humanin and MELAS-Syndrome

Humanin is a member of a new family of peptides that are encoded by short open reading frames within the mitochondrial genome. It is conserved in animals and is both neuroprotective and cytoprotective. Here we report that in

Topics: Adult; Aged, 80 and over; Alzheimer Disease; Animals; Animals, Genetically Modified; Caenorhabditis elegans; Caenorhabditis elegans Proteins; Case-Control Studies; Child; Cohort Studies; DNA, Mitochondrial; Female; Forkhead Transcription Factors; Gene Dosage; Humans; Infant, Newborn; Intracellular Signaling Peptides and Proteins; Longevity; Macaca mulatta; MELAS Syndrome; Mice; Middle Aged; Mitochondria; Models, Animal; Mole Rats; Pregnancy; Young Adult

Humanin (HN) was originally identified as an endogenous peptide that protects neuronal cells from apoptosis by mutant Alzheimer's disease genes. This 24-residue peptide has been recently shown to suppress apoptosis by interfering with activation of Bcl-2-associated X protein (Bax) in cytosol. In the present study, we showed that HN increases ATP levels in human lymphocytes, muscular TE671 cells, and neural SKN-MC cells, and protects these cells from serum deprivation-induced apoptosis. The suppressed apoptotic death of serum-deprived cells would be explained by the anti-Bax effect of HN; however, HN also increased ATP levels of serum-supplemented cells (non-apoptotic cells), in which Bax is likely to be inactive. This result suggests the presence of a certain mechanism independent of Bax inactivation to increase ATP levels of cells under non-apoptotic condition. By treatment with HN, the ATP levels of lymphocytes from patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) associated with A3243G mutant mtDNA were increased as well, suggesting that HN is able to prevent cells in MELAS from falling into ATP deficiency. Our quantitative PCR findings indicated that the HN-induced increase in ATP may not be a consequence of mitochondrial proliferation, because HN rather suppressed mtDNA replication. This suppression may be important in the treatment of affected cells in MELAS, since the mutant mtDNAs that increase during compensatory mtDNA replication for ATP deficiency cause excessive formation of reactive oxygen species, leading to further energy crisis. We thus propose that HN, which increases cellular ATP levels without inducing mtDNA replication, may be suited for the treatment of MELAS.

Topics: Adenosine Triphosphate; Adult; Apoptosis; Cell Survival; Cells, Cultured; DNA, Mitochondrial; Humans; Intracellular Signaling Peptides and Proteins; Lymphocytes; MELAS Syndrome; Middle Aged; Muscles; Mutation; Proteins

Humanin (HN) was originally identified as an endogenous peptide that protects neuronal cells from apoptosis induced by various types of Alzheimer's disease-related insults. We have previously indicated that HN increases cellular ATP levels and speculated that this peptide may rescue energy-deficient cells in mitochondrial disorders. Here, we report, for the first time, increased HN expression in skeletal muscles from patients with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS). HN was strongly positive in all ragged-red fibers (RRFs) and some non-RRFs, and most of them were type 1 fibers generally requiring higher energy than type 2 fibers. HN in these fibers was localized in mitochondria. HN expression was also increased in small arteries that strongly reacted for succinate dehydrogenase. Our experiments on muscular TE671 cells indicated the possibility that synthesized HN increases cellular ATP levels by directly acting on mitochondria. From these in vivo and in vitro findings, we propose that HN expression might be induced in response to the energy crisis within affected fibers and vessels in MELAS muscles and further be a possible therapeutic candidate for MELAS.

Topics: Adenosine Triphosphatases; bcl-2-Associated X Protein; Cell Line, Tumor; Chaperonin 60; Electron Transport Complex IV; Gene Expression Regulation; Humans; Immunohistochemistry; Indoles; Intracellular Signaling Peptides and Proteins; MELAS Syndrome; Muscle, Skeletal; Proto-Oncogene Proteins c-bcl-2; Rhabdomyosarcoma; Succinate Dehydrogenase