Adjunct Assistant Professor, Department of Biology, University of Massachusetts
Scientist, Pioneer Valley Life Sciences Institute
Ph.D.: Jawaharlal Nehru University, India
Mitochondrial Biogenesis; Mitochondrial Dysfunction & Disease; Aging
The long-term objectives of my group are to understand (i) how mitochondrial dysfunction leads to neurodegeneration and other age-associated diseases such as diabetes and cancer, and (ii) the molecular, biochemical and physiological causes of mitochondrial dysfunction. Our studies involve functional imaging, molecular biological, biochemical and physiological approaches to probe mitochondrial function and biogenesis. A special emphasis is given to studying mitochondrial function in intact cells.
Mitochondrial dysfunction is very often associated with a variety of human diseases starting in early childhood to late in life. Although neuromuscular degenerative diseases are more frequent, almost every tissue is associated with pathological conditions due to mitochondrial dysfunction. This is not surprising considering the key role mitochondria play in cellular bioenergetics, and in making life and death decisions. It has become clear that mitochondrial dysfunction should be considered in investigating all those diseases for which molecular and biochemical explanations are lacking. Most often mitochondrial dysfunction is due to partial deficiencies of the respiratory chain complexes with Complex I (NADH-ubiquinone oxidoreductase) being the leading cause. Thus, Complex I is the main focus of our studies to elucidate (i) the role of mitochondrial dysfunction in disease, and (ii) the process of mitochondrial biogenesis.
To understand how mitochondrial dysfunction could lead to disease, please see our working model on the "bioenergetic basis of disease". This model is based on our previous study showing that pathological/over- activation of neurons could lead to full use of their spare respiratory capacity suggesting that even a very minor impairment of the oxidative phosphorylation could be detrimental under conditions of acute high-energy demands. Although, it is possible that multiple mechanisms could play roles in mitochondrial dysfunction-mediated pathogenesis, our data suggest that the "bioenergetic deficit" could be a major driving factor in diseases of tissues with high bioenergetic demands.
Yadava N, Nicholls DG. (2007) Spare respiratory capacity rather than oxidative stress regulates glutamate excitotoxicity following partial respiratory inhibition of mitochondrial complex I with rotenone. J Neurosci., 27(27): 7310-7317
Nicholls DG, Johnson-Cadwell L, Vesce S, Jekabsons M, Yadava N. (2007) Bioenergetics of mitochondria in cultured neurons and their role in glutamate excitotoxicity. J Neurosci. Res., 85(15): 3206-3212
Ricci J.E., Munoz-Pinedo C., Fitzerald P., Bailly-Maitre B., Perkins G.A., Yadava N, Scheffler I.E., Ellisman M.H., Green D.R. (2004) Disruption of mitochondrial function during apoptosis is mediated by caspase cleavage of the p75 subunit (NDUFS1) of complex I of the electron transport chain. Cell, 117: 773-786
Yadava N., Potluri P., Scheffler I.E. (2008). Investigations of the potential effects of phosphorylation of the MWFE and ESSS subunits on complex I activity and assembly. Int. J. Biochem. Cell Biol., 40(3): 447-460
Yadava N., Houchens T., Potluri P., Scheffler I.E. (2004) Development and characterization of a conditional mitochondrial complex I assembly system. J. Biol. Chem.,279(13):12406-12413
Yadava N, Potluri P., Smith E., Bisevac A., Scheffler I. E. (2002) Species-specific and mutant MWFE proteins: their effect on the assembly of the mammalian mitochondrial complex I. J. Biol. Chem., 277(24): 21221-30; 277(45): 21221-21230
Scheffler I.E., Yadava N., Potluri P. (2004) Molecular genetics of complex I-deficient Chinese hamster cell lines. Biochim. Biophys. Acta, 1659:160-171