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The Mitochondrial-Derived Peptides, HumaninS14G and Small Humanin-like Peptide 2, Exhibit Chaperone-like Activity

Alan K Okada1, Kazuki Teranishi1, Fleur Lobo1

  • 1Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California, 90033, USA.

Scientific Reports
|August 12, 2017
PubMed

Insights

Mitochondrial-derived peptides (MDPs) like humaninS14G and SHLP2 inhibit islet amyloid polypeptide (IAPP) misfolding by targeting toxic amyloid seeds. These findings suggest MDPs as potential therapeutics for type 2 diabetes mellitus (T2DM).

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Background:

  • Mitochondrial-derived peptides (MDPs) are stress response factors with protective roles in amyloid disease models.
  • Their cytoprotective functions are often linked to anti-apoptotic activity, but their role in the unfolded protein response and direct interaction with amyloidogenic proteins is less understood.
  • Islet amyloid polypeptide (IAPP) misfolding is a critical pathogenic event in type 2 diabetes mellitus (T2DM).

Purpose of the Study:

  • To investigate the effects of the MDP analog humaninS14G (HNG) and the MDP small humanin-like peptide 2 (SHLP2) on IAPP misfolding.
  • To determine if MDPs can inhibit IAPP misfolding and amyloid seeding.
  • To elucidate the mechanism by which MDPs interact with IAPP.

Main Methods:

  • Thioflavin T fluorescence assays to monitor IAPP misfolding.
  • Seeded fluorescence and co-sedimentation studies to assess amyloid seeding and binding.
  • Electron paramagnetic resonance spectroscopy and circular dichroism to analyze MDP-IAPP interactions.

Main Results:

  • HNG inhibited IAPP misfolding at substoichiometric concentrations.
  • MDPs effectively blocked IAPP amyloid seeding and directly bound to misfolded, seeding-capable IAPP species.
  • MDPs do not bind to IAPP monomers, indicating a specific interaction with misfolded forms.

Conclusions:

  • MDPs exhibit novel chaperone-like activity by specifically targeting misfolded IAPP seeds, thereby inhibiting IAPP misfolding.
  • HNG and SHLP2, with their anti-apoptotic and potential metabolic benefits, are promising therapeutic candidates for T2DM.
  • Other MDPs may also be developed as therapeutics for protein-misfolding diseases.

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