Regulation of the mitochondrial apoptosis-induced channel, MAC, by BCL-2 family proteins

Abstract

Programmed cell death or apoptosis is central to many physiological processes and pathological conditions such as organogenesis, tissue homeostasis, cancer, and neurodegenerative diseases. Bcl-2 family proteins tightly control this cell death program by regulating the permeabilization of the mitochondrial outer membrane and, hence, the release of cytochrome c and other pro-apoptotic factors. Control of the formation of the mitochondrial apoptosis-induced channel, or MAC, is central to the regulation of apoptosis by Bcl-2 family proteins. MAC is detected early in apoptosis by patch clamping the mitochondrial outer membrane. The focus of this review is on the regulation of MAC activity by Bcl-2 family proteins. The role of MAC as the putative cytochrome c release channel during early apoptosis and insights concerning its molecular composition are also discussed.

Is MAC the knife that cuts cytochrome c from mitochondria during apoptosis?

“…Apoptosis is a conserved cell death mechanism essential for normal development and tissue homeostasis in multicellular organisms (reviewed in Danial and Korsmeyer 1 , Antonsson 2 , Sharpe et al 3 , Green and Kroemer 4 , Kuwana and Newmeyer 5 , Fadeel and Orrenius 6 , Lucken-Ardjomande and Martinou 7 , Martinez-Caballero et al 8 and Dejean et al 9 ). Two major signaling pathways leading to cell death by apoptosis have been identified.…”

“…[1][2][3]6,11 The Bcl-2 family of proteins is a key regulator of the mitochondrial response to apoptotic signals in the intrinsic pathway and contains both pro-and anti-apoptotic members (see other papers in this issue). Many of these proteins localize to mitochondria and finely control the process of apoptosis through regulation of the release of mitochondrial mediators of the apoptotic program into the cytosol (recently reviewed in Danial and Korsmeyer 1 , Antonsson 2 , Sharpe et al 3 , Green and Kroemer 4 , Kuwana and Newmeyer 5 , Lucken-Ardjomande and Martinou 7 , Martinez-Caballero et al 8 , Dejean et al 9 , Juin et al 12 ). The extrinsic and intrinsic pathways initially appeared to be independent.…”

A tale of two mitochondrial channels, MAC and PTP, in apoptosis

“…During this process, DNA fragments into a characteristic degradation pattern and the cell body is dispersed as apoptotic bodies that are eliminated by phagocytosis. Although the end result is the same, there are several means of achieving apoptosis (reviewed in [1][2][3][4][5][6][7][8][9][10][11][12]). The upstream signaling cascades triggering apoptosis are very different depending on the initiating stimuli and the targeted cells to be eliminated.…”

Evaluation of Mutation of Bcl2 SNPS With Risk of Squamous Cell Carcinoma Head and Neck (Hnscc) in Kashmiri Population.

“… 68% (34) patients were smokers as against 32%(16) non smokers.  Laryngeal squamous cell carcinoma were most common 50% (25) followed by sinonasal malignancy 18% (9) .  Out of 50 patients of head and neck squamous cell carcinoma, 31 BCL2 SNP mutations were seen which comprises 62% of total ( Heterozygous GC-16 and Homozygous CC-15 …”

“…Whereas the activated pro-apoptotic Bak and/or Bax would form MAC and mediate the release of cytochrome c, the anti-apoptotic Bcl-2 would block it, possibly through inhibition of Bax and/or Bak. [9] The Bcl-2 family has a general structure that consists of a hydrophobic helix surrounded by amphipathic helices.…”