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(Circulation Research. 2006;99:10.)
© 2006 American Heart Association, Inc.

Editorials

Mitochondria and Preconditioning

A Connexin Connection?

Andrew P. Halestrap

From the Department of Biochemistry and The Bristol Heart Institute, University of Bristol, Bristol BS8 1TD, UK.

Correspondence to Professor Andrew P. Halestrap, Department of Biochemistry, University of Bristol, Bristol BS8 1TD, UK. E-mail A.Halestrap@bristol.ac.uk

See related article, pages 93–101

Key Words: mitochondrial permeability transition pore • gap junctions • reactive oxygen species • preconditioning • phosphorylation

An extract of the first 250 words of the full text is provided, because this article has no abstract.

In recent years it has become widely accepted that mitochondria play a critical role in determining whether or not a heart recovers on reperfusion after a period of ischemia. A critical process in initiating cell death is the opening of the mitochondrial permeability transition pore (MPTP), a nonspecific pore in the inner mitochondrial membrane (IMM), that causes mitochondrial uncoupling and swelling. MPTP opening is triggered by matrix calcium overload, especially when accompanied by oxidative stress and adenine nucleotide depletion, conditions known to occur during ischemia.¹ During ischemia MPTP opening is inhibited by low pH, but on reperfusion opening only occurs when the pH returns to normal accompanied by a further burst of reactive oxygen species (ROS). Myocytes cannot maintain their ATP levels if the pores remain open leading to disruption of ionic homeostasis and ultimately necrosis, whereas transient pore opening may initiate apoptosis through MPTP-induced release of factors such as cytochrome C that activate the apoptotic caspase cascade.¹ The importance of the mitochondrial pathway in mediating reperfusion injury has been confirmed through the use of specific MPTP inhibitors such as cyclosporin A (CsA) and sanglifehrin A (SfA) that afford protection against reperfusion injury, as does genetic knockout of CyP-D, a key component of the MPTP.^1,2

Ischemic preconditioning (IPC) offers potent protection against reperfusion injury and has been shown to involve inhibition of MPTP opening, although the exact mechanisms responsible remain unclear.^1,3 Our own data imply an indirect effect, probably mediated by a decrease in ROS,⁴ while others have championed a . . . [Full Text of this Article]

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