My research is focused on understanding the mechanisms by which low mtDNA copy number and attendant retrograde signaling regulates genetic and epigenetic events during tumorigenesis. I have shown that a metabolic switch to glycolysis involving IGF1-receptor is the key to adaptation in cells with reduced mtDNA content. I have identified hnRNPA2 as a novel mitochondrial stress induced transcriptional coactivator of nuclear genes. I am currently studying the contribution of hnRNPA2 in chromatin remodeling, telomerase reactivation and telomere dysfunction in response to mitochondrial stress. I am also interested in understanding the contribution of mitochondrial genome defects in cellular reprogramming during epithelial-to-mesenchymal transition (EMT). My studies indicate that retrograde signaling regulates the expression of splicing regulatory factors involved in EMT. Most importantly, my findings suggest that retrograde signaling is a potential inducer of breast Cancer Stem Cells which has far reaching therapeutic implications.
I am studying the effect of hypoxia/ischemia-reperfusion injury on the stability of Cytochrome oxidase and respiratory chain supercomplexes. Our earlier work has shown that under hypoxia three of the subunits of Cytochrome oxidase are phosphorylated and subsequently degraded, resulting in the loss of Cytochrome oxidase activity. My work is focused on understanding the signaling and the nature of the kinase that leads to phosphorylation of these subunits. This work has therapeutic potential, as our findings have shown that kinase inhibitors which prevent phosphorylation of Cytochrome oxidase subunits during hypoxia/ischemia-reperfusion have protective effect against reperfusion injury in mouse hearts. The second aspect of my study is on the mitochondria to nucleus stress signaling initiated under hypoxic stress. Loss of cytochrome c oxidase activity under hypoxia results in mitochondrial dysfunction. I am studying the retrograde signaling involved in communicating this dysfunction to the nucleus and resulting changes in nuclear gene expression.
The primary research focus is to elucidate the molecular mechanisms regulating the dual targeting of Cytochrome P450 1B1 and CYP 2E1 to Endoplasmic reticulum and mitochondria using in vitro and in vivo approach. In particular, research efforts are focused to investigate the potential role mitochondrial CYP 2E1 and associated genetic polymorphism in inducing oxidative stress, DNA damage, alcohol toxicity, mitochondrial dysfunction and hepatotoxicity. Another major area of study involves deciphering the role of mitochondrial CYP 1B1 in polycyclic aromatic hydrocarbons induced mitochondrial dysfunction and carcinogenesis.
I am working on mitochondrial respiratory stress signaling (also called retrograde signaling) and how mitochondria promote adaptations in stress condition in multiple cellular model systems. We are trying to address the mechanisms and signaling pathways for the activation of p53 and HIF1α in mitochondrial retrograde signaling.
I am working on mechanisms of bimodal targeting of human CYP2D6 and 2C8 to mitochondria and its pathophysiological consequence in drug metabolism and toxicity. I am investigating how human mutations that increase mitochondrial targeting efficiencies of these proteins potentiate drug induced neural and cardiac toxicity.
Regulation of cytochrome oxidase gene expression, modulation of enzyme assembly/activity in CYP2E1 mediated mitochondrial dysfunction under alcohol induced oxidative stress conditions. Role of mitochondria targeted Cytochrome P-450 2C6 and the human analogue of 2C9 in drug metabolizing pathways in cell culture systems. Aryl hydrocarbon receptor mediated modulation and Protection during β-Napthoflavone induced mitochondrial dysfunction in mouse models.
I am working on the role of human cytochrome P450 2D6 in neurodegenerative diseases. My main focus is to understand how mitochondrial P450 2D6 is involved in metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin and disease model for Parkinson disease within dopaminergic neurons using cellular and animal models.
I am investigating the mechanistic role of mitochondria targeted CYP 2E1 in alcohol induced toxicity in intestinal epithelial cell lines and if this induces EMT in intestinal epithelium causing dysfunction. I am also studying the role of Benzo[a]pyrene and TCDD-mediated pancreatic mitochondrial dysfunction and its significance in pancreatitis, which is thought to be an early indicator of pancreatic cancer.
Here are a selection of recent publications for the Avadhani Laboratory. For a comprehensive list, please visit Dr. Avadhani's PubMed Link.
1: Bansal S, Anandatheerthavarada HK, Prabu GK, Milne GL, Martin MV, Guengerich FP, Avadhani NG. Human Cytochrome P450 2E1 Mutations That Alter MitochondrialTargeting Efficiency and Susceptibility to Ethanol-induced Toxicity in Cellular Models. J Biol Chem. 2013 May 3;288(18):12627-44
2: Bajpai P, Sangar MC, Singh S, Tang W, Bansal S, Chowdhury G, Cheng Q, Fang JK,Martin MV, Guengerich FP, Avadhani NG. Metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by mitochondrion-targeted cytochrome P450 2D6: implications in Parkinson disease. J Biol Chem. 2013 Feb 8;288(6):4436-51.
3: Sleeper MM, Rosato BP, Bansal S, Avadhani NG. Mitochondrial dysfunction in
myocardium obtained from clinically normal dogs, clinically normal anesthetized dogs, and dogs with dilated cardiomyopathy. Am J Vet Res. 2012
4: Srinivasan S, Avadhani NG. Cytochrome c oxidase dysfunction in oxidative
stress. Free Radic Biol Med. 2012 Sep 15;53(6):1252-63.
5: Tang W, Chowdhury AR, Guha M, Huang L, Van Winkle T, Rustgi AK, Avadhani NG.Silencing of IkBβ mRNA causes disruption of mitochondrial retrograde signaling and suppression of tumor growth in vivo. Carcinogenesis. 2012 Sep;33(9):1762-8.
6: Bansal S, Srinivasan S, Anandasadagopan S, Chowdhury AR, Selvaraj V, Kalyanaraman B, Joseph J, Avadhani NG. Additive effects of mitochondrion-targeted cytochrome CYP2E1 and alcohol toxicity on cytochrome c oxidase function and stability of respirosome complexes. J Biol Chem. 2012 May 4;287(19):15284-97.
7: Ren L, Hong SH, Chen QR, Briggs J, Cassavaugh J, Srinivasan S, Lizardo MM,
Mendoza A, Xia AY, Avadhani N, Khan J, Khanna C. Dysregulation of ezrin phosphorylation prevents metastasis and alters cellular metabolism in osteosarcoma. Cancer Res. 2012 Feb 15;72(4):1001-12.
8: Avadhani NG. Targeting of the same proteins to multiple subcellular destinations: mechanisms and physiological implications. FEBS J. 2011 Nov;278(22):4217
9: Avadhani NG, Sangar MC, Bansal S, Bajpai P. Bimodal targeting of cytochrome P450s to endoplasmic reticulum and mitochondria: the concept of chimeric signals. FEBS J. 2011 Nov;278(22):4218-29.
10: Yan C, Avadhani NG, Iqbal J. The effects of smoke carcinogens on bone. Curr Osteoporos Rep. 2011 Dec;9(4):202-9.
11: Raza H, Prabu SK, John A, Avadhani NG. Impaired mitochondrial respiratory
functions and oxidative stress in streptozotocin-induced diabetic rats. Int J Mol Sci. 2011;12(5):3133-47.