Mitochondrial DNA deletions sensitize cells to apoptosis at low heteroplasmy levels.
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 22 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 5kb common deletion (CD), affecting five tRNA genes, in transmitochondrial cybrid cell lines and found a slightly enhanced sensitivity to exogenous 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.
Schoeler
S
S
Institute of Neuropathology of the Otto-von-Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany.
Szibor
R
R
Gellerich
F N
FN
Wartmann
T
T
Mawrin
C
C
Dietzmann
K
K
Kirches
E
E
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D006822:Hybrid Cells / Q000187:drug effects; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism*; D012516:Osteosarcoma / Q000235:genetics* / Q000473:pathology*; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; D004272:DNA, Mitochondrial; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D006861:Hydrogen Peroxide