Research Interests: Mitochondrial Diseases, Dysfunction, and Biogenesis; Apoptosis, Diabetes, Obesity, Breast Cancer, and Aging
The long-term objectives of my group are to understand how mitochondrial dysfunction leads to neurodegeneration and diseases such as cancer and diabetes, as well as the molecular, biochemical, and physiological causes of mitochondrial dysfunction. Our studies involve a variety of approaches to explore the roots of this problem, including functional imaging to probe mitochondrial function and biogenesis. A special emphasis is given to studying mitochondrial function in intact cells. A schematic overview of our research interests is shown in Figure 1.
Mitochondrial dysfunction is very often associated with a variety of human diseases that occur across a life span, from 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 the role of mitochondrial dysfunction in disease and the process of mitochondrial biogenesis.
To understand how mitochondrial dysfunction could lead to disease, please see our working model on the "bioenergetic basis of neurodegeneration" in Figure 2. This model is based on our previous study showing that pathological overactivation of neurons could lead to full use of their spare respiratory capacity (Yadava & Nicholls 2007 This model proposes 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. A clear difference can be seen in cancer, wherein mitochondrial dysfunction provides survival advantages to cells.
For a very long time, it has been proposed that mitochondrial dysfunction may predispose some cells-for example, dividing cells-to become cancerous. This is supported by many clinical observations that cancer cells accumulate mutations in mitochondrial genes that are vital for mitochondrial function. However, there is no clear experimental evidence to support that mitochondrial dysfunction can cause cancer or how mutations in mitochondrial DNA are accumulated. In this connection, one ongoing project in my group is exploring the role of mitochondrial dysfunction in cancer development. Our working model is based on current thinking that functional mitochondria suppress tumorigenesis (Figure 3). Our recent study showing reversible regulation of tumor suppressor p53 by Complex I deficiency provides a mechanistic explanation for this (Compton et. al. 2011).
Our laboratory is focused on developing cellular and animal models for partial complex I deficiency. Using these models, we are deciphering the mechanisms by which complex I deficiency can confer opposite cell fates in neurodegeneration and cancer. This is essential for developing therapies targeting the mitochondrial metabolism to avoid potential side effects. We are also interested in understanding the regulation of mitochondrial metabolism in pancreatic β-cells. The mitochondrial metabolism plays a critical role in glucose-stimulated insulin secretion from β-cells, which is essential for maintaining blood glucose homeostasis. The failure of β-cells to appropriately secrete insulin in response to glucose results in type 2 diabetes, which presents us with one of the biggest health challenges of this century. The ongoing projects are aimed toward elucidating the consequences of complex I deficiency on bioenergetics and the tumor suppressor p53 protein in post-mitotic (neurons and muscles) and mitotic cells (fibroblasts, epithelial, and endothelial cells); elucidating the pancreatic β-cell-specific features of mitochondrial metabolism; and developing simple methods for monitoring mitochondrial metabolism in the context of pathophysiology.
Center for Endocrine and Metabolic Research
Center of Excellence in Apoptosis Research
Shannon Compton, Postdoctoral Fellow
Chul Kim, Postdoctoral Fellow
Pinal Patel, Research Lab Assistant
Compton C, Kim C, Griner N, Potluri P, Scheffler IE, Sen S, Jerry DJ, Schneider S, Yadava N. Mitochondrial dysfunction impairs tumor suppressor p53- expression/function. J Biol Chem. In press (2011).
Gerencser AA, Neilson A, Choi SW, Edman U, Yadava N, et al. Quantitative microplate-based respirometry with correction for oxygen diffusion. Anal Chem. 2009;81:6868-6878.
Amo T, Yadava N, Oh R, Nicholls DG, Brand, MD. Experimental assessment of bioenergetic differences caused by the common European mitochondrial DNA halpogroups H and T. Gene. 2008;411 (1-2): 69-76.
Yadava N, Potluri P, Scheffler IE. Investigations of the potential effects of phosphorylation of the MWFE and ESSS subunits on complex I activity and assembly. Int J Biochem Cell Biol. 2008;40(3):447-460.
Yadava N, Nicholls DG. Spare respiratory capacity rather than oxidative stress regulates glutamate excitotoxicity following partial respiratory inhibition of mitochondrial complex I with rotenone. J Neurosci. 2007;27(27):7310-7317.
Nicholls DG, Johnson-Cadwell L, Vesce S, Jekabsons M, Yadava N. Bioenergetics of mitochondria in cultured neurons and their role in glutamate excitotoxicity. J Neurosci Res. 2007;85(15):3206-3212.
Potluri P, Yadava N, Scheffler IE. The role of the ESSS protein in the assembly of a functional and stable mammalian mitochondrial complex I (NADH-ubiquinone oxidoreductase). Eur J Biochem. 2004;271; 3265-3273.
Ricci JE, Munoz-Pinedo C, Fitzgerald P, Bailly-Maitre B, Perkins GA, Yadava N, et al. 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. 2004;117:773-786.
Yadava N, Scheffler, IE. Import and orientation of the MWFE protein in mitochondrial NADH-ubiquinone oxidoreductase. Mitochondrion. 2004;4: 1-12.
Yadava N, Houchens T, Potluri P, Scheffler IE. Development and characterization of a conditional mitochondrial complex I assembly system. J Biol Chem. 2004;279(13):12406-12413.
Yadava N, Potluri P, Smith E, Bisevac A, Scheffler IE. Species-specific and mutant MWFE proteins: their effect on the assembly of the mammalian mitochondrial complex I. J Biol Chem. 2002;277(24):21221-21230.
Scheffler IE, Yadava N, Potluri P. Molecular genetics of complex I-deficient Chinese hamster cell lines. Biochim Biophys Acta. 2004;1659:160-171.
Yadava N, Potluri P, Smith E, Bisevac A, Scheffler IE. Species-specific and mutant MWFE proteins; their effect on the assembly of the mammalian mitochondrial complex I. J Biol Chem. 2002;277 (24): 21221-30; 277 (45): 21221-21230.
Scheffler IE, Yadava N. Molecular genetics of the mammalian NADH-ubiquinone oxidoreductase. J Bioenerg. Biomembr. 2001;33(3): 243-250.
Mitochondrial Champion for the United Mitochondrial Disease Foundation
Member of the Society for Neuroscience (SFN) 2005 to present
Member of the American Society for Biochemistry and Molecular Biology (ASBMB) 2001 to present
Mitochondrial Research Society (MRS) 2011 to present