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Mitochondrial DNA mutations induce mitochondrial biogenesis and increase the tumorigenic potential of Hodgkin and Reed–Sternberg cells

Lookup NU author(s): Dr Joanna Elson, Professor Robert Taylor

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by Oxford University Press, 2020.

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Abstract

Functioning mitochondria are crucial for cancer metabolism, but aerobic glycolysis is still considered to be an important pathway for energy production in many tumor cells. Here we show that two well established, classic Hodgkin lymphoma (cHL) cell lines harbor deleterious variants within mitochondrial DNA (mtDNA) and thus exhibit reduced steady-state levels of respiratory chain complexes. However, instead of resulting in the expected bioenergetic defect, these mtDNA variants evoke a retrograde signaling response that induces mitochondrial biogenesis and ultimately results in increased mitochondrial mass as well as function and enhances proliferation in vitro as well as tumor growth in mice in vivo. When complex I assembly was impaired by knockdown of one of its subunits, this led to further increased mitochondrial mass and function and, consequently, further accelerated tumor growth in vivo. In contrast, inhibition of mitochondrial respiration in vivo by the mitochondrial complex I inhibitor metformin efficiently slowed down growth. We conclude that, as a new mechanism, mildly deleterious mtDNA variants in cHL cancer cells cause an increase of mitochondrial mass and enhanced function as a compensatory effect using a retrograde signaling pathway, which provides an obvious advantage for tumor growth.

Publication metadata

Author(s): Haumann S, Boix J, Knuever J, Bieling A, Sanjurjo AV, Elson JL, Blakely EL, Taylor RW, Riet N, Abken H, Kashkar H, Hornig-Do HT, Wiesner RJ

Publication type: Article

Publication status: Published

Journal: Carcinogenesis

Year: 2020

Volume: 41

Issue: 12

Pages: 1735-1745

Print publication date: 01/12/2020

Online publication date: 07/04/2020

Acceptance date: 06/04/2020

Date deposited: 23/04/2020

ISSN (print): 0143-3334

ISSN (electronic): 1460-2180

Publisher: Oxford University Press

URL: https://doi.org/10.1093/carcin/bgaa032

DOI: 10.1093/carcin/bgaa032

PubMed id: 32255484

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