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Oxidative Medicine and Cellular Longevity
Volume 2019, Article ID 9165214, 13 pages
https://doi.org/10.1155/2019/9165214
Review Article

Mitochondrial Entry of Cytotoxic Proteases: A New Insight into the Granzyme B Cell Death Pathway

Department of Biomedical Science, University of Padova and Veneto Institute of Molecular Medicine, Via G. Orus 2, 35129 Padova, Italy

Correspondence should be addressed to Denis Martinvalet; ti.dpinu@telavnitram.sined

Received 2 February 2019; Accepted 8 April 2019; Published 21 May 2019

Guest Editor: Livia Hool

Copyright © 2019 Denis Martinvalet. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The mitochondria represent an integration and amplification hub for various death pathways including that mediated by granzyme B (GB), a granule enzyme expressed by cytotoxic lymphocytes. GB activates the proapoptotic B cell CLL/lymphoma 2 (Bcl-2) family member BH3-interacting domain death agonist (BID) to switch on the intrinsic mitochondrial death pathway, leading to Bcl-2-associated X protein (Bax)/Bcl-2 homologous antagonist/killer- (Bak-) dependent mitochondrial outer membrane permeabilization (MOMP), the dissipation of mitochondrial transmembrane potential (ΔΨm), and the production of reactive oxygen species (ROS). GB can also induce mitochondrial damage in the absence of BID, Bax, and Bak, critical for MOMP, indicating that GB targets the mitochondria in other ways. Interestingly, granzyme A (GA), GB, and caspase 3 can all directly target the mitochondrial respiratory chain complex I for ROS-dependent cell death. Studies of ROS biogenesis have revealed that GB must enter the mitochondria for ROS production, making the mitochondrial entry of cytotoxic proteases (MECP) an unexpected critical step in the granzyme death pathway. MECP requires an intact ΔΨm and is mediated though Sam50 and Tim22 channels in a mtHSP70-dependent manner. Preventing MECP severely compromises GB cytotoxicity. In this review, we provide a brief overview of the canonical mitochondrial death pathway in order to put into perspective this new insight into the GB action on the mitochondria to trigger ROS-dependent cell death.