Role of mitochondria as the gardens of cell death

Abstract

Mitochondria play a crucial role in regulating cell death, which is mediated by outer membrane permeabilization in response to death triggers such as DNA damage and growth factor deprivation. Mitochondrial membrane permeabilization induces the release of cytochrome c, Smac/DIABLO, and AIF, which are regulated by proapoptotic and antiapoptotic proteins such as Bax/Bak and Bcl-2/xL in caspase-dependent and caspase-independent apoptosis pathways. Mitochondrial dysfunction is mediated in two ways. The first is by increased calcium in mitochondria derived from endoplasmic reticulum (ER); this calcium increase is regulated by Bcl-2 and Bax through the ER-mitochondria connection and the unfolded protein response in the ER. The second is by the lysosomal enzyme cathepsin, which activates Bid through lysosome-mitochondria cross-signaling. The genomic responses in intracellular organelles after DNA damage are controlled and amplified in the cross-signaling via mitochondria; such signals induce apoptosis, autophagy, and other cell death pathways. This review discusses the recent advancements in understanding the molecular mechanism of mitochondria-mediated cell death.

Cell survival, cell death and cell cycle pathways are interconnected: Implications for cancer therapy

“…Also, members of the Bcl2 family such as Bcl2, Bax and Bak may localize to the ER. Through the mitochondria-ER connection a further important control mechanism of apoptosis exists that either rely on caspase-2 as the apical caspase or connect to the mitochondrial death pathway over cellular-stress-signaling mechanisms (Kim et al, 2006). Anti-apoptotic proteins can be blocked by binding with BH3-only proteins such as Bad and Bim (Huang, 2000;Mendoza et al, 2005).…”

“…Further proapoptotic members of the third class of Bcl2 family proteins are Bid, Noxa and Puma, which require Bax and Bak to mediate cell death. Bad and Bik cannot directly activate Bak and Bax, but act as sensitizers through binding to Bcl2 and Bcl-x L (Kim et al, 2006). Bad-like BH3 domains are able to dissociate Bax and Bak from Bcl2 and Bcl-x L .…”

Melatonin, Oxidative Stress, and the Aging Brain

“…Many key intracellular constituents are vulnerable to oxidative or nitrosylative damage, and this may increase with age (reviewed in [8]). Macromolecules are especially liable to injurious oxidative modification.…”

“…Macromolecules are especially liable to injurious oxidative modification. These include proteins [8][9][10][11], nucleic acids [12], and lipids [13]. Although an increased level of pro-oxidant activity with age has frequently been reported, the establishment of a causal relation whereby oxidant events result in impaired neurologic or behavioral status is more difficult to unequivocally demonstrate.…”

“…Mitochondrial dysfunction can also play an important role in the regulation of processes of cellular self-destruction, apoptosis, autophagy, and necrosis [8,9,43]. Control of these processes that relate to cell death is very responsive to imbalances in cellular homeostasis as gauged by such measures as Ca 2+ levels [44] and cellular redox status [45].…”