Mitochondrial Impairment by MitoBloCK-6 Inhibits Liver Cancer Cell Proliferation

Yaschar Kabiri; Anna Fuhrmann; Anna Becker; Luisa Jedermann; Carola Eberhagen; Ann-Christine König; Tiago Barros Silva; Fernanda Borges; Stefanie M Hauck; Bernhard Michalke; Percy Knolle; Hans Zischka

doi:10.3389/fcell.2021.725474

Mitochondrial Impairment by MitoBloCK-6 Inhibits Liver Cancer Cell Proliferation

Front Cell Dev Biol. 2021 Sep 20:9:725474. doi: 10.3389/fcell.2021.725474. eCollection 2021.

Authors

Affiliations

¹ Institute of Toxicology and Environmental Hygiene, School of Medicine, Technical University of Munich, Munich, Germany.
² Institute of Molecular Toxicology and Pharmacology, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
³ Research Unit Protein Science and Metabolomics and Proteomics Core Facility, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
⁴ CIQUP, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.
⁵ Research Unit Analytical BioGeoChemistry, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany.
⁶ Institute of Molecular Immunology and Experimental Oncology, University Hospital Rechts der Isar, Technical University of Munich, Munich, Germany.

Abstract

Augmenter of liver regeneration (ALR) is a critical multi-isoform protein with its longer isoform, located in the mitochondrial intermembrane space, being part of the mitochondrial disulfide relay system (DRS). Upregulation of ALR was observed in multiple forms of cancer, among them hepatocellular carcinoma (HCC). To shed light into ALR function in HCC, we used MitoBloCK-6 to pharmacologically inhibit ALR, resulting in profound mitochondrial impairment and cancer cell proliferation deficits. These effects were mostly reversed by supplementation with bioavailable hemin b, linking ALR function to mitochondrial iron homeostasis. Since many tumor cells are known for their increased iron demand and since increased iron levels in cancer are associated with poor clinical outcome, these results help to further advance the intricate relation between iron and mitochondrial homeostasis in liver cancer.

Keywords: HCC; disulfide relay system; heme; iron; mitochondria.