Partha Kasturi, PhD
Ph.D., Medical College of Wisconsin, 2001
The overall research interest of the laboratory is to define the physiological and molecular mechanisms that link mitochondrial function to cellular homeostasis, with an emphasis on understanding the degree of molecular defects, and the consequences of such molecular defects to systemic homeostasis.
1) Mitochondrial transport processes in physiology and disease pathology. A large number of molecules need to traverse the mitochondrial membranes to link the pathways of the cytosol with those of the mitochondrial matrix. Among these compounds are; a) keto acids derived from sugars, and fatty acids derived from fat, which are oxidized inside mitochondria to generate the cellular fuel ATP; b) amino acids, derived from protein break down, which are either interconverted or used in protein synthesis; c) vitamins which are required in the mitochondrial matrix as they act as co-factors for mitochondrial enzymes, and finally d) nucleotides, which are required for replication and transcription of mitochondrial DNA. However, the mitochondrial membrane is tightly sealed and is impermeable to most molecules. Thus, translocation of molecules across the mitochondrial membrane require transport proteins in the mitochondrial membrane. More than 60 different transport proteins belonging to different protein families, including the ABC transporter family, and the mitochondrial carrier family, have been identified in the mitochondrial membrane. Although the transport properties of some of these membrane proteins have been characterized the function of a vast majority of them has not yet been established. We are interested in studying the role of these orphan transporters in cellular metabolism and human physiology. We would also like to establish how they work in order to identify the molecular cause for the diseases that are associated with their dysfunction.
2) Inter-organelle crosstalk in normal physiology and environmental toxicology. The majority (1500 - 2000) of mitochondrial proteins are encoded in the nuclear genome, so programmed communication among nuclear, cytoplasmic, and mitochondrial compartments is essential for maintaining cellular health. Two main signaling systems exist in the cell: nuclear signaling to the mitochondria (anterograde signaling), and mitochondrial signaling to the nucleus (retrograde signaling). Both signaling systems can communicate intracellular energy needs or a need to compensate for dysfunction to maintain homeostasis. Conversely, both can also relay inappropriate signals in the presence of dysfunction in either system, and contribute to adverse health outcomes. Characterizing these differential signaling pathways, and understanding how cells detect, and respond to these signals is not only biologically important but may also serve as the backbone for identifying targets for clinical interventions aimed at prevention, and treatment of human disease. However, the molecular components of mitochondrial and nuclear (retrograde and anterograde) signaling networks and the specific stress-response pathways that determine the differential outcomes (adaptive vs pathologic) are not well defined and far from understood. We are interested in defining the signaling networks that are activated during inter-organelle crosstalk under normal physiological conditions. The information obtained is then used to ask more targeted mechanistic questions about how environmental exposure dysregulates this communication or function of either compartment, and the implications for long term cellular and organismal health.
3) Mitochondrial dynamics and metabolic flexibility in health and disease. Metabolic flexibility describes the ability of an organism to respond or adapt according to changes in metabolic or energy demand as well as the prevailing conditions or activity. Loss of this metabolic flexibility is strongly associated with the metabolic syndrome that include an array of risk factors such as insulin resistance, obesity and dyslipidemia. As the site of numerous biological processes-including oxidative phosphorylation (OXPHOS), the Krebs cycle, β-oxidation of fatty acids, calcium handling, and heme biosynthesis- mitochondria play a central role in regulating energy balance and metabolic flexibility. In order to achieve this metabolic flexibility mitochondria engage in several dynamic behaviors, including fusion, fission, transport and mitophagy. From yeast to mammals, these dynamic behaviors have been shown to be important in both normal physiology and disease states. Our current studies are focused on understanding how environmental stimuli regulate the key mitochondrial dynamics of fusion, fission and transport and how deregulation of these processes lead to metabolic inflexibility and metabolic disease.
1. Chavan, H., Christudoss, P., Mickey, K., Tessman, R., Ni, H. M., Swerdlow, R., Krishnamurthy, P. (2017) Arsenite effects on mitochondrial bioenergetics in human and mouse primary hepatocytes follows a non-linear dose response. Oxidative Medicine and Cellular Longevity. 9251303: 1-12. PMC5253485.
