The identity and regulation of the mitochondrial permeability transition pore: Where the known meets the unknown

Magdalena Juhaszova, Su Wang, Dmitry B. Zorov, H. Bradley Nuss, Marc Gleichmann, Mark P. Mattson, Steven J. Sollott

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

The mitochondrial permeability transition (MPT) pore complex is a key participant in the machinery that controls mitochondrial fate and, consequently, cell fate. The quest for the pore identity has been ongoing for several decades and yet the main structure remains unknown. Established "dogma" proposes that the core of the MPT pore is composed of an association of voltage-dependent anion channel (VDAC) and adenine nucleotide translocase (ANT). Recent genetic knockout experiments contradict this commonly accepted interpretation and provide a basis for substantial revision of the MPT pore identity. There is now sufficient evidence to exclude VDAC and ANT as the main pore structural components. Regarding MPT pore regulation, the role of cyclophilin D is confirmed and ANT may still serve some regulatory function, although the involvement of hexokinase II and creatine kinase remains unresolved. When cell protection signaling pathways are activated, we have found that the Bcl-2 family members relay the signal from glycogen synthase kinase-3 beta onto a target at or in close proximity to the pore. Our experimental findings in intact cardiac myocytes and neurons indicate that the current "dogma" related to the role of Ca2+ in MPT induction requires reevaluation. Emerging evidence suggests that after injury-producing stresses, reactive oxygen species (but not Ca2+) are largely responsible for the pore induction. In this article we discuss the current state of knowledge and provide new data related to the MPT pore structure and regulation.

Original languageEnglish (US)
Title of host publicationAnnals of the New York Academy of Sciences
Pages197-212
Number of pages16
Volume1123
DOIs
StatePublished - Mar 2008
Externally publishedYes

Publication series

NameAnnals of the New York Academy of Sciences
Volume1123
ISSN (Print)00778923
ISSN (Electronic)17496632

Keywords

  • Adenine nucleotide translocase
  • Bcl-2
  • Ca
  • Cyclophilin D
  • Hexokinase II
  • Reactive oxygen species
  • Voltage-dependent anion channel

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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