title: SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore.
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.
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Santhanam
authors.initials: S
authors.lastname: Shanmughapriya
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Sudarsan
authors.initials: S
authors.lastname: Rajan
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Nicholas E
authors.initials: NE
authors.lastname: Hoffman
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Higgins
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Dhanendra
authors.initials: D
authors.lastname: Tomar
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Neeharika
authors.initials: N
authors.lastname: Nemani
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Hines
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Dylan J
authors.initials: DJ
authors.lastname: Smith
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Akito
authors.initials: A
authors.lastname: Eguchi
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Sandhya
authors.initials: S
authors.lastname: Vallem
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Farah
authors.initials: F
authors.lastname: Shaikh
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Maggie
authors.initials: M
authors.lastname: Cheung
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Leonard
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Stolakis
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Wolfers
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Ibetti
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: J Kurt
authors.initials: JK
authors.lastname: Chuprun
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Neelakshi R
authors.initials: NR
authors.lastname: Jog
authors.affiliation: Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Houser
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.affiliation: Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA; Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Elrod
authors.affiliation: Department of Biochemistry, Temple University School of Medicine, Philadelphia, PA 19140, USA; Center for Translational Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA; Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA. Electronic address: madeshm@temple.edu.
authors.forename: Muniswamy
authors.initials: M
authors.lastname: Madesh
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D016923:Cell Death; D021983:Cyclophilins / Q000737:chemistry / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial; D008666:Metalloendopeptidases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism*; D000097322:Peptidyl-Prolyl Isomerase D
chemical_list: D000074183:ATPases Associated with Diverse Cellular Activities; D002118:Calcium; D021983:Cyclophilins; D008666:Metalloendopeptidases; D017382:Reactive Oxygen Species; D050995:Voltage-Dependent Anion Channel 1; C494762:VDAC1 protein, human; C112889:SPG7 protein, human; C114456:PPID protein, human; D000097322:Peptidyl-Prolyl Isomerase D