Category
Mitochondrial Health
A class of peptides either derived from mitochondrial DNA or designed to target mitochondrial function. MOTS-c and Humanin are encoded within the mitochondrial genome itself, making them unique among peptide research targets.
4 peptides in this category
What are mitochondrial peptides?
Mitochondrial peptides are a recently discovered class of signaling molecules encoded within the mitochondrial genome itself. MOTS-c and Humanin are the two best characterized: both are produced by mitochondria and secreted to regulate systemic metabolism, stress responses, and cell survival. MOTS-c improves insulin sensitivity and metabolic flexibility via AMPK activation. Humanin provides neuroprotection against amyloid toxicity and ischemic injury. SS-31 (elamipretide) is a synthetic peptide that targets the inner mitochondrial membrane to preserve electron transport chain function under oxidative stress, and is in clinical trials for heart failure.
Mitochondria contain their own genome — a small, circular DNA molecule encoding 13 proteins plus the RNA machinery needed for their translation. For decades, researchers focused almost exclusively on these 13 protein-coding genes. In 2013, the discovery of Humanin and subsequently MOTS-c revealed that mitochondrial DNA also encodes small peptides that are secreted and act as systemic signaling molecules. This was a significant conceptual shift: mitochondria are not simply energy factories but active participants in whole-body metabolic signaling through these peptides.
MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) regulates nuclear gene expression by activating AMPK and modulating the folate and methionine cycle in a way that improves metabolic flexibility and insulin sensitivity. Humanin is cytoprotective, particularly in the context of amyloid toxicity and ischemic injury, and declines with age. SS-31 (elamipretide) is not mitochondrially encoded but specifically targets the inner mitochondrial membrane by binding cardiolipin, stabilizing the electron transport chain under oxidative stress and restoring ATP production in damaged mitochondria. It has entered phase II and III clinical trials for heart failure and Barth syndrome.
Compounds
Peptides in this category
Humanin
PreclinicalHN · mitochondria-derived peptide humanin
Humanin is a 21-amino-acid mitochondria-derived peptide (MDP) encoded within the 16S rRNA gene of mitochondrial DNA. It is cytoprotective against Alzheimer's-related neuronal death, reduces oxidative stress, improves insulin sensitivity, and suppresses apoptosis through multiple pathways (STAT3, IGFBP-3, FPRL1). Circulating humanin levels decline with age, linking it to age-related diseases.
MOTS-c
PreclinicalMitochondrial ORF of the 12S rRNA Type-C
MOTS-c is a 16-amino-acid mitochondria-derived peptide encoded within the 12S rRNA gene. It regulates AMPK signaling, enhances insulin sensitivity, promotes muscle glucose uptake independently of insulin, and improves exercise capacity. Animal studies show it extends lifespan and protects against diet-induced obesity and age-related metabolic dysfunction. It translocates to the nucleus under stress to regulate adaptive gene expression.
SHLP2
PreclinicalSmall Humanin-Like Peptide 2
SHLP2 is a mitochondria-derived peptide (MDP) encoded in the 16S rRNA region of the mitochondrial genome, from the same region as humanin. It promotes mitochondrial biogenesis, reduces reactive oxygen species, and inhibits apoptosis in multiple cell types. Research shows it protects against age-related macular degeneration, reduces atherosclerosis risk, and is inversely correlated with type 2 diabetes and Parkinson's disease. Circulating SHLP2 declines with age.
SS-31
Phase IIElamipretide · Szeto-Schiller 31
SS-31 (elamipretide) is a tetrapeptide that selectively targets cardiolipin in the inner mitochondrial membrane, stabilizing cristae architecture and enhancing ATP synthesis efficiency. It reduces mitochondrial ROS production and protects against ischemia-reperfusion injury, heart failure, and aging-related mitochondrial dysfunction. Phase 2 trials have been conducted for heart failure with preserved ejection fraction and Barth syndrome.
Research applications
What researchers are studying
Metabolic regulation via AMPK
MOTS-c activates AMPK in skeletal muscle and liver, increasing glucose uptake, beta-oxidation, and mitochondrial biogenesis. In aged mice with diet-induced insulin resistance, MOTS-c administration improves insulin sensitivity to near-normal levels. The peptide's effects on one-carbon metabolism also suggest involvement in epigenetic regulation, as this pathway supplies methyl groups for DNA and histone methylation.
Neuroprotection from amyloid toxicity
Humanin binds amyloid beta peptide directly and reduces its aggregation and cytotoxicity in neuronal cultures. It also activates the STAT3 and PI3K/Akt survival pathways, protecting cells from apoptosis induced by amyloid, oxidative stress, and ischemia. CSF levels of Humanin are lower in Alzheimer's patients than in age-matched controls, suggesting a potential deficit in endogenous neuroprotective signaling.
Inner membrane stabilization
SS-31 (elamipretide) penetrates the inner mitochondrial membrane and binds cardiolipin, a phospholipid critical for organizing the electron transport chain complexes. Under oxidative stress, cardiolipin peroxidation disrupts this organization and releases cytochrome C, triggering apoptosis. SS-31 prevents this cascade, preserving ATP production in ischemia-reperfusion models and improving cardiac and renal function in disease models.
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