Collateral deletion of the mitochondrial AAA+ ATPase ATAD1 sensitizes cancer cells to proteasome dysfunction
Year: 2022
Type: article
Abstract: PTEN is a potent tumor suppressor gene that is frequently mutated or deleted in human cancers. Such deletions often include portions of the 10q23 locus beyond the bounds of PTEN itself, in many cases resulting in the disruption of additional genes. Coincidental loss of PTEN -adjacent genes might impose vulnerabilities that could either affect patient outcome basally or be exploited therapeutically. Here we describe how the loss of ATAD1 , which is adjacent to and frequently co-deleted with PTEN , predisposes cancer cells to apoptosis and correlates with improved survival in cancer patients. ATAD1 directly and specifically extracts the pro-apoptotic BIM protein from mitochondria to inactivate it. Cells lacking ATAD1 are hypersensitive to clinically used proteasome inhibitors, which increase BIM and trigger apoptosis. Thus, we demonstrate that mitochondrial protein quality control interfaces with cell death in a clinically actionable manner.
Source: eLife
DOI: 10.7554/elife.82860
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Awards: G107029098, G1143187280, Mechanistic Investigation of Proteostasis at the Outer Mitochondrial Membrane, G5147630776, University of Utah Interdisciplinary Training Program in Computational Approaches to Diabetes and Metabolism Research, G5851049912, Mitochondrial quality control as a selective vulnerability in cancers with chromosome 10q deletion, Defining intracellular mitochondrial heterogeneity establishment and maintenance, G9000070422, G9000165854, G9000225111, G9000238105, G9000310867, Mechanisms of metabolite signaling, Interdisciplinary Training Program in Metabolism, G913442283, G9274809
OpenAlex ID: W4309514409