Frontotemporal lobar degeneration (FTLD) is a common cause of young onset dementia and is characterised by focal neuropathology. The reasons for the regional neuronal vulnerability are not known. Mitochondrial mechanisms have been implicated in the pathogenesis of FTLD, raising the possibility that frontotemporal regional mutations of mitochondrial DNA (mtDNA) are contributory causes. Here we applied dual sequencing of the entire mtDNA at high depth to identify high-fidelity single nucleotide variants (mtSNVs) and mtDNA rearrangements in post mortem brain tissue of people affected by FTLD and age-matched controls. Both mtSNVs and mtDNA rearrangements were elevated in the temporal lobe, with the greatest burden seen in FTLD. mtSNVs found in multiple brain regions also reached a higher heteroplasmy levels in the temporal lobe. The temporal lobe of people with FTLD had a higher burden of ribosomal gene variants predicted to affect intra-mitochondrial protein synthesis, and a higher proportion of missense variants in genes coding for respiratory chain subunits. In conclusion, heteroplasmic mtDNA variants predicted to affect oxidative phosphorylation are enriched in FTLD temporal lobe, and thus may contribute to the regional vulnerability in pathogenesis.

额颞叶变性（FTLD）是年轻发病痴呆的常见原因，其特征是局灶性神经病理学。区域神经元脆弱性的原因尚不清楚。线粒体机制与 FTLD 的发病机制有关，这增加了线粒体 DNA (mtDNA) 额颞叶区域突变是致病原因的可能性。在这里，我们对整个 mtDNA 进行了高深度的双重测序，以识别受 FTLD 影响的人和年龄匹配的对照者死后脑组织中的高保真单核苷酸变异 (mtSNV) 和 mtDNA 重排。颞叶 mtSNV 和 mtDNA 重排均升高，其中 FTLD 负担最大。在多个大脑区域中发现的 mtSNV 在颞叶中也达到了更高的异质性水平。FTLD 患者颞叶的核糖体基因变异负担较高，预计会影响线粒体内蛋白质合成，并且编码呼吸链亚基的基因错义变异比例较高。总之，预计影响氧化磷酸化的异质性 mtDNA 变异在 FTLD 颞叶中富集，因此可能导致发病机制中的区域脆弱性。