“Triple-hit” pathogenic mechanism of Leber hereditary optic neuropathy

Leber hereditary optic neuropathy (LHON) is a mitochondrial genetic optic neuropathy predominantly affecting retinal ganglion cells and leading to irreversible visual loss. Although primary mtDNA mutations, including m.11778G>A, m.14484T>C, and m.3460G>A, provide the molecular basis of LHON, they do not fully explain incomplete penetrance, male predominance, or clinical heterogeneity. Based on familial genetic studies and functional evidence, this review summarizes "triple-hit" pathogenic mechanism of LHON. The first hit consists of primary mtDNA mutations that impair respiratory chain complex I activity and mitochondrial bioenergetics. The second hit involves mitochondrial modifier variants, specific mtDNA haplogroup backgrounds, and nuclear modifier genes such as PRICKLE3 and YARS2, which further lower the threshold for disease expression. The third hit includes environmental and physiological factors, such as smoking, alcohol exposure, metabolic dysregulation, and sex hormone-related differences, which may further compromise mitochondrial compensatory capacity and thereby trigger retinal ganglion cell degeneration in genetically susceptible individuals. This review provides an integrated framework for understanding the genetic basis, modifier effects, and pathogenic mechanisms of LHON, with implications for risk assessment and genetic counseling.