The mitochondrial T1095C mutation increases gentamicin-mediated apoptosis.

Area of Science:

• Genetics
• Mitochondrial Biology
• Neuroscience

Background:

• A heteroplasmic mitochondrial DNA (mtDNA) mutation, T1095C, in the 12S ribosomal RNA (rRNA) gene was previously identified in an Italian family.
• This family exhibited maternally inherited parkinsonism, antibiotic-mediated deafness, and peripheral neuropathy.

Purpose of the Study:

• To investigate the pathogenic role of the T1095C mtDNA mutation.
• To determine the mutation's effect on cellular function and susceptibility to antibiotic toxicity.

Main Methods:

• Generation of a transmitochondrial cybrid cell line from the proband.
• Assessment of mitochondrial glutathione levels and activity of respiratory chain complex II/III.
• Exposure of cybrid cells to an aminoglycoside antibiotic and measurement of apoptosis.

Main Results:

• The cybrid cell line showed selective depletion of mitochondrial glutathione.
• A decrease in the activity of mitochondrial respiratory chain complex II/III was observed.
• Cells with the mutation exhibited a ten-fold increase in apoptosis when exposed to aminoglycoside antibiotics compared to controls.

Conclusions:

• The T1095C mutation plays a pathogenic role in the observed family phenotype.
• The mutation confers increased risk for aminoglycoside-induced cellular toxicity.
• This finding has implications for managing patients with this mtDNA mutation, particularly regarding antibiotic treatment.