Overview
Humanin is a small naturally occurring peptide that was originally discovered encoded within the mitochondrial genome, making it part of a relatively recently identified class of molecules known as mitochondria-derived peptides (MDPs). It is a 21-amino acid peptide found across multiple species, including humans, and is notable for being one of the first peptides recognized as being translated from mitochondrial ribosomal RNA rather than nuclear DNA. Humanin has drawn significant scientific interest for its role in cellular processes, particularly in relation to mitochondrial function and cell survival signaling, and researchers have studied it in the context of oxidative stress, neurological models, and inflammatory pathways. It is available in synthetic form for laboratory use and is studied strictly for research purposes, with no approved applications for human therapeutic use.
Research & Bioactivity
Humanin is a mitochondria-derived peptide encoded within the mitochondrial genome, and researchers have studied it extensively in the context of mitochondrial function, cellular stress responses, and apoptosis regulation. Studies have examined its role in models of neurotoxicity, including in vitro investigations using PC12 cells exposed to rotenone, where research has explored how Humanin may influence reactive oxygen species formation through signaling pathways involving SIRT3, Nrf2, and HO-1. Researchers have also investigated Humanin and its more potent analogue Humanin-G in animal and cellular models of sepsis-associated acute respiratory distress syndrome, with particular focus on endothelial cell mitochondrial integrity under inflammatory conditions. Beyond acute stress models, research has investigated Humanin's potential involvement in the resolution of inflammatory processes and its classification within a broader family of mitochondrial-encoded peptides thought to participate in mito-nuclear communication. Some research has also explored circulating levels of Humanin in the context of brain aging and exercise interventions, reflecting scientific interest in how this peptide may serve as a marker or mediator of mitochondrial health across different physiological conditions.
Published Research
Humanin-G protects septic ARDS by mediating mitochondrial function in lung vascular endothelial cells.
Wu X, Li Y, Lin X, Yu Z, Mu S, et al. — 2026
Recent investigations show that mitochondrial impairment significantly contributes to endothelial damage in septic acute respiratory distress syndrome (ARDS). Humanin (HN) and its derivative Humanin-G (HNG) are mitochondrial polypeptides which have been identified as inhibitors of cellular apoptosis and neuroprotective agents against oxidative stress. This study aims to elucidate the effects of HNG on pulmonary vascular endothelial damage. In septic ARDS patients, serum concentrations of HN increased markedly on Day 1, followed by a progressive decrease from Day 3 to Day 7. A murine model of septic ARDS was established through intraperitoneal injection of lipopolysaccharide. The results showed that HNG pretreatment significantly reduced inflammatory factor expression in both in vivo and in vitro settings, as confirmed by qPCR and Western blot. Furthermore, HNG treatment conferred protection against lung injury, restored mitochondrial morphology, improved mitochondrial respiratory function, and corrected impaired membrane potential, as assessed by H&E staining, transmission electron microscopy, Seahorse analysis, and JC-1 staining, respectively. Additionally, protein-peptide interaction analysis suggested that HNG binds to the interleukin-6 receptor alpha, and immunoprecipitation confirmed that HNG competitively interacts with the IL-6 receptor family in comparison to IL-6. Furthermore, WB analysis indicated that the protective effects of HNG on mitochondria may be largely due to the suppression of STAT3 expression in septic lung endothelial cells. In summary, this study suggests that the administration of the mitochondrial peptide HNG confers protective effects and mitigates mitochondrial damage by inhibiting the downstream pro-inflammatory pathways of IL-6/STAT3 in the pulmonary vascular endothelial cells of septic ARDS.
Humanin improved the rotenone-induced reactive oxygen species formation in PC12 cells by modulating the SIRT3/Nrf2/HO-1 signaling pathway.
Shan Y, Liu X, Ge W, Zhang Q, Yan S — 2026
ObjectiveMitochondrial dysfunction is the key factor in rotenone-induced neurotoxicity in dopaminergic neurons. This study aimed to investigate the role and potential mechanism of the mitochondrial DNA encoded peptide Humanin (HN) in alleviating rotenone-induced neurotoxicity.MethodsRotenone was added to the cultured PC12 cells to induce neurotoxicity. PC12 cells were preincubated with HN, which has a protective effect. Cell counting kit-8 (CCK-8) was used to evaluate PC12 cell viability. Flow cytometry to detect the content of reactive oxygen species (ROS) in PC12 cells. Western blot analysis was used to detect the expression of superoxide dismutase 2 (SOD2), acetylated SOD (Ac-SOD), sirtuin 3 (SIRT3), nuclear factor erythroid 2-related factor 2 (Nrf2), heme-oxygenase-1 (HO-1), and NAD(P)H:quinone oxidoreductase 1 (NQO1). The corresponding kits were used to measure the NAD+/NADH ratio and SOD content separately.ResultsHN pretreatment significantly increased PC12 cell survival, reduced ROS formation, and increased the NAD/NADH ratio. It also increased the expression of SIRT3, Nrf2, HO-1, and NQO1 proteins and decreased the expression of Ac-SOD protein under rotenone exposure. At the same time, it also activated the Nrf2/HO-1 signaling pathway, which depends on HN-mediated SIRT3 activation.ConclusionThese results suggest that HN plays a protective role in rotenone-induced neurotoxicity by suppressing oxidative stress and activating the antioxidant response via the Nrf2/HO-1 pathway, which is regulated by SIRT3 in PC12 cells.
