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Hyperpolarized mitochondria accumulate in Drosophila Hipk-overexpressing cells to drive tumor-like growth.

Authors
  • Wong, Kenneth Kin Lam1, 2
  • Liao, Jenny Zhe1, 2
  • Shih, Claire R Y1, 2
  • Harden, Nicholas1, 2
  • Verheyen, Esther M3, 2
  • 1 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, V5A 1S6, Canada. , (Canada)
  • 2 Centre for Cell Biology, Development and Disease, Simon Fraser University, Burnaby, British Columbia, V5A 1S6, Canada. , (Canada)
  • 3 Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, V5A 1S6, Canada [email protected] , (Canada)
Type
Published Article
Journal
Journal of Cell Science
Publisher
The Company of Biologists
Publication Date
Dec 09, 2020
Volume
133
Issue
23
Identifiers
DOI: 10.1242/jcs.250944
PMID: 33199523
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Both functional and dysfunctional mitochondria are known to underlie tumor progression. Here, we establish use of the proto-oncogene Drosophila Homeodomain-interacting protein kinase (Hipk) as a new tool to address this paradox. We find that, in Hipk-overexpressing tumor-like cells, mitochondria accumulate and switch from fragmented to highly fused interconnected morphologies. Moreover, elevated Hipk promotes mitochondrial membrane hyperpolarization. These mitochondrial changes are at least in part driven by the upregulation of Myc. Furthermore, we show that the altered mitochondrial energetics, but not morphology, is required for Hipk-induced tumor-like growth, because knockdown of pdsw (also known as nd-pdsw; NDUFB10 in mammals; a Complex I subunit) abrogates the growth. Knockdown of ATPsynβ (a Complex V subunit), which produces higher levels of reactive oxygen species (ROS) than pdsw knockdown, instead synergizes with Hipk to potentiate JNK activation and the downstream induction of matrix metalloproteinases. Accordingly, ATPsynβ knockdown suppresses Hipk-induced tumor-like growth only when ROS scavengers are co-expressed. Together, our work presents an in vivo tumor model featuring the accumulation of hyperfused and hyperpolarized mitochondria, and reveals respiratory complex subunit-dependent opposing effects on tumorigenic outcomes.This article has an associated First Person interview with the first author of the paper. © 2020. Published by The Company of Biologists Ltd.

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