Predominant cellular mitochondrial dysfunction in the TOP3A gene caused Bloom syndrome-like disorder

Abstract

Background TOP3A is a subunit of the BLM-TOP3A-RMI1/2 complex, which promotes processing of double Holliday junction dissolution and also plays an important role in decatenation and segregation of human mtDNA. Recently, TOP3A mutations have been reported to cause Bloom syndrome-like disorder. However, whether the two function play equal roles in the disease pathogenesis is unclear. Results Beside the common clinical manifestations in the reported TOP3A-deficiency, our patients also exhibited liver lipid storage with hepatomegaly and elevated liver enzyme. In cellular and molecular biological studies, TOP3A deficiency decreased the cellular protein level of RMI1 and RMI2, and moderately increased sister chromatid exchanges and decreased cell proliferation compared with BLM or RMI2 deficiency. These changes were rescued by ectopic expression of either of the wildtype TOP3A or TOP3A-D479G. In contrast, reduced mitochondrial ATP generation and oxygen consumption rates observed in TOP3A defective cells were rescued by over-expression of the wildtype TOP3A, but not TOP3A-D479G. Conclusions Considering the severe disease course and the impact of the TOP3A-D479G mutation on the genome stability and mitochondrial metabolism, we propose that the impaired mitochondrial metabolism plays an important role in the pathogenesis of TOP3A-deficient Bloom-like disease.

Human topoisomerases and their roles in genome stability and organization

“…1e ). A transcript isoform of TOP3A is also essential for mtDNA replication and segregation 12 , 13 (Box 1 ). Unique among the human topoisomerases, TOP3B — similar to its yeast and bacterial paralogs Top3 and Topo III, respectively — acts as a dual DNA and RNA topoisomerase 14 , 15 .…”

“…The mitochondrial isoform of topoisomerase 3A (TOP3A) 186 , 368 is required at the end of replication to decatenate the daughter mtDNA molecules, which are intertwined across their OriH regions, a process that is facilitated by mitochondrial TOP1 (TOP1MT) and is independent of the usual TOP3A-interacting Bloom syndrome protein (BLM)–TOP3A–RecQ-mediated genome instability proteins (RMI1/2) (BTR) dissolvasome complex 12 . Mutations in TOP3A have been reported in individuals with combined Bloom and mitochondrial syndromes characterized by dilated cardiomyopathy, mtDNA depletion in muscles and progressive external ophthalmoplegia syndrome 13 , 187 . In the fruit fly, inactivation of mitochondrial TOP3A results in defective genome integrity and mitochondrial functions with accelerated ageing and infertility 186 , 193 (Table 1 ).…”

Controlling the topology of mammalian mitochondrial DNA

“…However, a number of these patients with truncating variants in TOP3A also exhibited cardiomyopathy, not typically observed in Bloom syndrome, that is likely to be attributable to the loss of activity of the mitochondrial isoform of TOP3A [208]. A further two siblings were also recently reported with a Bloom syndrome-like disorder with cardiomyopathy and mitochondrial dysfunction, resulting from compound heterozygous truncating and missense variants in TOP3A [209]. The relative contributions of the nuclear and mitochondrial isoforms of TOP3A to the clinical features of TOP3A-related disease warrant further investigation.…”