Defining the Role of TOP1MT in mtDNA Stability, Release, and Innate Immunity

Lena DuPont

Document Type

Article

Publication Date

8-9-2024

Keywords

JMG

Abstract

TOP1MT is a mitochondria-localized topoisomerase that is encoded in the nuclear genome. Cells and animals lacking TOP1MT are viable, but exhibit reduced mitochondrial DNA (mtDNA) copy number, increased mtDNA instability, and an enhanced susceptibility to mtDNA damaging agents like the chemotherapy drug Doxorubicin. Loss of TOP1MT has also been linked to the release of mtDNA from mitochondria into the cytoplasm, leading to activation of innate immune signaling1,2 . Our hypothesis was depletion of TOP1MT will result in an increased susceptibility to mtDNA instability, which will lead to the release of mtDNA into the cytosol and sensing via the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. Dox treatment was shown to induce the release of mitochondrial DNA into the cytoplast, due to the aggregation of nucleoids and changing mitochondrial network phenotype. Ifit3 levels were seen to be raised in Top1mt-/- mouse embryonic fibroblast (MEF) cells, but they showed no increased expression of ZBP1 when exposed to doxorubicin for 24 hours, whereas exposure to LPS heightened ZBP1 expression. In future studies this period should be extended to see if the effects of doxorubicin exposure on mtDNA damage and release into the cytoplasm could be seen.

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