SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore

Santhanam Shanmughapriya, Sudarsan Rajan, Nicholas E. Hoffman, Andrew M. Higgins, Dhanendra Tomar, Neeharika Nemani, Kevin J. Hines, Dylan J. Smith, Akito Eguchi, Sandhya Vallem, Farah Shaikh, Maggie Cheung, Nicole J. Leonard, Ryan S. Stolakis, Matthew P. Wolfers, Jessica Ibetti, J. Kurt Chuprun, Neelakshi R. Jog, Steven R. Houser, Walter J. KochJohn W. Elrod, Muniswamy Madesh

Producción científica: Articlerevisión exhaustiva

161 Citas (Scopus)

Resumen

Mitochondrial permeability transition is a phenomenon in which the mitochondrial permeability transition pore (PTP) abruptly opens, resulting in mitochondrial membrane potential (δΨm) dissipation, loss of ATP production, and cell death. Several genetic candidates have been proposed to form the PTP complex, however, the core component is unknown. We identified a necessary and conserved role for spastic paraplegia 7 (SPG7) in Ca2+- and ROS-induced PTP opening using RNAi-based screening. Loss of SPG7 resulted in higher mitochondrial Ca2+ retention, similar to cyclophilin D (CypD, PPIF) knockdown with sustained δΨm during both Ca2+ and ROS stress. Biochemical analyses revealed that the PTP is a heterooligomeric complex composed of VDAC, SPG7, and CypD. Silencing or disruption of SPG7-CypD binding prevented Ca2+- and ROS-induced δΨm depolarization and cell death. This study identifies an ubiquitously expressed IMM integral protein, SPG7, as a core component of the PTP at the OMM and IMM contact site.

Idioma originalEnglish (US)
Páginas (desde-hasta)47-62
Número de páginas16
PublicaciónMolecular Cell
Volumen60
N.º1
DOI
EstadoPublished - 2015
Publicado de forma externa

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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