SCAN1-TDP1 trapping on mitochondrial DNA promotes mitochondrial dysfunction and mitophagy

Area of Science:

• Molecular Biology
• Neurogenetics
• Mitochondrial Biology

Background:

• Spinocerebellar ataxia with axonal neuropathy (SCAN1) is a neurodegenerative disorder caused by mutations in the tyrosyl-DNA phosphodiesterase 1 (TDP1) gene.
• TDP1's role in repairing topoisomerase I-DNA covalent complexes is crucial, but its specific involvement in mitochondrial DNA (mtDNA) repair and SCAN1 pathogenesis is unclear.

Purpose of the Study:

• To investigate the role of mitochondria in SCAN1 pathogenesis.
• To elucidate the mechanism by which mutant TDP1 (TDP1 H493R) affects mtDNA and mitochondrial function in SCAN1.

Main Methods:

• Cellular models expressing SCAN1-associated TDP1 mutation (TDP1 H493R).
• Analysis of TDP1-mtDNA interactions and mitochondrial damage.
• Investigation of mitochondrial dynamics (fission/fusion) and mitophagy induction.
• Use of nanoparticles to deliver Top1 poison (mito-SN38) into mitochondria.

Main Results:

• Mutant TDP1 (TDP1 H493R) selectively binds to mtDNA in regulatory regions.
• This binding is exacerbated by Top1 poisons, leading to accumulated mtDNA damage.
• TDP1 H493R-induced mtDNA damage triggers Drp1-mediated mitochondrial fission and blocks mitobiogenesis.
• The cell initiates PTEN-induced kinase 1 (PINK1)-dependent mitophagy to remove damaged mitochondria.

Conclusions:

• Mitochondrial dysfunction, characterized by TDP1 H493R-mtDNA trapping and subsequent mitophagy, is central to SCAN1 pathogenesis.
• Neurons utilize mitophagy as a survival mechanism to eliminate dysfunctional mitochondria, preserving fit ones.
• Understanding this mechanism offers potential therapeutic targets for SCAN1 and related neurodegenerative diseases.