Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland, Australia.
Harry Perkins Institute of Medical Research, QEII Medical Centre, The University of Western Australia, Nedlands, Western Australia, Australia.
Nat Cell Biol. 2023 Aug;25(8):1111-1120. doi: 10.1038/s41556-023-01192-y. Epub 2023 Jul 17.
The ability to balance conflicting functional demands is critical for ensuring organismal survival. The transcription and repair of the mitochondrial genome (mtDNA) requires separate enzymatic activities that can sterically compete, suggesting a life-long trade-off between these two processes. Here in Caenorhabditis elegans, we find that the bZIP transcription factor ATFS-1/Atf5 (refs. ) regulates this balance in favour of mtDNA repair by localizing to mitochondria and interfering with the assembly of the mitochondrial pre-initiation transcription complex between HMG-5/TFAM and RPOM-1/mtRNAP. ATFS-1-mediated transcriptional inhibition decreases age-dependent mtDNA molecular damage through the DNA glycosylase NTH-1/NTH1, as well as the helicase TWNK-1/TWNK, resulting in an enhancement in the functional longevity of cells and protection against decline in animal behaviour caused by targeted and severe mtDNA damage. Together, our findings reveal that ATFS-1 acts as a molecular focal point for the control of balance between genome expression and maintenance in the mitochondria.
平衡相互冲突的功能需求的能力对于确保生物体的生存至关重要。线粒体基因组 (mtDNA) 的转录和修复需要分离的酶活性，这些活性可能会在空间上竞争，这表明这两个过程之间存在终身的权衡。在这里，我们在秀丽隐杆线虫中发现，bZIP 转录因子 ATFS-1/Atf5（参考文献）通过定位于线粒体并干扰 HMG-5/TFAM 和 RPOM-1/mtRNAP 之间的线粒体起始转录复合物的组装，来调节这种平衡，有利于 mtDNA 修复。ATFS-1 介导的转录抑制通过 DNA 糖苷酶 NTH-1/NTH1 以及解旋酶 TWNK-1/TWNK 降低年龄相关的 mtDNA 分子损伤，从而增强细胞的功能寿命，并防止因靶向和严重的 mtDNA 损伤导致动物行为下降。总之，我们的研究结果表明，ATFS-1 作为控制线粒体中基因组表达和维持平衡的分子焦点。
