Lack of mitochondrial topoisomerase I ( TOP1mt ) impairs liver regeneration

Abstract

The liver has an exceptional replicative capacity following partial hepatectomy or chemical injuries. Cellular proliferation requires increased production of energy and essential metabolites, which critically depend on the mitochondria. To determine whether Top1mt, the vertebrate mitochondrial topoisomerase, is involved in this process, we studied liver regeneration after carbon tetrachloride (CCl 4 ) administration. TOP1mt knockout (KO) mice showed a marked reduction in regeneration and hepatocyte proliferation. The hepatic mitochondrial DNA (mtDNA) failed to increase during recovery from CCl 4 exposure. Reduced glutathione was also depleted, indicating increased reactive oxygen species (ROS). Steadystate levels of ATP, O 2 consumption, mtDNA, and mitochondrial mass were also reduced in primary hepatocytes from CCl 4 -treated KO mice. To further test whether Top1mt acted by enabling mtDNA regeneration, we tested TOP1mt KO fibroblasts and human colon carcinoma HCT116 cells and measured mtDNA after 3-d treatment with ethidium bromide. Both types of TOP1mt knockout cells showed defective mtDNA regeneration following mtDNA depletion. Our study demonstrates that Top1mt is required for normal mtDNA homeostasis and for linking mtDNA expansion with hepatocyte proliferation.liver regeneration | mitochondrial topoisomerase I | cell proliferation | mitochondrial DNA replication | mitochondrial homeostasis

Transcription profiling suggests that mitochondrial topoisomerase IB acts as a topological barrier and regulator of mitochondrial DNA transcription

“…7B). These results suggest that TOP1MT might play a previously unknown role in the mtDNA NCR by regulating the termination of transcription and facilitating replication (21,24,37).…”

“…The functions of TOP1MT have remained relatively unexplored since the discovery of the gene 15 years ago (18,22). In contrast to other nuclear-encoded genes that sustain mtDNA maintenance, TOP1MT is not essential (21,24,26,37) and is restricted to vertebrates (22). Two recent studies show that TOP1MT is required for mtDNA copy number expansion during liver regeneration (24) and myocardial adaptation to mitochondrial poisoning by doxorubicin (37).…”

“…TOP1MT has recently been shown to facilitate mtDNA replication during liver regeneration and following ethidium bromide exposure (24). Yet, TOP1MT is not essential for mouse development, probably due to the presence of TOP3A, TOP2A, and TOP2B in mitochondria complementing its function (21).…”

Topoisomerases and the regulation of neural function

“…This phenotypic spectrum suggests specific physiologic roles for the respective topoisomerases; Top1, 2α and 3α during replication, but specialized roles for Top2β and 3β after tissue formation. Inactivation of the mitochondrial specific form of Top1 is compatible with viability, and mice are relatively normal unless challenged with stress that requires enhanced mitochondrial functions 45 . Consistent with its specific role in meiosis, Spo11 inactivation result in a viable, but infertile mouse 23 .…”

Prospects for Searching Multitarget Topoisomerase Inhibitors With Antitumor Properties

“…Однако описаны некоторые хинолоны, ингибирующие hTop1 и hTop2, не вызывая «отравления», активные на опухолевых моделях [3,[5][6][7]. Поиск новых перспективных противоопухолевых ингибиторов топоизомераз определяется зависимостью их каталитической активности от структуры [8][9][10][11][12][13][14][15][16][17]. Оказалось, что независимо от типа фермента большинство из них проявляет значимую противоопухолевую активность, сопряженную с побочным действием различной направленности.…”