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Granzymes and Mitochondria

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Abstract

Cytotoxic T lymphocytes and natural killer cells eliminate infected cells from the organism by triggering programmed cell death (apoptosis). The contents of the lytic granules of killer cells, including pore-forming proteins perforins and proteolytic enzymes granzymes, are released with the following penetration of the released proteins into the target cells. Granzyme B initiates mitochondria-dependent apoptosis via (i) proapoptotic Bid protein, (ii) Mcl-1 and Bim proteins, or (iii) p53 protein. As a result, cytochrome c is released from the mitochondria into the cytoplasm, causing formation of apoptosomes that initiate the proteolytic cascade of caspase activation. Granzymes M, H, and F cause cell death accompanied by the cytochrome c release from the mitochondria. Granzyme A induces generation of reactive oxygen species (ROS), which promotes translocation of the endoplasmic reticulum-associated SET complex to the nucleus where it is cleaved by granzyme A, leading to the activation of nucleases that catalyze single-strand DNA breaks. Granzymes A and B penetrate into the mitochondria and cleave subunits of the respiratory chain complex I. One of the complex I subunits is also a target for caspase-3. Granzyme-dependent damage to complex I leads to the ROS generation and cell death.

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Abbreviations

FeS cluster:

iron–sulfur cluster

FMN:

flavin mononucleotide

GAAD:

granzyme A-activated DNase

NK cell:

natural killer cell

O—̣2 :

superoxide anion radical

ROS:

reactive oxygen species

Δμ̄H+ :

proton electrochemical gradient

Δψ:

transmembrane difference in electric potential

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Acknowledgements

The author is grateful to Prof. V. D. Samuilov for reading the manuscript and valuable comments.

Funding

This work was financed by the Research Support (NIR) Program of the Federal Budget (NIR registration number at the Center for Information Technologies and Systems AAAA-A16-116021660081-0).

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  1. Lomonosov Moscow State University, Faculty of Biology, 119991, Moscow, Russia

    D. B. Kiselevsky

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Russian Text © The Author(s), 2020, published in Biokhimiya, 2020, Vol. 85, No. 2, pp. 155–164.

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Kiselevsky, D.B. Granzymes and Mitochondria. Biochemistry Moscow 85, 131–139 (2020). https://doi.org/10.1134/S0006297920020017

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  • DOI: https://doi.org/10.1134/S0006297920020017

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