FRB domain of human TOR protein induces compromised proliferation and mitochondrial dysfunction in Leishmaniadonovani promastigotes. (August 2022)

• Record Type: Journal Article
• Authors: Chakraborty, Sudipta; Mukherjee, Soumyajit; Biswas, Priyam; Ghosh, Alok; Siddhanta, Anirban
• Is Part Of: Parasitology international. Volume 89(2022)
• Publication Date: 2022-08
• Subjects: FRB domain -- mTOR -- Oxygen consumption -- Respiratory complex -- Mitochondria -- Leishmania donovani; Parasitology -- Periodicals; Parasites -- Periodicals; Parasitic Diseases -- Periodicals; Parasitology -- Periodicals; Parasitologie -- Périodiques; 571.99905
• DOI: 10.1016/j.parint.2022.102591
• Languages: English
• ISSNs: 1383-5769

Abstract

Abstract: Visceral leishmaniasis (VL) or Kala-azar, the second-largest parasitic killer worldwide, is caused by Leishmania donovani . The drugs to treat VL are toxic and expensive. Moreover, their indiscriminate use gave rise to resistant strains. The high rate of parasite proliferation within the host macrophage cells causes pathogenesis. In the proliferative pathway, FRB domain of TOR protein is ubiquitously essential. Although orthologues of mTOR protein are reported in trypanosomatids and Leishmania but therein depth molecular characterization is yet to be done. Considerable protein sequence homology exists between the TOR of kinetoplastidas and mammals. Interestingly, exogenous human FRB domain was shown to block G1 to S transition in mammalian cancer cells. Thus, we hypothesized that expression of human FRB domain would inhibit the proliferation of Leishmania donovani . Indeed, promastigotes stably expressing wild type human FRB domain show 4.7 and 1.5 folds less intra- and extra-cellular proliferations than that of untransfected controls. They also manifested 2.65 times lower rate of glucose stimulated oxygen consumption. The activities of all respiratory complexes were compromised in the hFRB expressing promastigotes. In these cells, depolarized mitochondria were 2-fold more than control cells. However, promastigotes expressing its mutant version (Trp 2027 -Phe) has shown similar characteristics like untransfected cells. Thus, this study reveals greater insights on the conserved role of TOR in the regulation of the respiratory complexes in L. donovani . The slow growing variant of FRB expressing promastigotes will have great potential to be exploited as a prophylactic agent against leishmaniasis. Graphical abstract: Unlabelled Image Highlights: Expression of wild type hFRB domain in the L. donovani promastigotes led to the inactivation of downstream TOR functions. Wild type hFRB but not the mutant (Trp 2027 -Phe) results in less infective "proliferation deficient" L. donovani parasites. Wild type hFRB caused dysfunction in mitochondrial respiration that is in part due to its depolarization in L. donovani . Mutant hFRB (Trp 2027 -Phe) expressing promastigotes has shown similar phenotype like untransfected control.