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MODULATION OF BAX/BAK DEPENDENT APOPTOSIS BY SIRTUIN 3 AND MITOCHONDRIAL PERMEABILITY TRANSITION BY SIRTUIN 4

by
Manish Verma
M.S., 2007
Manipal University, India

Thesis Advisor: John Pastorino, Ph.D.

Cell and Molecular Biology Program

Science Center, Room 290

Thursday, June 6, 2013
12 PM


Abstract

Sirtuins were first identified in budding yeast S. cerevisiae and was shown to regulate the extension of lifespan. Yeast Sir2p silenced transcription at silent mating loci, telomeres and also suppressed recombination of rDNA which in turn extended replicative lifespan. Over expression of Sir2p promoted global deacetylation of histones indicating that Sir2p maybe a histone deacetylase. In humans there are seven sirtuins, Sirt1-7, of which three (Sirt3-5) are localized to mitochondria. Sirt3 and Sirt5 possess deacetylase activity where as Sirt4 possess ADP-ribosyltransferase activity. Sirtuin 3 (Sirt3) is the major deacetylase in the mitochondrial matrix and regulates various metabolic pathways by regulating the acetylation status of key metabolic enzymes. Though the metabolic regulation by Sirt3 is extensively studied, the role of Sirt3 cancer progression and regulation of apoptotic pathway is still unclear. Cancer cells show increased glycolysis, Warburg’s effect, which is achieved by over expression of hexokinase II, the rate limiting enzyme of glycolysis which then translocates to outer mitochondrial membrane (OMM). On the OMM hexokinase II interacts with voltage dependent anion channel (VDAC), a component of mitochondrial permeability transition pore (mPTP). Hexokinase II binding is modulated by the expression of Sirt3 as depletion of Sirt3 promotes hexokinase II binding and over expression induces dissociation. Dissociation of hexokinase II sensitizes cancer cells to induction of apoptosis and stimulates activation of pro apoptotic proteins, Bax and Bak. Thus, Sirt3 modulates Bax and Bak dependent apoptosis by regulating hexokinase II binding to the OMM.

In contrast to apoptosis, opening of mPTP caused by oxidative stress, leads to mitochondrial injury and eventually necrotic cell death. The component of mPTP, though controversial, consists of Cyclophilin d in the matrix, Adenine nucleotide translocator (ANT) in the inner mitochondrial membrane and VDAC on the outer mitochondrial membrane. Sirtuin 4 (Sirt4), also localized to mitochondria, possesses ADP-ribosyltransferase activity. Sirt4 ribosylates glutamate dehydrogenase (GDH-1) and inhibits its activity. Sirt4 regulates the induction of permeability transition, as down regulation of Sirt4 inhibits PTP induction which is dependent on GDH-1. Suppression of Sirt4 increases GDH-1 activity which protects against PTP induction by calcium overload and thiol reactive agent phenylarsine oxide or cytotoxicity induced by TNF and doxorubicin.


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