Amyloid β, α-synuclein and the c subunit of the ATP synthase: Can these peptides reveal an amyloidogenic pathway of the permeability transition pore?

Giuseppe F. Amodeo, Evgeny V. Pavlov

Research output: Contribution to journalArticlepeer-review

Abstract

Mitochondrial Permeability Transition (PT) is a phenomenon of increased permeability of the inner mitochondrial membrane in response to high levels of Ca2+ and/or reactive oxygen species (ROS) in the matrix. PT occurs upon the opening of a pore, namely the permeability transition pore (PTP), which dissipates the membrane potential uncoupling the respiratory chain. mPT activation and PTP formation can occur through multiple molecular pathways. The specific focus of this review is to discuss the possible molecular mechanisms of PTP that involve the participation of mitochondrially targeted amyloid peptides Aβ, α-synuclein and c subunit of the ATP synthase (ATPase). As activators of PTP, amyloid peptides are uniquely different from other activators because they are capable of forming channels in lipid bilayers. This property rises the possibility that in this permeabilization pathway the formation of the channel involves the direct participation of peptides, making it uniquely different from other PTP induction mechanisms. In this pathway, a critical step of PTP activation involves the import of amyloidogenic peptides from the cytosol into the matrix. In the matrix these peptides, which would fold into α-helical structure in native conditions, interact with cyclophilin D (CypD) and upon stimulation by elevated ROS and/or the Ca2+ spontaneously misfold into β-sheet ion conducting pores, causing PTP opening.

Original languageEnglish (US)
Article number183531
JournalBiochimica et Biophysica Acta - Biomembranes
Volume1863
Issue number3
DOIs
StatePublished - Mar 1 2021

Keywords

  • Amyloidogenic peptides
  • Calcium
  • Ion channels
  • Misfolded proteins
  • Mitochondria
  • Permeability tradition pore

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Cell Biology

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