Mitochondrial-derived peptide humanin as therapeutic target in cancer and degenerative diseases

ABSTRACT

Introduction: Mitochondrial-derived peptides (MDPs) are encoded within the mitochondrial genome. They signal within the cell or are released to act as autocrine/paracrine/endocrine cytoprotective factors playing a key role in the cellular stress response. The first reported and better characterized MDP is humanin (HN), which exerts robust protective effects against a myriad of cytotoxic stimuli in many cell types. These effects have led to the evaluation of HN and its analogs as therapeutic targets for several chronic diseases.

Areas covered: We describe the latest findings on the mechanism of action of HN and discuss the role of HN as therapeutic target for neurodegenerative and cardiovascular diseases, diabetes, male infertility, and cancer. Since HN can be detected in circulation, we also depict its value as a biomarker for these diseases.

Expert opinion: HN analogs and peptide mimetics have been developed over the last decade and show promising results in preclinical models of degenerative diseases. Local administration of gene therapy vectors that overexpress or silence endogenous HN could also hold therapeutic potential. Controversy on the role of HN in cancer progression and chemoresistance should be addressed before the translation of these therapeutic approaches.

KEYWORDS:

• Humanin
• cancer
• mitochondrial-derived peptides
• therapeutic targets

Article highlights

• Humanin exerts a robust cytoprotective effect that inhibits the intrinsic proapoptotic pathway and restores mitochondrial function.

• Humanin can be secreted and exerts its cytoprotective effect in autocrine, paracrine, and endocrine manners through binding to membrane receptors.

• Circulating levels of Humanin could hold value as biomarkers in several diseases.

• Although the role of Humanin as chemoprotective has been demonstrated in normal cells, its role in tumor progression and chemoresistance remains controversial.

• Humanin and its analogs have therapeutic potential for the treatment of degenerative diseases, but their role in the pathogenesis of cancer needs to be ruled out before translation to the clinical practice.

• Local overexpression or silencing of endogenous Humanin using gene therapy vectors could improve the efficacy and safety profile of therapeutic strategies that target this peptide.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This work was funded by Consejo Nacional de Investigaciones Científicas y Tecnológicas (doctoral fellowship awarded to AS Asad and postdoctoral fellowship to MF Gottardo), Agencia Nacional de Promoción Científica y Tecnológica (PICT 2015–3309 to M Candolfi; PICT 2014–0334 to A Seilicovich, doctoral fellowships to AJ Nicola Candia and CF Zuccato), Instituto Nacional del Cáncer (Argentina, Asistencia Financiera IV to M Candolfi) and the University of Buenos Aires.