Regulation of the mitochondrial permeability transition pore by the outer membrane does not involve the peripheral benzodiazepine receptor (translocator protein of 18 kDa (TSPO))

Justina Šileikyte, Elizabeth Blachly-Dyson, Randall Sewell, Andrea Carpi, Roberta Menabò, Fabio Di Lisa, Fernanda Ricchelli, Paolo Bernardi, Michael Forte

Research output: Contribution to journalArticle

104 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)13769-13781
Number of pages13
JournalJournal of Biological Chemistry
Volume289
Issue number20
DOIs
StatePublished - May 16 2014

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GABA-A Receptors
Membranes
Proteins
Permeability
Mitochondrial Membranes
mitochondrial permeability transition pore
Steroid hormones
Ligands
Cell death
Pathologic Processes
Reperfusion Injury
Benzodiazepines
Cell Death
Genes
Steroids
Cholesterol
Hormones
Tissue

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Medicine(all)

Cite this

Regulation of the mitochondrial permeability transition pore by the outer membrane does not involve the peripheral benzodiazepine receptor (translocator protein of 18 kDa (TSPO)). / Šileikyte, Justina; Blachly-Dyson, Elizabeth; Sewell, Randall; Carpi, Andrea; Menabò, Roberta; Di Lisa, Fabio; Ricchelli, Fernanda; Bernardi, Paolo; Forte, Michael.

In: Journal of Biological Chemistry, Vol. 289, No. 20, 16.05.2014, p. 13769-13781.

Research output: Contribution to journalArticle

Šileikyte, Justina ; Blachly-Dyson, Elizabeth ; Sewell, Randall ; Carpi, Andrea ; Menabò, Roberta ; Di Lisa, Fabio ; Ricchelli, Fernanda ; Bernardi, Paolo ; Forte, Michael. / Regulation of the mitochondrial permeability transition pore by the outer membrane does not involve the peripheral benzodiazepine receptor (translocator protein of 18 kDa (TSPO)). In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 20. pp. 13769-13781.
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