Bioavailability and cytosolic kinases modulate response to deoxynucleoside therapy in TK2 deficiency.

ABSTRACT:

Background

TK2 is a nuclear gene encoding the mitochondrial matrix protein thymidine kinase 2 (TK2), a critical enzyme in the mitochondrial nucleotide salvage pathway. Deficiency of TK2 activity causes mitochondrial DNA (mtDNA) depletion, which in humans manifests predominantly as a mitochondrial myopathy with onset typically in infancy and childhood. We previously showed that oral treatment of the Tk2 H126N knock-in mouse model (Tk2^-/-) with the TK2 substrates, deoxycytidine (dCtd) and thymidine (dThd), delayed disease onset and prolonged median survival by 3-fold. Nevertheless, dCtd + dThd treated Tk2^-/- mice showed mtDNA depletion in brain as early as postnatal day 13 and in virtually all other tissues at age 29 days.

Methods

To enhance mechanistic u

SUBMITTER: Lopez-Gomez C 

PROVIDER: S-EPMC6710986 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature