title: Regulation of the mitochondrial permeability transition pore by the outer membrane does not involve the peripheral benzodiazepine receptor (Translocator Protein of 18 kDa (TSPO)).
abstract: Translocator protein of 18 kDa (TSPO) is a highly conserved, ubiquitous protein localized in the outer mitochondrial membrane, where it is thought to play a key role in the mitochondrial transport of cholesterol, a key step in the generation of steroid hormones. However, it was first characterized as the peripheral benzodiazepine receptor because it appears to be responsible for high affinity binding of a number of benzodiazepines to non-neuronal tissues. Ensuing studies have employed natural and synthetic ligands to assess the role of TSPO function in a number of natural and pathological circumstances. Largely through the use of these compounds and biochemical associations, TSPO has been proposed to play a role in the mitochondrial permeability transition pore (PTP), which has been associated with cell death in many human pathological conditions. Here, we critically assess the role of TSPO in the function of the PTP through the generation of mice in which the Tspo gene has been conditionally eliminated. Our results show that 1) TSPO plays no role in the regulation or structure of the PTP, 2) endogenous and synthetic ligands of TSPO do not regulate PTP activity through TSPO, 3) outer mitochondrial membrane regulation of PTP activity occurs though a mechanism that does not require TSPO, and 4) hearts lacking TSPO are as sensitive to ischemia-reperfusion injury as hearts from control mice. These results call into question a wide variety of studies implicating TSPO in a number of pathological processes through its actions on the PTP.
authors.affiliation: From the Consiglio Nazionale delle Ricerche Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, I-35121 Padova, Italy.
authors.forename: Justina
authors.initials: J
authors.lastname: Šileikytė
authors.affiliation: the Vollum Institute, Oregon Health and Sciences University, Portland, Oregon 97239, and.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Blachly-Dyson
authors.affiliation: the Vollum Institute, Oregon Health and Sciences University, Portland, Oregon 97239, and.
authors.forename: Randall
authors.initials: R
authors.lastname: Sewell
authors.affiliation: From the Consiglio Nazionale delle Ricerche Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, I-35121 Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Carpi
authors.affiliation: From the Consiglio Nazionale delle Ricerche Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, I-35121 Padova, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Menabò
authors.affiliation: From the Consiglio Nazionale delle Ricerche Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, I-35121 Padova, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Di Lisa
authors.affiliation: the Consiglio Nazionale delle Ricerche Institute of Biomedical Technologies at the Department of Biology, University of Padova, I-35121 Padova, Italy.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Ricchelli
authors.affiliation: From the Consiglio Nazionale delle Ricerche Institute of Neuroscience and Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, I-35121 Padova, Italy, bernardi@bio.unipd.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bernardi
authors.affiliation: the Vollum Institute, Oregon Health and Sciences University, Portland, Oregon 97239, and forte@ohsu.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Forte
mesh_terms: D000818:Animals; D005260:Female; D017353:Gene Deletion; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010539:Permeability; D018079:Receptors, GABA / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: C463819:Bzrp protein, mouse; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018079:Receptors, GABA
keywords: Drug Action; Gene Knockout; Mitochondria; Mitochondrial Permeability Transition; Photodynamic Effect; Porphyrin