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

被引：184

作者：

Shanmughapriya, Santhanam ^{[1
,2
]}

Rajan, Sudarsan ^{[1
,2
]}

Hoffman, Nicholas E. ^{[1
,2
]}

Higgins, Andrew M. ^{[1
,2
]}

Tomar, Dhanendra ^{[1
,2
]}

Nemani, Neeharika ^{[1
,2
]}

Hines, Kevin J. ^{[1
,2
]}

Smith, Dylan J. ^{[1
,2
]}

Eguchi, Akito ^{[1
,2
]}

Vallem, Sandhya ^{[1
,2
]}

Shaikh, Farah ^{[1
,2
]}

Cheung, Maggie ^{[1
,2
]}

Leonard, Nicole J. ^{[1
,2
]}

Stolakis, Ryan S. ^{[1
,2
]}

Wolfers, Matthew P. ^{[1
,2
]}

Ibetti, Jessica ^{[2
,3
]}

Chuprun, J. Kurt ^{[2
,3
]}

Jog, Neelakshi R. ^{[1
,2
]}

Houser, Steven R. ^{[4
]}

Koch, Walter J. ^{[2
,3
]}

Elrod, John W. ^{[2
,3
]}

Madesh, Muniswamy ^{[1
,2
,4
]}

机构：

[1] Temple Univ, Sch Med, Dept Biochem, Philadelphia, PA 19140 USA

[2] Temple Univ, Sch Med, Ctr Translat Med, Philadelphia, PA 19140 USA

[3] Temple Univ, Sch Med, Dept Pharmacol, Philadelphia, PA 19140 USA

[4] Temple Univ, Sch Med, Cardiovasc Res Ctr, Philadelphia, PA 19140 USA

来源：

MOLECULAR CELL | 2015年 / 60卷 / 01期

关键词：

CYCLOPHILIN-D; ATP SYNTHASE; SPASTIC PARAPLEGIA; CA2+ UPTAKE; CELL-DEATH; C-SUBUNIT; CALCIUM; CHANNELS; IMPAIRMENT; ACTIVATION;

D O I：

10.1016/j.molcel.2015.08.009

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Mitochondrial permeability transition is a phenomenon in which the mitochondrial permeability transition pore (PTP) abruptly opens, resulting in mitochondrial membrane potential (Delta psi(m)) 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 cyclophilinD(CypD, PPIF) knock-down with sustained Delta psi(m) 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 Delta psi(m) 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.

引用

页码：47 / 62

页数：16

共 46 条

[1]

An uncoupling channel within the c-subunit ring of the F1FO ATP synthase is the mitochondrial permeability transition pore [J].