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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.<\/jats:p>","DOI":"10.1093\/carcin\/bgaa032","type":"journal-article","created":{"date-parts":[[2020,4,6]],"date-time":"2020-04-06T19:11:43Z","timestamp":1586200303000},"page":"1735-1745","source":"Crossref","is-referenced-by-count":14,"title":["Mitochondrial DNA mutations induce mitochondrial biogenesis and increase the tumorigenic potential of Hodgkin and Reed\u2013Sternberg cells"],"prefix":"10.1093","volume":"41","author":[{"given":"Sophie","family":"Haumann","sequence":"first","affiliation":[{"name":"Center for Physiology and Pathophysiology, Institute of Vegetative Physiology, Medical Faculty, University of Cologne, Cologne, Germany"},{"name":"Department of Pediatrics, Medical Faculty and University Hospital of 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W","family":"Taylor","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, Newcastle University, Newcastle upon Tyne UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicole","family":"Riet","sequence":"additional","affiliation":[{"name":"Department I for Internal Medicine, Medical Faculty and University of Cologne, 50931 Cologne, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hinrich","family":"Abken","sequence":"additional","affiliation":[{"name":"Department I for Internal Medicine, Medical Faculty and University of Cologne, 50931 Cologne, Germany"},{"name":"Center for Molecular Medicine Cologne, 50931 Cologne (CMMC), University of Cologne, 50931 Cologne, Germany"},{"name":"RCI, Regensburg Center for Interventional Immunology, Chair Gene-Immunotherapy, University Hospital Regensburg, Regensburg, 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