Systematic review of mitochondrial-derived peptides—humanin, MOTS-c, and SHLPs—as therapeutic candidates for neurodegenerative diseases including Alzheimer's, Parkinson's, and Huntington's disease, evaluating evidence from cellular and animal studies for neuroprotection, mitochondrial function preservation, and reduction of neuroinflammation and oxidative stress. Provides a comprehensive neurology-focused synthesis of MOTS-c. Positions MOTS-c alongside other MDPs as a therapeutic candidate class for neurodegenerative conditions—establishing the mechanistic rationale for clinical investigation of mitochondrial peptide supplementation in diseases where mitochondrial dysfunction drives progressive neuronal loss.
Abstract
Mitochondrial-derived peptides (MDPs), including humanin, MOTS-c, and small humanin-like peptides (SHLPs), have emerged as promising therapeutic candidates for neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). This review systematically evaluates current literature retrieved from databases including PubMed, Scopus, and Web of Science using keywords such as "mitochondrial-derived peptides," "neurodegeneration," "humanin," "MOTS-c," and "SHLPs." Studies were included based on their relevance to mitochondrial function, oxidative stress, neuroprotection, and anti-inflammatory mechanisms in AD, PD, and HD models. Despite growing interest, current research remains limited in understanding the precise molecular pathways. Our review highlights their role in mitigating disease-specific pathologies such as Amyloid-beta (Aβ) toxicity in AD, dopaminergic neuron loss in PD, and mutant huntingtin aggregation in HD while also emphasizing their potential to attenuate oxidative stress and neuroinflammation. By identifying critical knowledge gaps, particularly in the areas of molecular mechanisms of MDPs in neuroprotection, targeted delivery, and clinical translation, this review provides a comprehensive framework to guide future investigations.
Authors
Thakur, Rahul; Chauhan, Aman; Moudgil, Hardika; Singh, Sukhpal; Devi, Rooma