In addition to being maternally inherited, as due to usually homoplasmic mtDNA mutations affecting complex I subunits (m.3460G > A/MT-ND1, m.11778G > A/MT-ND4, and m.14484T > C/MT-ND6) (Table 1), LHON is characterized by (1) male prevalence, (2) incomplete penetrance in both genders, (3) very cell-specific target, the RGCs, and, finally, (4) a subacute onset and rapidly evolving natural history, which is an unusual feature for neurodegeneration. Here, MT-ND4 is linked to Leber hereditary optic neuropathy.