Humanin (HN), a novel peptide consisting of 24 amino acid residues, prevents neuronal cell death caused by amyloid โค and all known familial Alzheimer's disease mutants. We previously proposed that HN had a broader spectrum of cytoprotection from the finding that HN rescued naive rat pheochromocytoma cells from serum deprivation-induced death. Our analyses on human lymphocytes harboring A3243G mitochondrial DNA mutation (MELAS cells) suggested HN as a therapeutic tool for MELAS. We showed that HN suppressed the decline of intracellular ATP concentration, which was more exaggerated in a serum-deprived lymphocyte of the MELAS patients than in control cells. We further demonstrated that HN inhibited the preferential increase of mutant mtDNA caused by serum deprivation. The number of mitochondrial DNA copies, which was increased more to compensate for serum deprivation-induced reduction of energy production within the MELAS cell compared with the normal lymphocyte, was reduced by HN treatment. All these results implied the beneficial effect of HN to the therapy of MELAS whose pathophysiology is mainly related with mutation-induced decline in ability to supply cellular energy requirements.