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

TitleSPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore.
Publication TypeJournal Article
Year of Publication2015
AuthorsShanmughapriya, S, Rajan, S, Hoffman, NE, Higgins, AM, Tomar, D, Nemani, N, Hines, KJ, Smith, DJ, Eguchi, A, Vallem, S, Shaikh, F, Cheung, M, Leonard, NJ, Stolakis, RS, Wolfers, MP, Ibetti, J, J Chuprun, K, Jog, NR, Houser, SR, Koch, WJ, Elrod, JW, Madesh, M
JournalMol Cell
Volume60
Issue1
Pagination47-62
Date Published2015 Oct 01
ISSN1097-4164
KeywordsBinding Sites, Calcium, Cell Death, Cyclophilins, HEK293 Cells, HeLa Cells, Humans, Membrane Potential, Mitochondrial, Metalloendopeptidases, Mitochondria, Mitochondrial Membranes, Reactive Oxygen Species, RNA Interference, Voltage-Dependent Anion Channel 1
Abstract

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 Ca(2+)- and ROS-induced PTP opening using RNAi-based screening. Loss of SPG7 resulted in higher mitochondrial Ca(2+) retention, similar to cyclophilin D (CypD, PPIF) knockdown with sustained ΔΨm during both Ca(2+) 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 Ca(2+)- 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.

DOI10.1016/j.molcel.2015.08.009
Alternate JournalMol. Cell
Citation Key10.1016/j.molcel.2015.08.009
PubMed ID26387735
PubMed Central IDPMC4592475
Grant List1S10RR027327 / RR / NCRR NIH HHS / United States
R01HL086699 / HL / NHLBI NIH HHS / United States
R01HL119306 / HL / NHLBI NIH HHS / United States
R01 HL119306 / HL / NHLBI NIH HHS / United States
P01 DA037830 / DA / NIDA NIH HHS / United States
R01 GM109882 / GM / NIGMS NIH HHS / United States
S10 RR027327 / RR / NCRR NIH HHS / United States
R01 HL123966 / HL / NHLBI NIH HHS / United States
P01 HL091799 / HL / NHLBI NIH HHS / United States
R01GM109882 / GM / NIGMS NIH HHS / United States
R01 HL086699 / HL / NHLBI NIH HHS / United States