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SPG7 Is an Essential and Conserved Component of the Mitochondrial Permeability Transition Pore
Open accessAbstract
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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“An RNA interference (RNAi)-based screening identified SPG7, paraplegin matrix AAA peptidase subunit (SPG7) as an essential component of the PTPC acting as part of VDAC-containing and CYPD-containing hetero-oligomers [406].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [406]
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Metadata
- Authors
- 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., Elrod, J. W., & Madesh, M.
- Affiliations
- Temple University (US)
- Corresponding author
- Madesh, Muniswamy
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 60
- Issue
- 1
- Pages
- 47-62
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4592475
- OpenAlex
- W1895235630
- Cited by
- 209
- References
- 49
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 10 · 2023: 17 · 2022: 20 · 2021: 13 · 2020: 25 · 2019: 23 · 2018: 26 · 2017: 22 · 2016: 24 · 2015: 1
- FWCI
- 10.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1S10RR027327, R01GM109882, R01HL086699, R01HL119306)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Keywords
- SPG7, mitochondrial permeability transition pore, mitochondrial permeability transition, cyclophilin D, voltage-dependent anion channel, mitochondrial membrane potential, reactive oxygen species, mitochondrial depolarization, cell death, inner membrane, outer membrane, RNAi screening
- MeSH terms
- ATPases Associated with Diverse Cellular Activities, Peptidyl-Prolyl Isomerase D, Binding Sites, Calcium, HeLa Cells, Humans, Metalloendopeptidases, Mitochondria, Cell Death, Reactive Oxygen Species, Cyclophilins, RNA Interference, Voltage-Dependent Anion Channel 1, Mitochondrial Membranes, Membrane Potential, Mitochondrial, HEK293 Cells
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