Leber's hereditary optic neuropathy (LHON) is caused by point mutations in mitochondrial DNA (mtDNA) encoding subunits of Complex I (NADH dehydrogenase). The most common pathogenic mutations are at mtDNA positions 11778, 3460, and 14484. Why does retinal ganglion cell degeneration occur selectively in LHON despite the ubiquitous expression of Complex I?

• A Retinal cells preferentially use beta-oxidation and have no Complex I
• B The optic nerve axons express a unique Complex I isoform encoded by nuclear DNA
• C Retinal cells lack mitochondria and depend entirely on glycolysis
• D Retinal ganglion cells have high energy demand and long unmyelinated axons making them particularly vulnerable to ATP deficit and oxidative stress from impaired Complex I ✓

Explanation

Retinal ganglion cells (RGCs) have exceptionally high mitochondrial energy requirements for axonal signal transmission over their long, small-diameter, unmyelinated axons (the optic nerve portion). Impaired Complex I reduces the mitochondrial membrane potential, decreasing ATP synthesis and increasing superoxide generation. RGCs are uniquely vulnerable because: (1) their axons are unmyelinated within the optic disc (oxygen-rich, metabolically demanding region), (2) they lack saltatory conduction (no myelin), and (3) they have limited capacity for anaerobic compensation. This cell-type vulnerability explains tissue-selective presentation despite systemic mtDNA mutation.

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

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Written and medically reviewed by the StethoPrep medical team.