Elamipretide Promotes Mitophagosome Formation and Prevents Its Reduction Induced by Nutrient Excess in INS1 β-cells

J Mol Biol. 2018 Dec 7;430(24):4823-4833. doi: 10.1016/j.jmb.2018.10.020. Epub 2018 Oct 30.

Abstract

Elamipretide is a tetrapeptide that restores defects in mitochondrial function, binds to cardiolipin, and is being tested in clinical trials for mitochondria-related diseases. However, whether elamipretide modulates mitochondrial quality control and dynamics, processes essential to preserve mitochondrial function, is unclear. Thus, we tested the effects of elamipretide on mitochondrial morphology, mitophagosome formation, and their early disruption induced by excess nutrients in INS1 β-cells. Elamipretide treatment was sufficient to increase engulfment of mitochondria into autophagosomes in control INS1 β-cells, without inducing widespread changes in mitochondrial morphology or membrane potential. In an early pathogenic context mimicked by short-term exposure to nutrient excess, elamipretide treatment prevented both mitochondrial fragmentation and defects in the engulfment of mitochondria into autophagosomes. On the other hand, elamipretide did not prevent lysosomal defects induced by nutrient excess. Accordingly, elamipretide treatment did not entail benefits on pathogenic p62 and LC3II accumulation or on insulin secretory function. In conclusion, our data show that elamipretide selectively stimulates the engulfment of mitochondria into autophagosomes and prevents its defects induced by nutrient excess. Thus, we propose that improved selectivity of mitochondrial quality control processes might contribute to the benefits stemming from elamipretide treatments in other disease models.

Keywords: SS-31; elamipretide; lipotoxicity; mitochondria; mitophagy; β-cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagosomes / metabolism*
  • Cell Line
  • Humans
  • Insulin-Secreting Cells / cytology*
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Lysosomes / metabolism
  • Membrane Potential, Mitochondrial
  • Microtubule-Associated Proteins / metabolism
  • Mitochondria / drug effects*
  • Mitochondria / metabolism
  • Mitochondrial Turnover / drug effects
  • Nutrients / pharmacology*
  • Oligopeptides / pharmacology*
  • RNA-Binding Proteins / metabolism

Substances

  • MAP1LC3A protein, human
  • Microtubule-Associated Proteins
  • Oligopeptides
  • P62 protein, human
  • RNA-Binding Proteins
  • arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide