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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.

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Fig. 1
Fig. 2

Abbreviations

Smac:

Second mitochondria-derived activator of caspase

DIABLO:

Direct inhibitor of apoptosis-binding protein with low pI

AIF:

Apoptosis-inducing factor

MMP:

Mitochondrial membrane permeabilization

VDAC:

Voltage-dependent anion channel

ANT:

Adenine nucleotide translocator

ROS:

Reactive oxygen species

ER:

Endoplasmic reticulum

PCD:

Programmed cell death

SERCA:

Sarcoplasmic/ER Ca2+ ATPase

UPR:

Unfolded protein response

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Kim, R., Emi, M. & Tanabe, K. Role of mitochondria as the gardens of cell death. Cancer Chemother Pharmacol 57, 545–553 (2006). https://doi.org/10.1007/s00280-005-0111-7

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