
作者：
Dmitriev, Ruslan I.;Papkovsky, Dmitri B.
通讯作者：
Papkovsky, Dmitri B.
影响因子：
5.5
作者：
Mirabello V;Cortezon-Tamarit F;Pascu SI
通讯作者：
Pascu SI
DOI：
10.1073/pnas.1621511114
发表时间：
2017-05-23
影响因子：
11.1
作者：
Ferrari, Michele;Jain, Isha H.;Zapol, Warren M.
通讯作者：
Zapol, Warren M.
影响因子：
56.9
作者：
Chakraborty, Abhishek A.;Laukka, Tuomas;Kaelin, William G., Jr.
通讯作者：
Kaelin, William G., Jr.