MiP2005: Session 8

Mitochondrial Physiology Network 10.9: 97 (2005) - download pdf


Mitochondrial function in cardiac ischemia-reperfusion injury and ischemic preconditioning.

Paul S Brookes

Department of Anesthesiology, University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642, USA. - paul_brookes@urmc.rochester.edu

    Mitochondrial dysfunction has long been recognized as a key event in cardiac ischemia-reperfusion (I-R) injury.  In addition recent evidence has invoked a role for mitochondria in ischemic preconditioning (IPC).  Several aspects of mitochondrial function have been investigated in both I-R and IPC, including: (i) the proton permeability (H+) leak of the inner membrane, (ii) post-translational modifications to complex I, (iii) the role of nitric oxide (NO) and its redox cohorts, and (iv) the regulation of ROS generation by O2 tension and NO.  To accomplish this, several unique methodologies have been combined, including open-flow respirometry [1], proteomics, chemiluminescent NO detection and novel mitochondrially targeted drugs.

    Results are summarized as follows: (i) H+ leak is reversibly elevated in IPC via a UCP dependent mechanism, and is further elevated irreversibly in I-R by a mechanism involving AMP stimulation of the ANT, and transient PT pore opening.  (ii)  Thiols in the 75kDa subunit of complex I are damaged in I-R, and this leads to ROS generation without significant loss of enzymatic activity.  (iii) Complex I can be S-nitrosated on specific subunits under various conditions.  (iv) ROS generation by mitochondria does not increase under hypoxia, but actually decreases with O2 tension.  The ramifications of these findings for therapeutic intervention in I-R injury, in particular the use of mitochondrially-targeted antioxidants, will be discussed.

1. Brookes PS, Kraus DW, Shiva S, Doeller JE, Barone MC, Patel RP, Lancaster JR Jr, Darley-Usmar V (2003) Control of mitochondrial respiration by NO, effects of low oxygen and respiratory state. J. Biol. Chem. 278: 31603-31609.


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Mitochondrial Physiology