Scientists gave mice a peptide called humanin through the nose and saw it get into the brain, boost the cells' power plants, and protect against Parkinson‑like damage, improving the animals' movement. The peptide also made cells produce more of its own kind and turned on a growth‑signal pathway. However, human levels of the peptide didn’t differ in patients, and no human dosing or safety data are available yet.

<b>Rationale:</b> Mitochondrial dysfunction is a key factor in the pathogenesis of Parkinson's disease (PD). Accordingly, many aspects of mitochondrial function have been studied as a putative therapeutic target. Here we present a novel strategy to promote mitochondrial function and protect against Parkinson's disease by the peptide encoded within mitochondrial genome, mitochondria-derived peptide (MDP) humanin (HN). <b>Methods:</b> To test humanin as a potential biomarker in PD, we measured protein levels of circulating humanin from the plasma of PD patients and transgenic or neurotoxic mouse models of PD. Next, we aimed to identify whether HN peptide treatment can regulate its activity or expression. Using mouse models of PD, we assessed HN delivery to the brain via the nasal route of administration. We further revealed a possible mechanism underlying the therapeutic effectiveness of HN peptide for PD using <i>in vitro</i> and <i>ex vivo</i> model of PD. <b>Results:</b> Although the expression of intracellular HN was not correlated with PD, HN treatment itself could induce intracellular HN expression and enhance mitochondrial biogenesis inducing mitochondrial gene expression. After intranasal administration, HN peptide resulted in neuroprotection and behavioral recovery in an animal model of PD. Interestingly, HN peptide following intranasal delivery was found within the brain, mainly via the trigeminal pathways. Mechanistically, HN treatment induced activation of phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway which led to enhanced mitochondrial biogenesis resulting in upregulation of mitochondrial gene including humanin. <b>Conclusion</b>: These data support a novel role of mitochondrial protein humanin in mitochondrial function and neuronal survival against Parkinson's disease, in which humanin treatment is sufficient for stimulating mitochondrial gene expression.