Mitochondrial-Derived Peptides in Metabolic and Neuroprotective Mechanisms

Mitochondrial-derived peptides (MDPs) constitute a class of bioactive molecules encoded within the mitochondrial genome that exert endocrine-like functions across tissues. Key members include humanin, small humanin-like peptides (SHLPs) and the mitochondrial open reading frame of the 12S rRNA type-c (MOTS-c). These peptides have emerged as critical regulators of cellular metabolism, insulin sensitivity and energy homeostasis, as well as potent mediators of stress resilience in neurons. They engage distinct receptor systems and intracellular signalling cascades—such as chemokine receptor activation, PI3K/AKT and STAT3 pathways—to modulate mitochondrial biogenesis, glucose uptake, thermogenesis and synaptic survival. The ability of MDPs to cross the blood–brain barrier and influence hypothalamic circuits links peripheral energy status to central appetite regulation. Moreover, exercise and dietary interventions can stimulate endogenous production of MDPs, underpinning their role as mitokines in inter-organ communication. The dual capacity of these peptides to preserve metabolic balance and confer neuroprotection positions them as promising targets for therapies in obesity, diabetes and neurodegenerative disorders.

Research from Nature Portfolio

Recent studies have characterised the actions of SHLP2, revealing that both systemic and central administration of this peptide protects mice from high-fat diet–induced obesity and enhances insulin sensitivity. SHLP2 activates pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus, suppressing food intake and promoting thermogenesis via engagement of a chemokine receptor. Separately, research on MOTS-c has demonstrated that exercise induces its expression in skeletal muscle and circulation, where it orchestrates nuclear gene networks governing metabolism, proteostasis and muscle adaptation to stress. Intermittent administration of MOTS-c in aged mice improves physical capacity and healthspan, highlighting its potential to modulate age-dependent metabolic decline. Foundational work has also shown that humanin administration can prevent age-related cognitive impairment in rodent models, indicating broad protective effects across metabolic and neural systems.

Mitochondrial-Derived Peptides in Metabolic and Neuroprotective Mechanisms publication trend

The graph below shows the total number of articles in mitochondrial-derived peptides in metabolic and neuroprotective mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Mitochondrial-Derived Peptides (MDPs): Small bioactive peptides encoded by mitochondrial DNA that act as signalling molecules in multiple tissues.

Humanin (HN): A 24-amino-acid peptide with cytoprotective and neuroprotective properties, regulating apoptosis and metabolic pathways.

SHLPs (Small Humanin-Like Peptides): A family of peptides homologous to humanin, encoded within the 16S rRNA region, involved in cell viability and energy homeostasis.

MOTS-c: A 16-amino-acid peptide derived from the 12S rRNA region that modulates nuclear gene expression, muscle adaptation and whole-body metabolism.

Mitokine: A mitochondrial stress-induced factor released into circulation that mediates inter-organ communication and systemic adaptation.

PI3K/AKT Signalling: A key intracellular pathway activated by growth factors and peptides that promotes cell survival, metabolism and mitochondrial biogenesis.

References

1. Mitochondria-derived peptide SHLP2 regulates energy homeostasis through the activation of hypothalamic neurons. Nature Communications (2023).
2. Intranasal delivery of mitochondrial protein humanin rescues cell death and promotes mitochondrial function in Parkinson's disease. Theranostics (2023).
3. MOTS-c is an exercise-induced mitochondrial-encoded regulator of age-dependent physical decline and muscle homeostasis. Nature Communications (2021).
4. Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans. Scientific Reports (2018).
5. Mitochondrial stress and mitokines in aging. Aging Cell (2023).
6. Mitochondrial-Derived Peptides Are Down Regulated in Diabetes Subjects. Frontiers in Endocrinology (2019).