Scientists discovered that the humanin peptide, known for protecting brain cells, actually comes in many slightly different forms that are made from nuclear DNA, not just mitochondria. Some of these versions are active in the body and can be turned on by things like beta‑carotene, while tiny changes in their sequence can make them work better or worse at stopping cell death.

Humanin (HN) is a recently identified neuroprotective and antiapoptotic peptide derived from a portion of the mitochondrial MT-RNR2 gene. We provide bioinformatic and expression data suggesting the existence of 13 MT-RNR2-like nuclear loci predicted to maintain the open reading frames of 15 distinct full-length HN-like peptides. At least ten of these nuclear genes are expressed in human tissues, and respond to staurosporine (STS) and beta-carotene. Sequence comparisons of the nuclear HN isoforms and their homologues in other species reveal two consensus motifs, encompassing residues 5-11 (GFS/NCLLL), and 14-19 (SEIDLP/S). Proline vs serine in position 19 may determine whether the peptide is secreted or not, while threonine in position 13 may be important for cell surface receptor binding. Cytoprotection against the STS-induced apoptosis conferred by the polymorphic HN5 variant, in which threonine in position 13 is replaced with isoleucine, is reduced compared to the wild type HN5 peptide.