The paper shows that some tiny proteins made inside mitochondria, like MOTS‑c, can move into the cell nucleus when cells are stressed and directly turn on genes that help protect the cell. This is the first clear proof that a mitochondria‑derived peptide can act like a hormone inside the nucleus, hinting it might influence aging and stress resistance, though humanin itself wasn’t directly studied.

Mitochondria⁻nucleus (mitonuclear) retrograde signaling via nuclear import of otherwise mitochondrial targeted factors occurs during mitochondrial unfolded protein response (UPR^mt), a mechanism that counters mitochondrial and cellular stresses. Other than nuclear encoded proteins, mitochondrial DNA (mtDNA)-encoded peptides, such as humanin, are known to have important pro-survival and metabolic regulatory functions. A recent report has indicated that another mtDNA-encoded peptide, the mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), could translocate into the nucleus upon stress induction. In the nucleus, MOTS-c binds to DNA and regulates the transcription of stress response genes in concert with other transcription factors. This is the first clear example of a mitochondria-derived peptide (MDP) acting in the nucleus to affect transcriptional responses to stress. Thus, MOTS-c may bear some characteristics of a 'mitokine' factor that mediates mitohormesis, influencing cell survival as well as organismal health and longevity.