Mechanisms of retinal ganglion specific-cell death in Leber hereditary optic neuropathy

These results demonstrate that RGC-5 mitochondria produce superoxide at significantly lower rates than brain mitochondria. Tighter regulation of superoxide levels in RGCs would prevent aberrant apoptosis signaling. LHON mtDNA mutations may interfere with superoxide regulation, possibly leading to aberrant RGC death and consequent optic neuropathy.

Superoxide production in mitochondria isolated from the RGC-5 cell line, rat brain, or neuroblastoma SK-N-AS cells was measured and correlated with levels of mitochondrial electron transport chain (METC) complexes.

Leber hereditary optic neuropathy (LHON)

The rate of superoxide production in brain mitochondria was more than 5 times the rate in RGC-5 cells when complex I substrates were used. Rotenone significantly increased the rate of superoxide production in brain but not RGC-5 mitochondria. Succinate-dependent superoxide production was similar in brain and RGC-5 mitochondria, but was increased by the complex III inhibitor antimycin A only in brain cells. Neuroblastoma mitochondria demonstrated similar superoxide generation rates as brain cells. Lower rates of superoxide production probably reflected lower levels of METC components. Conclusions: These results demonstrate that RGC-5 mitochondria produce superoxide at significantly lower rates than brain mitochondria. Tighter regulation of superoxide levels in RGCs would prevent aberrant apoptosis signaling. LHON mtDNA mutations may interfere with superoxide regulation, possibly leading to aberrant RGC death and consequent optic neuropathy.