Mori 2023 J Biol Chem
| Mori MP, Penjweini R, Ma J, Alspaugh G, Andreoni A, Kim YC, Wang PY, Knutson JR, Hwang PM (2023) Mitochondrial respiration reduces exposure of the nucleus to oxygen. J Biol Chem 299:103018. https://doi.org/10.1016/j.jbc.2023.103018 |
Mori MP, Penjweini R, Ma J, Alspaugh G, Andreoni A, Kim YC, Wang PY, Knutson JR, Hwang PM (2023) J Biol Chem
Abstract: 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.
• Bioblast editor: Gnaiger E
Labels: MiParea: Respiration, mt-Biogenesis;mt-density, nDNA;cell genetics
Stress:Hypoxia
Regulation: Oxygen kinetics
