A heterogeneous group of multisystem disorders affecting Various tissues and Often including neuromuscular symptoms is caused by Mutations of the mitochondrial genome, which codes 13 polypeptides of oxidative phosphorylation (OXPHOS) complexes and tRNA genes needed for their translation. Since the link between OXPHOS dysfunction and clinical phenotype remains enigmatic in many,, diseases, a possible role of enhanced apoptosis is discussed besides bioenergetic crisis of affected cells. We analyzed the proapoptotic impact of the mitochondrial 5 kb common deletion (CD), affecting five tRNA genes, in transmitochondrial cybrid cell lines and found a slightly enhanced sensitivity to exogenons oxidative stress (H2O2) and a pronounced sensitization against death receptor stimulation (TRAIL) at a rather low CD heteroplasmy level of 22%. Mitochondrial deletions confer enhanced susceptibility against proapoptotic signals to proliferating cells, which might explain the elimination of deletions from hematopoietic stem cells. (c) 2005 Elsevier Inc. All rights reserved.