Leber hereditary optic neuropathy (LHON) is caused by maternally inherited mitochondrial DNA mutations predominantly affecting complex I of the ETC. Why are retinal ganglion cells particularly susceptible to complex I defects?

• A Retinal ganglion cells have the lowest density of mitochondria in the body
• B Retinal ganglion cell axons in the unmyelinated optic nerve head have high ATP demands (mitochondria-dependent axonal conduction) with limited anaerobic glycolysis capacity, making them exquisitely dependent on oxidative phosphorylation ✓
• C Retinal ganglion cells exclusively use ketone bodies as fuel and are unable to oxidize NADH
• D The optic nerve has uniquely high mtDNA mutation rates due to light-induced oxidative damage

Explanation

Retinal ganglion cell axons, particularly in the unmyelinated segment of the optic nerve head, have extremely high energy requirements for axonal potential propagation (mitochondria are densely packed here) and rely predominantly on oxidative phosphorylation. Unlike myelinated axons (where saltatory conduction reduces energy needs), the unmyelinated optic nerve head requires continuous Na⁺/K⁺-ATPase activity. Complex I (NADH ubiquinone oxidoreductase) mutations causing LHON reduce ATP production and increase ROS, selectively causing retinal ganglion cell apoptosis. The threshold effect of heteroplasmy and the bioenergetic vulnerability of these specific cells explain tissue specificity.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.