We investigated the effect of the mitochondrial DNA (mtDNA) polymorphism G10398A found in African-American women with aggressive breast cancer on apoptosis and tumorigenesis. We generated human cytoplasmic hybrid (cybrid) by repopulation of recipient 0 cells (devoid of mtDNA) with donor mtDNA derived from patients with breast cancer harboring the G10398A polymorphism. We investigated a number of functional phenotypes of the G10398A cybrid. The G10398A cybrid showed a slower proliferation rate and progression through the cell cycle, as well as increased complex I activity, increased levels of reactive oxygen species and depolarized mitochondria. The G10398A cybrid also showed resistance to apoptosis triggered by etoposide. Resistance to apoptosis was mediated by Akt activation. In addition, our studies showed that the G10398A cybrid cells form an increased number of anchorage-independent colonies in vitro and metastases in mice. Together our studies suggest that the G10398A variant confers resistance to apoptosis and promotes metastasis. © 2009 The Japan Society of Human Genetics All rights reserved.