Laboratory of Molecular Biology, School of Biological Sciences, Indian Association for the Cultivation of Science, 2A & B, Raja S. C. Mullick Road, Jadavpur, Kolkata 700032, India.
Department of Chemistry, Indian Institute of Science Education and Research (IISER) Pune, Dr. Homi Bhabha Road, Pashan, Pune, Maharashtra 411008, India.
Sci Adv. 2019 Nov 6;5(11):eaax9778. doi: 10.1126/sciadv.aax9778. eCollection 2019 Nov.
A homozygous mutation of human tyrosyl-DNA phosphodiesterase 1 (TDP1) causes the neurodegenerative syndrome, spinocerebellar ataxia with axonal neuropathy (SCAN1). TDP1 hydrolyzes the phosphodiester bond between DNA 3'-end and a tyrosyl moiety within trapped topoisomerase I (Top1)-DNA covalent complexes (Top1cc). TDP1 is critical for mitochondrial DNA (mtDNA) repair; however, the role of mitochondria remains largely unknown for the etiology of SCAN1. We demonstrate that mitochondria in cells expressing SCAN1-TDP1 (TDP1) are selectively trapped on mtDNA in the regulatory non-coding region and promoter sequences. Trapped TDP1-mtDNA complexes were markedly increased in the presence of the Top1 poison (mito-SN38) when targeted selectively into mitochondria in nanoparticles. TDP1-trapping accumulates mtDNA damage and triggers Drp1-mediated mitochondrial fission, which blocks mitobiogenesis. TDP1 prompts PTEN-induced kinase 1-dependent mitophagy to eliminate dysfunctional mitochondria. SCAN1-TDP1 in mitochondria creates a pathological state that allows neurons to turn on mitophagy to rescue fit mitochondria as a mechanism of survival.
人类酪氨酰 DNA 磷酸二酯酶 1（TDP1）的纯合突变导致神经退行性疾病，脊髓小脑共济失调伴轴索性神经病（SCAN1）。TDP1 水解 DNA 3'端和拓扑异构酶 I（Top1）-DNA 共价复合物（Top1cc）内的酪氨酸部分之间的磷酸二酯键。TDP1 对线粒体 DNA（mtDNA）修复至关重要；然而，线粒体在 SCAN1 病因学中的作用在很大程度上仍然未知。我们证明，表达 SCAN1-TDP1（TDP1）的细胞中的线粒体在线粒体调控非编码区和启动子序列中的 mtDNA 上被选择性捕获。当在纳米颗粒中选择性靶向线粒体时，存在 Top1 毒药（mito-SN38）时，被捕获的 TDP1-mtDNA 复合物显着增加。TDP1 捕获会积累 mtDNA 损伤并引发 Drp1 介导的线粒体裂变，从而阻止线粒体生物发生。TDP1 促使 PTEN 诱导的激酶 1 依赖性线粒体自噬以消除功能失调的线粒体。线粒体中的 SCAN1-TDP1 造成一种病理状态，使神经元能够开启线粒体自噬以挽救适合的线粒体作为生存机制。
