[The "Triple-hit" pathogenic mechanism of Leber hereditary optic neuropathy]

Leber hereditary optic neuropathy (LHON) is a classic mitochondrial disorder primarily affecting retinal ganglion cells and leading to irreversible visual loss. Although primary mitochondrial DNA (mtDNA) mutations, such as m.11778G>A, m.14484T>C, and m.3460G>A, provide the genetic basis of LHON, they do not fully explain its incomplete penetrance, male predominance, or clinical heterogeneity. Based on familial genetic analyses and functional studies, this review proposes a "triple hit" pathogenic mechanism for LHON. The first hit consists of primary mtDNA mutations, mainly affecting respiratory chain complex I activity and impairing 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 and influence penetrance among mutation carriers. The third hit comprises non genetic triggers and individual physiological conditions, including smoking, alcohol consumption, metabolic abnormalities, and sex hormone related differences, which may further compromise mitochondrial compensatory capacity and ultimately trigger retinal ganglion cell degeneration. This review provides an integrated framework for understanding the pathogenic mechanisms of LHON, with implications for risk screening, genetic counseling, and mechanism driven clinical research.