The mitochondrial T1095C mutation increases gentamicin-mediated apoptosis.
We have previously reported a heteroplasmic mtDNA mutation (T1095C) in the 12SrRNA gene of an Italian family with features of maternally-inherited parkinsonism, antibiotic-mediated deafness and peripheral neuropathy. In the present study, we demonstrate that a transmitochondrial cybrid line derived from the proband of this family shows selective depletion of mitochondrial glutathione and decreases in the activity of complex II/III. Moreover, when exposed to an aminoglycoside antibiotic these cells responded with a ten-fold increase in the number of apoptotic cells compared to controls. These results support a pathogenic role for the T1095C mutation and indicate that the mutation increases the risk for aminoglycoside-induced toxicity.
Discipline of Medical Biochemistry and Centre for Neuroscience, School of Medicine, Flinders University, Adelaide, South Australia, Australia. hakan.muyderman@flinders.edu.au
Hakan
H
Muyderman
Neil R
NR
Sims
Masashi
M
Tanaka
Noriyuki
N
Fuku
Ravinarayan
R
Raghupathi
Dominic
D
Thyagarajan
D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000378:metabolism / Q000633:toxicity; D017209:Apoptosis; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000235:genetics*; D020459:Genes, rRNA; D005839:Gentamicins / Q000009:adverse effects* / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D007558:Italy; D008928:Mitochondria / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D012335:RNA, Ribosomal / Q000235:genetics
D000900:Anti-Bacterial Agents; D004272:DNA, Mitochondrial; D005839:Gentamicins; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S