[Humanin: a mitochondria-hidden peptide serving inflammation resolution].
Maraux M, Saas P, Cherrier T — 2026
Preserving brain health in aging: structural and biochemical benefits of water based resistance training, a randomized controlled trial.
Hosseini MH, Baghalishahi M, Moshrefi M, Pinto-Fraga J, Khajeh S, et al. — 2026
BACKGROUND: Brain aging leads to structural changes, especially atrophy, which can result in dysfunction. Mitochondrial dysfunction is thought to explain the structural changes in brain aging. OBJECTIVE: This study aimed to investigate the effects of a 12-week water-based resistance training (WBRT) program on brain structural integrity, mitochondrial-related growth factors, oxidative stress, and inflammation in older women. METHODS: A total of 24 older women (mean age:66) were randomly assigned to a WBRT group ( = 12) or a control (CON) group ( = 12). Participants in the WBRT group performed supervised resistance training in water three times per week for 12 weeks. Brain structural changes were assessed using magnetic resonance imaging (MRI), and blood samples were analyzed for Humanin (HN), Fibroblast Growth Factor 21 (FGF21), Growth Differentiation Factor 15 (GDF-15), Brain-Derived Neurotrophic Factor (BDNF), and Insulin-like Growth Factor 1 (IGF-1) as well as oxidative and inflammation biomarkers. RESULTS: The WBRT group showed significant increases in gray matter, subcortical gray matter, cerebellar gray matter volume, and cerebrum white matter compared to the CON group ( < 0.05). Furthermore, WBRT resulted in significant increases in BDNF, IGF-1, FGF21, and GDF-15 levels ( < 0.05). Malondialdehyde decreased, and glutathione peroxidase increased, with significant reductions in tumor necrosis factor-alpha and an increase in interleukin-10 in the WBRT group compared to the CON group ( < 0.05), suggesting anti-inflammatory and antioxidant effects of WBRT. CONCLUSION: These findings support the potential beneficial effects of WBRT as an non-pharmacological intervention to counteract age-related brain atrophy and promote brain health in aging populations. TRIAL REGISTRATION: IR.KMU.REC.1402.068, 29/06/2023 SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12877-026-07413-x.
Small but mighty: mitochondrial DNA at the centre of retrograde signalling.
Harding E, Bazzani V, Vascotto C — 2026
Mitochondria form highly dynamic and interconnected networks that continuously communicate with the cytoplasm and the nucleus to maintain cellular homeostasis and coordinate adaptive responses to stress. This bidirectional communication, known as mito-nuclear crosstalk, is essential for regulating metabolism, redox balance, immune activation, and cell fate decisions. While retrograde signalling has traditionally been viewed as a consequence of metabolic or oxidative perturbations, mounting evidence positions mitochondrial DNA (mtDNA) as a central and active regulator of these signalling pathways. Beyond encoding essential subunits of the electron transport chain, mtDNA functions as a signalling hub that conveys information about mitochondrial functional status to the nucleus. Perturbations in mtDNA integrity, copy number, or expression initiate retrograde responses through metabolic rewiring, alterations in redox and calcium signalling, and activation of stress-responsive transcriptional programmes. In addition, mtDNA-derived products, including mitochondrial-derived non-coding RNAs (mt-ncRNAs) and mitochondrial-derived peptides (MDPs), have emerged as key messengers that shuttle between cellular compartments, reshape nuclear gene expression, and influence cellular and systemic responses to stress. These molecules participate in diverse processes, ranging from mitochondrial biogenesis and quality control to innate immune activation and epigenetic regulation. This review synthesises current knowledge on mtDNA-driven retrograde signalling, highlighting both classical and emerging mechanisms by which the mitochondrial genome communicates with the nucleus. We discuss how mtDNA instability, defective repair, and altered mitochondrial dynamics trigger signalling cascades involving metabolic sensors, calcium fluxes, and innate immune pathways. We further examine the growing evidence supporting regulatory roles for mt-ncRNAs, including small RNAs, long non-coding RNAs, double-stranded RNAs, and circular RNAs, as well as MDPs such as Humanin, SHLPs, and MOTS-c, in coordinating adaptive nuclear responses. By integrating these diverse signalling modalities, this review highlights mtDNA as an integral and active signalling platform that coordinates mitochondrial stress sensing with nuclear adaptive responses.