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

Mol Cell. 2015 Oct 1;60(1):47-62. doi: 10.1016/j.molcel.2015.08.009.

Santhanam Shanmughapriya ¹, Sudarsan Rajan ¹, Nicholas E Hoffman ¹, Andrew M Higgins ¹, Dhanendra Tomar ¹, Neeharika Nemani ¹, Kevin J Hines ¹, Dylan J Smith ¹, Akito Eguchi ¹, Sandhya Vallem ¹, Farah Shaikh ¹, Maggie Cheung ¹, Nicole J Leonard ¹, Ryan S Stolakis ¹, Matthew P Wolfers ¹, Jessica Ibetti ², J Kurt Chuprun ², Neelakshi R Jog ¹, Steven R Houser ³, Walter J Koch ², John W Elrod ², Muniswamy Madesh ⁴

Affiliations

1 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.
2 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.
3 Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, PA 19140, USA.
4 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.

PMID: 26387735 DOI: 10.1016/j.molcel.2015.08.009

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.

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