Mitochondrial DNA mutations induce mitochondrial biogenesis and increase the tumorigenic potential of Hodgkin and Reed–Sternberg cells. (7th April 2020)

• Record Type: Journal Article
• Authors: Haumann, Sophie; Boix, Julia; Knuever, Jana; Bieling, Angela; Vila Sanjurjo, Anton; Elson, Joanna L; Blakely, Emma L; Taylor, Robert W; Riet, Nicole; Abken, Hinrich; Kashkar, Hamid; Hornig-Do, Hue-Tran; Wiesner, Rudolf J
• Is Part Of: Carcinogenesis. Volume 41:Number 12(2020)
• Page Start: 1735
• Page End: 1745
• Publication Date: 2020-04-07
• Subjects: Carcinogenesis -- Periodicals; Cancer -- Genetic aspects -- Periodicals; Cancer -- Prevention -- Periodicals; Cancer -- Periodicals; 616.994071
• DOI: 10.1093/carcin/bgaa032
• Languages: English
• ISSNs: 0143-3334

Abstract

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. Abstract : We show that Hodgkin lymphoma cell lines harbor deleterious mtDNA variants. Instead of causing a bioenergetic defect, as expected, a retrograde signaling response increases mitochondrial biogenesis, mitochondrial function and cell proliferation, leading to enhanced tumor growth in vivo .