Hypoxia-reoxygenation induced damage in the myocardium: the role of mitochondria

Further evidence that cyclosporin A protects mitochondria from calcium overload by inhibiting a matrix peptidyl-prolyl cis-trans isomerase. Implications for the immunosuppressive and toxic effects of cyclosporin

“…3. In summary, our hypothesis is based on the observation that Ca2+-induced swelling may also be inhibited by bongkrekic acid and ADP, which stabilize the 'm' conformation of the carrier, while carboxyatractyloside, which stabilizes the 'c' conformation, enhances swelling [8][9][10][11]. The c conformation is believed to have a proline residue (Pro-61) that is exposed to the matrix surface, but this residue is hidden in the m conformation [18,19].…”

“…These mitochondria become swollen, leaky and unable to support oxidative phosphorylation as a result of the opening of a non-specific permeability pathway in the mitochondrial inner membrane [6,9]. Pore opening is also modulated by effectors of the adenine nucleotide translocase [6][7][8][9][10][11], which had led us [8] and others [11] to implicate this protein in pore formation. We have demonstrated that both rat liver and heart mitochondria possess about 120 pmol of PPIase/mg of protein, and that inhibition of this enzyme by cyclosporin A parallels the inhibition ofmitochondrial swelling induced by high Ca2+ concentrations.…”

Mitochondrial calcium handling and oxidative stress

“…Subsequent isolation of the mitochondria has confirmed that they are functionally impaired. In particular, they are depleted of adenine nucleotides and exhibit inhibition, to varying degrees, of the respiratory chain, especially complex I, the oligomycin-sensitive ATPase and the adenine nucleotide translocase [4,, In the ischaemic/reperfused heart these effects are associated with an increase in mitochondrial Ca2+ content and are substantially reduced if ruthenium red is present in the perfusion medium [7, 81. It has been known for many years that a [7,81. It has been known for many years that a combination of oxidative stress and increased mitochondrial Ca2+ content is damaging to isolated mitochondria [ 1, 2, 10, 111 and it would seem likely that the effects seen in vivo reflect the same phenomenon.…”

Mechanism of Ischemia and Reperfusion Injury to the Heart: From the Viewpoint of Nitric Oxide and Mitochondria

“…In addition to Ox-Phos, reperfusion in-jury also leads to cardiolipin oxidation, 55,60,61 the induction of a large proton leak across the mitochondrial inner membrane, 41,62 Ca 2+ overload, overproduction of ROS, PTP opening, and cell death. [62][63][64][65][66][67][68][69][70][71][72][73] A majority of these observations have been made in mitochondria isolated from hearts after reperfusion, meaning that the time course of mitochondrial damage during reperfusion injury is difficult to study (because mitochondrial isolation typically takes 1∼2 h).…”