African haplogroup L3 gave rise to macrohaplogroups M and N, which colonized Europe and Asia. N differed from M in harboring the ND3 G10398A (A114T) and ATP6 G8701A (A59T) variants. In Europe, N gave rise to haplogroup H, and H acquired the tRNA^Gln A4336G variant to generate H5a, which predisposes to AD, PD, and both AD and PD (17). The ND1 A3397G (M31V) missense mutation arose twice in Europeans, once on H5a and once independently, and in both cases was associated with predisposition to both AD and PD (17). Both tRNA^Gln A4336G and ND1 A3397G (M31V) mutations are likely to reduce mitochondrial complex I activity, augmenting the founding N variants. The ND1 T3394C (Y30H) mutation, which is adjacent to the ND1 M31 codon, arose on N and M mtDNAs. When arising on N haplogroups B and F, the ND1 T3394C (Y30H) variant is associated with complex I deficiency and increased penetrance of the primary LHON mutations. However, complex I activity is also modulated by N haplogroup background, with haplogroup F mtDNAs having lower complex I activity than haplogroup B mtDNAs, consistent with haplogroup F predisposition to diabetes (23). The ND1 T3394C (Y30H) mutation has arisen on several M mtDNAs, with all haplogroup M9 mtDNAs having the 3394C allele. Both M9 and 3394C mtDNAs increase in frequency with altitude in Tibet. Finally, M9 complex I activity is equal to or greater than that of any of the N haplogroups with the wild-type T3394 allele (20). Asterisks indicate that the stated complex I activity is predicted, based on the known genotype and complex I activities determined for cell lines harboring ND1 T3394C (Y30H)–containing mtDNAs.