Mechanism of activation of cytochrome c peroxidase activity by cardiolipin

Vladimirov, Yu. A.; Проскурнина, Е. В.; Izmailov, D. Yu.; Новиков, А. А.; Brusnichkin, A. V.; Осипов, А. Н.; Kagan, Valerian E.

doi:10.1134/s0006297906090070

Cited by 38 publications

(22 citation statements)

References 35 publications

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“…Peroxidase activity increases significantly when the protein is partially unfolded or the Met80-Fe bond is weakened or ruptured by exposure to CL. 27,34 Our studies suggest that SS-31 prevents CL from breaking the Met80-Fe coordination in cyt c. A proposed model for this mechanism is illustrated in Figure 9B. Unlike other inhibitors of cyt c peroxidase that have been described, [49][50][51][52] SS-31 is selectively targeted to CL rather than the mitochondrial matrix and does not alter CL composition or the normal interaction between CL and cyt c.…”

Section: Discussionmentioning

confidence: 77%

“…22,33 We found that Ca 2+ directly stimulates cyt c peroxidase activity in a dose-dependent manner ( Figure 2E), and SS-31 inhibited Previous studies suggest that the insertion of a CL acyl chain into the heme crevice of cyt c disrupts the Met80-Fe coordinate and exposes the heme Fe. 34,35 Disruption of the Met80-Fe ligation can be monitored by circular dichroism (CD). 36,37 The addition of CL to cyt c resulted in the loss of the negative Cotton peak at 419 nm and was prevented by the addition of SS-31 in a 1:1 ratio with cyt c ( Figure 3B).…”

Section: Cl-induced Cyt C Peroxidase Activitymentioning

confidence: 99%

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The Mitochondrial-Targeted Compound SS-31 Re-Energizes Ischemic Mitochondria by Interacting with Cardiolipin

Birk

Liu

Soong

et al. 2013

Journal of the American Society of Nephrology

390

431

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Ischemia causes AKI as a result of ATP depletion, and rapid recovery of ATP on reperfusion is important to minimize tissue damage. ATP recovery is often delayed, however, because ischemia destroys the mitochondrial cristae membranes required for mitochondrial ATP synthesis. The mitochondria-targeted compound SS-31 accelerates ATP recovery after ischemia and reduces AKI, but its mechanism of action remains unclear. Here, we used a polarity-sensitive fluorescent analog of SS-31 to demonstrate that SS-31 binds with high affinity to cardiolipin, an anionic phospholipid expressed on the inner mitochondrial membrane that is required for cristae formation. In addition, the SS-31/cardiolipin complex inhibited cytochrome c peroxidase activity, which catalyzes cardiolipin peroxidation and results in mitochondrial damage during ischemia, by protecting its heme iron. Pretreatment of rats with SS-31 protected cristae membranes during renal ischemia and prevented mitochondrial swelling. Prompt recovery of ATP on reperfusion led to rapid repair of ATP-dependent processes, such as restoration of the actin cytoskeleton and cell polarity. Rapid recovery of ATP also inhibited apoptosis, protected tubular barrier function, and mitigated renal dysfunction. In conclusion, SS-31, which is currently in clinical trials for ischemiareperfusion injury, protects mitochondrial cristae by interacting with cardiolipin on the inner mitochondrial membrane. Ischemic AKI occurs in many clinical settings, including shock, sepsis, and cardiovascular surgery, and it leads to increased mortality in critically ill patients. 1 Ischemia-reperfusion injury is also a critical issue in organ transplantation, where it can result in delayed graft function, and is a major risk factor for chronic allograft nephropathy. 2,3 Tissue injury occurs during ischemia as a result of ATP depletion. The rapid drop in ATP leads to cytoskeletal changes in tubular epithelial cells, because ATP is required for actin polymerization, 4 resulting in breakdown of the brush border, loss of cell-cell contact, disruption of barrier function, and cell detachment. 5 These cytoskeletal changes are reversible if the duration of ischemia is brief and ATP recovery occurs rapidly on reperfusion. Mitochondrial function is pivotal to the recovery of ATP in proximal tubular cells, because they have minimal glycolytic capacity and must rely on oxidative phosphorylation for ATP synthesis. However, ATP recovery is often delayed on reperfusion, because ischemia results in loss of cristae membranes and mitochondrial swelling. 6,7 The recovery of ATP can be further compromised by mitochondrial permeability transition (MPT) during

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Section: Discussionmentioning

confidence: 77%

Section: Cl-induced Cyt C Peroxidase Activitymentioning

confidence: 99%

The Mitochondrial-Targeted Compound SS-31 Re-Energizes Ischemic Mitochondria by Interacting with Cardiolipin

Birk

Liu

Soong

et al. 2013

Journal of the American Society of Nephrology

390

431

View full text Add to dashboard Cite

show abstract

“…We used luminol-dependent CL for studies of peroxidase activity of cytochrome c associated with cardiolipin [7]. The kinetics of CL (initial elevation of fluorescence and its subsequent drop) confirms Fig.…”

Section: Activated CLmentioning

confidence: 67%

“…Cardiolipin specifically potentiated the initially low peroxidase activity of cytochrome c many times stronger than free fatty acids or anionic detergents. Activation of the cytochrome c peroxidase activity is now regarded as the initial stage of apoptosis [7].…”

Section: Activated CLmentioning

confidence: 99%