ApoptosisT.SURENDRA1540644I BCZApoptotic resistance is a hallar! o" h#an cancers.Recent advances have contributed to our understanding of the molecule mechanisms that intimately integrate cell metabolism and apoptosis.Coordinated activation of the proapoptotic Bclinic-2 family and the caspase family during apoptosis often leads to premeabilization of the mitochondrial outer membrane and release of multiple enzymes that normally function in regulating energy production and metabolism.Theroles of these metabolic enzymes in promoting caspase activation demonstrate a primordial need to couple apoptotic cell death and metabolic catastrophic during cellular destruction.The Bcl-2 family alsodirectly interacts with the multiple metabolic regulators to protect or promote mitochondrial damage during apoptosis.However the integration of metabolism and apoptosis is not simply limited to the maintenance of mitochondrial integrity.! recent study demonstrates that the "at! comple# protein "-$-acetyltrnasferase comple# is re%uired for &"! damage-mediated apoptosis and suggests that the regulation of protein acetylation might provide an important mechanism for regulating apoptotic sensitivity.'ince acetyl-Co! (coenzyme !) is a *ey cofactor for the "at! comple# protein acetylation is sub+ect to the availability of acetyl-Co! and thus under metabolic regulation.The revelation that protein "-$-acetylation is regulated by Bcl-#, a ma+or antiapoptotic mitochondrial protein demonstrates a mechanism by which metabolism can regulate the activation of multiple *ey apoptotic factors simultaneously.-ore than a half century ago .tto /arburg discovered the cancer cells prefer glycolysis a rather ine0cient metabolic pathway for reducing glucose into energy.This peculiar preference of tumour cells has since been recognised as a metabolic hallmar* of cancers.'ince evading apoptosis is critical for cancer cells to achieve uncontrolled growth is and proliferation be metabolic features of cancers must play an important role in regulating the apoptosis machinery.Thus a molecular understanding of the lin* between metabolic and apoptotic sensitivity iswarranted.!poptosis is a highly regulated form of cell death that functions to meantissue in homeostasis by eliminating unnecessary or damaged cells.1n Caenorhabditis elegan developmental apoptosis is controlled by an elegant and linear genetic program.1n mammals however the core apoptotic program has been dramatically e#panded resulting in an intricate suit of regulatory pathways that in2uence apoptotic sensitivity. !lthough biochemical approaches have uncovered many factors that regulate apoptotic cell death it is clear that any nation of many downstream proapoptotic e3ecters are not su0cient for evading the fate of cell death.The comple#ity of the mammalian apoptotic pathways suggests that summation of multiple intercellular signalling events rather than a simple linear pathway that determines a cell4s 5nal fate to live or die.Recent studies indicate that apoptotic networ* is incorporated into multiple cell physiological processes including cell metabolism..ur understanding of how these haemostatic processes in2uence apoptotic sensitivity at the molecular level is now emerging.1n this review we describe a recent 5ndings that reveal an intimate integration of cellular metabolism and apoptosis."ew insights into this problem will reveal powerful mechanisms whereby cancer cells evade cell death and identify new targets for cancer therapy.$ART 1.T%E C&RE A$&$T&TIC 'AC%INER(Caspase) A *ail+ o" C+steine $roteases that 'e,iate ApoptosisThe 5rst *ey insights into the molecule mechanism regulating apoptotic cell death came from genetic studies in the nematode C. elegans.These genetic studies revealed that apoptotic pathway can be activatedin all cells and that the canonical apoptotic machinery is highly conserved in all metazoans from invertebrates to vertebrates.The apoptotic machinery is operated by coordinated regulation of multiple signals transducers receptors enzymes and gene-regulating proteins.!mong the master regulators of programmed cell death the family of cysteine proteases *nown as caspase critical for mediating the signal transfusion and e#ecution of apoptosis./hile C6&-7 is the solitary caspase re%uired for programmed cell death in C. elegans numerous caspase are re%uired for apoptosis in more comple# organisms such as &rosophila and mammals.'uch e#tensive e#pansion of the caspase family during evolution warrants multiple modes of regulation to *eep inappropriate caspase activation at bay and is described below.&epending on the mode of their activation members of the caspase family are classi5ed as upstream 8initiator9 caspase that are activated upon their proteolytic cleavage by the initiator caspase.The initiator caspase contain a long amino-terminal pro-domain which allows the formation of the protein comple#es that regulate their activation and inhibition.Caspases are synthesised as inactive zymogens *nown as procaspase that re%uire allosteric conformational changes and:or speci5c cleavage after select aspartate residue to become activated.The initial processing of the inactive caspase separates the large and small subunits followed by the removal of the amino-terminal domain to form the catalytically active protease.Conse%uently caspase activation leads to a cascade of e#tensive proteolytic events at the proteome level that ultimately results in apoptotic cell death.Caspase-Acti.atin/ Cople0esThrough homotupic interactions with the prodomains of caspase adaptor proteins facilitate the assembly of large multimeric comple#es as caspase activation platforms.The recruitment of speci5c initiator caspase is determined by their long prodomain via a caspase recruitment domain or death-e3ector domain.1n response to speci5c developmental cues the adaptor protein C6&-; which is composed of an amino-terminal C!R& and a nucleotide-binding domain oligomerizesto promote the activation of C6&-7.&rosophila !paf-< a C6&-; li*e molecule is responsible for the activation of the ma+or 2y initiator caspase &ronc in response to cellular stresses such as &"! damage./hile a single adaptor protein C6&-; is re%uired for the activation of C6&-7 in case C. elegans multiple adaptor proteins are re%uired for caspase activation in mammals by promoting the formation of uni%ue protein comple#es under di3erent conditions.1n mammals four speci5c caspase-activating comple#es have become characterised.These comple#es include the apoptosome which she mediates the activation of caspase-= via interaction with the adaptor !>!?-< (apoptotic protease-activating factor-:!T> that promotes caspase-7 activation. 1ntermolecular interaction of the amino-terminal C!R& andcarbo#y-terminal /&;D repeat region releasing the C!R& for apoptosome assembly. >ersumably !paf-< bound to !T>:d!T> further supports enacting con5rmation where the amino-terminal C!R& is free to bind to cspaase-=.Resulting conformational change facilities the formation of the hepatameric structure of the apoptosome.Ta*en together these observations show that loss of mitochondrial integrity and subse%uent cytochrome c a *ey metabolic enzyme as a signal ampli5er during apoptosis may demonstrate a primordial need for metabolic catastrophe during cellular destruction.The Bcl-1 *ail+'tudies in C.elegans indicate that proteolytic caspase cascade is under tight regulation by C6&-= and 6E,- during apoptosis.1n &rosophila &rob-