2. Tan, E. P., McGreal, S. R., Graw, S., Tessman, R., Koppel, S. J., Dhakal, P., Zhang, Z., Machaceki, M., Zachara, N. E., Koestler, D. C., Peterson, K. R., Thyfault J. P., Swerdlow, R. Krishnamurthy, P., DiTachio, L, Apte, U., and Slawson , C. (2017) Sustained O-GlcNAcylation Reprograms mitochondrial function to regulate energy metabolism. Journal of Biological Chemistry. 292(36): 14941-14962. PMC5592672
3. Li, J., Wang, Y., Matye, D. J., Chavan, H., Krishnamurthy, P., Li, F., and Li, T., (2017). Sortlin1 Modulates hepatic cholesterol lipotoxicity in mice via functional interaction with liver carboxylersterase 1. Journal of Biological Chemistry. 292(1):146-160. 146-160. PMC5217674
4. Wang, Y., Ding, Y., Li, J., Chavan, H., Matye, D., Ni, H. M., Chiang, J. L., Krishnamurthy, P.,
Ding, W. X., Li, T. (2016) Targeting the enterohepatic bile acid signaling induces hepatic authophagy via a CYP7A1-AKT-mTOR axis in mice. Cellular and Molecular Gastroenterology and Hepatology. 22(3): 245 - 260. PMC5331786
5. Du, K., Ramachandran, A., Weemhoff, J. L., Chavan, H., Xie, Y., Krishnamurthy, P., Jaeschke, H. (2016) Metformin Protects Against Acetaminophen Hepatotoxicity by attenuation of Mitochondrial Oxidant Stress and Dysfunction. Toxicological Sciences. 154(2):214-226. PMC5139063
6. Chavan, H., Li, F., Tessman, R., Mickey, K., Dorko, K., Schmitt, T., Kumar, S., Gunewardena, S., Gaikwad, N., and Krishnamurthy, P. (2015) Functional coupling of ATP-Binding cassette transporter Abcb6 to cytochrome P450 expression and activity in liver. Journal of Biological Chemistry 290: 7871-7886. PMC4367286
7. Liu, X., Lu, Y., Guan, X., Dong, B., Chavan, H., Wang, J., Zhang, Y., Krishnamurthy, P., Li, F. (2015) Metabolomics reveals the formation of aldehydes and iminium in geftinib metabolism. Biochemical Pharmacology. 97(1): 111-121. PMID: 26212543
8. Chavan, H., Khan, M. M., Tegos, G. P., and Krishnamurthy, P., (2013). Efficient purification and reconstitution of ABCB6 for functional and structural studies. Journal of Biological Chemistry. 288(31): 22658-22669. PMC3829351
9. Chavan, H., and Krishnamurthy, P., (2012). Polycyclic aromatic hydrocarbons (PAHs) mediate transcriptional activation of the ATP binding cassette transporter ABCB6 gene via the Aryl Hydrocarbon receptor (AhR). Journal of Biological Chemistry. 287(38): 32054-32068. PMC3442536
10. Krishnamurthy, P., Schwab, M., Takenaka, K., Nachagari, D., Morgan, J., Leslie, M., Du, W., Boyd, K., Cheok, M., Nakauchi, H., Marzolini, C., Kim, R. B., Poonkuzhali, B., Schuetz, E., Evans, W. E., Relling, M. V., and Schuetz, J. D. (2008). Transporter mediated protection against Thiopurine-induced hematopoietic toxicity. Cancer Research. 68(13): 4983-4989. PMC3323115
11. Li, C., Krishnamurthy, P., Penmatsa, H., Mars, K. L., Wang, X., Zaccolo, M., Jalink, K., Li, M., Nelson, D. J., Schuetz, J. D and Naren, A. P. (2007). Spatiotemporal coupling of cAMP Transporter to CFTR Chloride Channel Function in the Gut Epithelia. Cell 131(5): 940-951. PMC2174212
12. Krishnamurthy, P., Du, G., Fukuda, Y., Daxi, S., Sampath, J., Mercer, K. E., Wang, J., Sosa-pineda, B., Murti, G., and Schuetz, J. D. (2006) Identification of a mammalian mitochondrial porphyrin transporter. Nature 443(7111): 586-589. PMID 17006453