Ghosh, ArijitArijitGhoshBhattacharjee, SangheetaSangheetaBhattacharjeeChowdhuri, Srijita PaulSrijita PaulChowdhuriMallick, AbhikAbhikMallickRehman, IshitaIshitaRehmanBasu, SudiptaSudiptaBasuDas, Benu BrataBenu BrataDas2025-08-312025-08-312019-11-0610.1126/sciadv.aax97782-s2.0-85074656653https://d8.irins.org/handle/IITG2025/2314231723605A 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^H493R) are selectively trapped on mtDNA in the regulatory non-coding region and promoter sequences. Trapped TDP1^H493R-mtDNA complexes were markedly increased in the presence of the Top1 poison (mito-SN38) when targeted selectively into mitochondria in nanoparticles. TDP1^H493R-trapping accumulates mtDNA damage and triggers Drp1-mediated mitochondrial fission, which blocks mitobiogenesis. TDP1^H493R 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.trueArticlehttps://advances.sciencemag.org/content/advances/5/11/eaax9778.full.pdf237525486 November 201952eaax9778arJournal54WOS:000499736100084