Impaired flickering of the permeability transition pore causes SPG7 spastic paraplegia

Irene Sambri, Filomena Massa, Francesca Gullo, Simone Meneghini, Laura Cassina, Michela Carraro, Giorgia Dina, Angelo Quattrini, Lorenzo Patanella, Annamaria Carissimo, Antonella Iuliano, Filippo Santorelli, Franca Codazzi, Fabio Grohovaz, Paolo Bernardi, Andrea Becchetti, Giorgio Casari

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Mutations of the mitochondrial protein paraplegin cause hereditary spastic paraplegia type 7 (SPG7), a so-far untreatable degenerative disease of the upper motoneuron with still undefined pathomechanism. The intermittent mitochondrial permeability transition pore (mPTP) opening, called flickering, is an essential process that operates to maintain mitochondrial homeostasis by reducing intra-matrix Ca2+ and reactive oxygen species (ROS) concentration, and is critical for efficient synaptic function. Methods: We use a fluorescence-based approach to measure mPTP flickering in living cells and biochemical and molecular biology techniques to dissect the pathogenic mechanism of SPG7. In the SPG7 animal model we evaluate the potential improvement of the motor defect, neuroinflammation and neurodegeneration by means of an mPTP inducer, the benzodiazepine Bz-423. Findings: We demonstrate that paraplegin is required for efficient transient opening of the mPTP, that is impaired in both SPG7 patients-derived fibroblasts and primary neurons from Spg7−/− mice. We show that dysregulation of mPTP opening at the pre-synaptic terminal impairs neurotransmitter release leading to ineffective synaptic transmission. Lack of paraplegin impairs mPTP flickering by a mechanism involving increased expression and activity of sirtuin3, which promotes deacetylation of cyclophilin D, thus hampering mPTP opening. Pharmacological treatment with Bz-423, which bypasses the activity of CypD, normalizes synaptic transmission and rescues the motor impairment of the SPG7 mouse model. Interpretation: mPTP targeting opens a new avenue for the potential therapy of this form of spastic paraplegia. Funding: Telethon Foundation grant (TGMGCSBX16TT); Dept. of Defense, US Army, grant W81XWH-18–1–0001

Original languageEnglish
Article number103050
JournalEBioMedicine
Volume61
DOIs
Publication statusPublished - Nov 2020

Keywords

  • Hereditary spastic paraplegia
  • Mitochondria
  • Paraplegin
  • Permeability transition pore
  • SPG7
  • Synaptic vesicles

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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