Twinkle (encoded by the [TWNK gene](/genes/twnk), also known as PEO1/C10orf2) is the mitochondrial replicative helicase essential for mitochondrial DNA (mtDNA) replication. Mutations cause progressive external ophthalmoplegia (PEO) and other mitochondrial disorders with significant neurological involvement.
Overview
Twinkle is a 684-amino acid ring-shaped hexameric helicase that unwinds the mitochondrial DNA double helix during replication<sup>[1]</sup>. It is the only replicative DNA helicase in mitochondria and works in concert with [DNA polymerase γ (POLG)](/genes/polg) and mitochondrial single-stranded DNA-binding protein (mtSSB) in the mitochondrial replisome<sup>[2]</sup>. Mutations in TWNK cause autosomal dominant progressive external ophthalmoplegia (adPEO), infantile-onset spinocerebellar ataxia (IOSCA), and mtDNA depletion syndromes, all featuring prominent neurodegeneration<sup>[3]</sup>. [@korhonen2004]
Twinkle (encoded by the [TWNK gene](/genes/twnk), also known as PEO1/C10orf2) is the mitochondrial replicative helicase essential for mitochondrial DNA (mtDNA) replication. Mutations cause progressive external ophthalmoplegia (PEO) and other mitochondrial disorders with significant neurological involvement.
Overview
Twinkle is a 684-amino acid ring-shaped hexameric helicase that unwinds the mitochondrial DNA double helix during replication<sup>[1]</sup>. It is the only replicative DNA helicase in mitochondria and works in concert with [DNA polymerase γ (POLG)](/genes/polg) and mitochondrial single-stranded DNA-binding protein (mtSSB) in the mitochondrial replisome<sup>[2]</sup>. Mutations in TWNK cause autosomal dominant progressive external ophthalmoplegia (adPEO), infantile-onset spinocerebellar ataxia (IOSCA), and mtDNA depletion syndromes, all featuring prominent neurodegeneration<sup>[3]</sup>. [@korhonen2004]
Connection to aging: mtDNA deletions accumulate with normal aging in [substantia nigra](/brain-regions/substantia-nigra) neurons — Twinkle mutations accelerate this process
[Spelbrink JN et al., Human mitochondrial DNA deletions associated with mutations in the gene encoding Twinkle, a phage T7 gene 4-like protein localized in mitochondria (2001) (2001)](https://doi.org/10.1038/ng0701-223)
[Korhonen JA et al., Reconstitution of a minimal mtDNA replisome in vitro (2004) (2004)](https://doi.org/10.1093/emboj/cdg438)
[Unknown, Suomalainen A & Isohanni P, Mitochondrial DNA depletion syndromes — many genes, common mechanisms (2010) (2010)](https://doi.org/10.1016/j.nmd.2009.11.007)
[Nikali K et al., Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky (2005) (2005)](https://doi.org/10.1093/hmg/ddi328)
[Bender A et al., High levels of mitochondrial DNA deletions in substantia nigra neurons in aging and Parkinson disease (2006) (2006)](https://doi.org/10.1038/ng1769)