Lower mitochondrial DNA copy number in ATTRV50M Swedish carriers

Abstract Background Hereditary transthyretin (TTR) amyloidosis caused by TTR p.Val50Met (ATTRV50M) is a progressive systemic disease caused by misfolding of the protein transthyretin (TTR). The conversion of TTR into an amyloidogenic state has recently been found to be strongly influenced by a non-native disulfide bond, thus also a redox environment. Variation in mitochondrial DNA (mtDNA) copy number serves as an indirect marker of redox imbalance and mitochondrial dysfunction. MtDNA is moreover strictly maternally inherited, supporting previous findings where maternal inheritance of the pathogenic variant also results in both a more severe disease and an earlier onset. Considering these aspects, we aimed to investigate mtDNA levels in Swedish TTRp.Val50Met carriers. Methods 304 individuals were divided into three groups: symptomatic and asymptomatic TTR p.Val50Met carriers, and healthy non-carrier controls. Relative mtDNA copy number was quantified from buffy coat samples using multiplex qPCR. Results Symptomatic TTR p.Val50Met carriers showed a significantly lower copy number ( p = 0.002) compared to the asymptomatic carriers. When stratified by sex, a significantly lower mtDNA copy number in symptomatic compared to asymptomatic carriers was observed only among males ( p = 0.028). Furthermore, a significant difference in copy number (< 0.001) could be demonstrated in ≥ 50 year-olds (considered late onset in Swedish ATTRV50M population) betweensymptomatic and asymptomatic TTR p.Val50Met carriers, which could not be seen in < 50 year-olds (Swedish early onset). Conclusion These findings indicate an association between lower mtDNA copy numbers and symptomatic disease in Swedish TTR p.Val50Met carriers, suggesting potential mitochondrial involvement in disease progression.