VDAC2 and Bak scarcity in liver mitochondria enables targeting hepatocarcinoma while sparing hepatocytes

Shamim Naghdi, Piyush Mishra, Soumya Sinha Roy, David Weaver, Ludivine Walter, Erika Davies, Anil Noronha Antony, Xuena Lin, Gisela Moehren, Mark A. Feitelson, Christopher A. Reed, Tullia Lindsten, Craig B. Thompson, Hien T. Dang, Jan B. Hoek, Erik S. Knudsen and György Hajnóczky ()
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Shamim Naghdi: Department of Pathology and Genomic Medicine and Thomas Jefferson University
Piyush Mishra: Department of Pathology and Genomic Medicine and Thomas Jefferson University
Soumya Sinha Roy: Department of Pathology and Genomic Medicine and Thomas Jefferson University
David Weaver: Department of Pathology and Genomic Medicine and Thomas Jefferson University
Ludivine Walter: Department of Pathology and Genomic Medicine and Thomas Jefferson University
Erika Davies: Department of Pathology and Genomic Medicine and Thomas Jefferson University
Anil Noronha Antony: Department of Pathology and Genomic Medicine and Thomas Jefferson University
Xuena Lin: Department of Pathology and Genomic Medicine and Thomas Jefferson University
Gisela Moehren: Department of Pathology and Genomic Medicine and Thomas Jefferson University
Mark A. Feitelson: Department of Pathology and Genomic Medicine and Thomas Jefferson University
Christopher A. Reed: Thomas Jefferson University
Tullia Lindsten: University of Pennsylvania
Craig B. Thompson: University of Pennsylvania
Hien T. Dang: Thomas Jefferson University
Jan B. Hoek: Department of Pathology and Genomic Medicine and Thomas Jefferson University
Erik S. Knudsen: Thomas Jefferson University
György Hajnóczky: Department of Pathology and Genomic Medicine and Thomas Jefferson University

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Differences between normal tissues and invading tumors that allow tumor targeting while saving normal tissue are much sought after. Here we show that scarcity of VDAC2, and the consequent lack of Bak recruitment to mitochondria, renders hepatocyte mitochondria resistant to permeabilization by truncated Bid (tBid), a Bcl-2 Homology 3 (BH3)-only, Bcl-2 family protein. Increased VDAC2 and Bak is found in most human liver cancers and mitochondria from tumors and hepatic cancer cell lines exhibit VDAC2- and Bak-dependent tBid sensitivity. Exploring potential therapeutic targeting, we find that combinations of activators of the tBid pathway with inhibitors of the Bcl-2 family proteins that suppress Bak activation enhance VDAC2-dependent death of hepatocarcinoma cells with little effect on normal hepatocytes. Furthermore, in vivo, combination of S63845, a selective Mcl-1 inhibitor, with tumor-nectrosis factor-related, apoptosis-induncing ligand (TRAIL) peptide reduces tumor growth, but only in tumors expressing VDAC2. Thus, we describe mitochondrial molecular fingerprint that discriminates liver from hepatocarcinoma and allows sparing normal tissue while targeting tumors.

Date: 2025
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DOI: 10.1038/s41467-025-56898-4

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