SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore.
Publication/Presentation Date
10-1-2015
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.
Volume
60
Issue
1
First Page
47
Last Page
62
ISSN
1097-4164
Published In/Presented At
Shanmughapriya, S., Rajan, S., Hoffman, N. E., Higgins, A. M., Tomar, D., Nemani, N., Hines, K. J., Smith, D. J., Eguchi, A., Vallem, S., Shaikh, F., Cheung, M., Leonard, N. J., Stolakis, R. S., Wolfers, M. P., Ibetti, J., Chuprun, J. K., Jog, N. R., Houser, S. R., Koch, W. J., … Madesh, M. (2015). SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore. Molecular cell, 60(1), 47–62. https://doi.org/10.1016/j.molcel.2015.08.009
Disciplines
Medicine and Health Sciences
PubMedID
26387735
Department(s)
Department of Surgery
Document Type
Article