Dr.Samit Adhya
Scientist G
Ph.D. (USA), F.N.A., F.N.A. Sc
Contact -sadhya@iicb.res.in
Current Research Interest
The GE lab is currently engaged in the elucidation of the mechanisms of the transport of tRNA and related molecules across biological membranes. The model organism being used for these studies is the kinetoplastid protozoon Leishmania tropuica. These kinetoplastid flagellates with complex life cycles in insect and mammalian hosts are evolutionarily ancient organisms that possess a rich variety of RNA metabolic pathways to be investigated. The single mitochondrion has a disc-shaped kinetoplast consisting of a network of DNA circles that encode ~18 different proteins but no tRNA. The tRNA necessary for mitochondrial protein synthesis is efficiently imported from the cytosol. Thus, mitochondrial tRNA import represents an evolved capability of these organism that are absent from higher organisms, a fact of considerable practical importance.
- Work in our laboratory over the last several years has led to the isolation, for the first time internationally, a multi-protein complex from L. tropica inner mitochondrial membranes that is functional for tRNA import in vitro.
- We are currently engaged in identifying and characterizing the functions of the many subunits of this complex.
- During the course of these investigations, we also developed a highly efficient protocol for conditional knockdown of L. tropica proteins using long antisense RNA, as well as a new method for purifying bacterially expressed parasite proteins in functional form. A combination of these genetic and biochemical approaches was used to obtain a molecular definition of the entire complex.
Mitochondria are now recognized to be at the epicenter of a wide variety of human diseases, as well as in the ‘normal’ process of aging. Mitochondrial dysfunction, leading to reduced ATP generation, causes progressive degeneration of various tissues, especially the nervous and muscular systems, as well as sensory and endocrine defects. A subgroup of these disorders is caused by mutations in human mitochondrial tRNA genes.
- We were excited to find that the Leishmania RNA Import Complex (RIC) induces import of cytosolic tRNAs into human mitochondria, and that imported tRNALys is functional in supported translation of mRNAs in mitochondria containing a patient-derived mutation in the organellar tRNALys gene.
- Importantly, RIC is taken up efficiently by primary as well as cultured mammalian cells and intracellularly targeted to mitochondria, where it induces import of cytosolic tRNAs.
- We showed that as a result, the respiratory function of cybrid cells carrying a tRNALys mutation was restored to near-normal levels.
- Thus, for the first time, a functional macromolecular complex derived from an evolutionarily distant organism was used to repair an intracellular defect in human cells.
- This novel concept of ‘complex therapy’ will be the subject of intensive investigations in the laboratory in the coming years.
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| Names of the group members including regular staff with designation and research fellows: |
| Staff: |
Fellow/RA |
1. Tapas Chowdhury
2. Mahua Bhattacharyya |
1. Sudarshana Basu
2. Pratik Home
3. Gunjan Dhar
4. Saikat Mukherjee
5. Biraj Mahato
6. Sandip Kolay
7. Sukanta Jash |
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List of important Publications:
- Bhattacharyya, S.N., Chatterjee, S. and Adhya, S. (2002) Mitochondrial RNA import in Leishmania tropica: aptamers homologous to multiple tRNA domains that interact cooperatively or antagonistically at the inner membrane. Mol. Cell. Biol. 22, 4372-4382.
- Bhattacharyya, S.N., Chatterjee, S., Goswami, S., Tripathi, G., Dey, S.N. and Adhya, S. (2003) “Ping-Pong” interactions between mitochondrial tRNA import receptors within a multiprotein complex. Mol. Cell. Biol. 23, 5217-5224.
- Goswami, S., Chatterjee, S., Bhattacharyya, S. N., Basu, S. and Adhya, S. (2003) Allosteric regulation of tRNA import: interactions between tRNA domains at the inner membrane of leishmania mitochondria. Nucl. Acids Res. 31, 5552-5559.
- Ghosh, S., Goswami, S. and Adhya, S. (2003) Role of superoxide dismutase in survival of Leishmania within the macrophage. Biochem. J. 369, 447-452.
- Adhya, S., Basu, S., Bhattacharyya, S.N., Chatterjee, S., Dhar, G., Goswami, S., Ghosh, S., Home, P., Mahata, B. and Tripathi, G. (2003) Mitochondrial differentiation in kinetoplastid protozoa: A plethora of RNA controls. Differentiation 71, 549-556.
- Bhattacharyya, S.N. and Adhya, S. (2004) tRNA-triggered ATP hydrolysis and generation of membrane potential by the Leishmania mitochondrial tRNA import complex. J. Biol. Chem. 279, 11259-11263.
- Bhattacharyya, S.N. and Adhya, S. (2004) The complexity of mitochondrial tRNA import. RNA Bio. 1, 84-88.
- Mahata, B., Bhattacharyya, S.N., Mukherjee, S. and Adhya, S. (2005) Correction of translational defects in patient-derived mutant mitochondria by complex-mediated import of a cytoplasmic tRNA. J. Biol. Chem. 280, 5141-5144.
- Goswami, S., Dhar, G., Mukherjee, S., Mahata, B., Chatterjee, S., Home, P. and Adhya, S. (2006) A bi-functional tRNA import receptor from Leishmania mitochondria Proc. Natl. Acad. Sci. USA, 103, 8354-8359.
- Goswami, S. and Adhya, S. (2006) The a subunit of Leishmania F1 ATP synthase hydrolyzes ATP in presence of tRNA. J. Biol. Chem. 281, 18914-18917.
- Chatterjee, S., Home, P., Mukherjee, S., Mahata, B., Goswami, S., Dhar, G. and Adhya, S. (2006) An RNA-binding respiratory component mediatres import of type II tRNAs into Leishmania mitochondria. J. Biol. Chem. 281, 25270-25277.
- Mahata, B., Mukherjee, S., Mishra, S., Bandyopadhyay, A. and Adhya, S. (2006) Functional delivery of a cytosolic tRNA into mutant mitochondria of human cells. Science 314, 471-474.
- Mukherjee, S., Basu, S., Home, P., Dhar, G., and Adhya, S. (2007). Necessary and sufficient factors for import of tRNA into the kinetoplast-mitochondrion. EMBO Rep. 8, 589-595.
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