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Mitochondrial dysfunction in ischaemia-reperfusion
1Department of Medical Chemistry, University of Helsinki, Finland.
Abstract:
The mitochondrial dysfunction in ischaemia-reperfusion is shortly reviewed. During ischaemia the ATP level and pH drops, phospholipids are degraded, membrane permeabilities increased and the cytosolic levels of Na+ and Ca2+ raised. During the following reperfusion the Ca2+ levels may further increase while pH is raised. The oxidative phosphorylation is resumed and the ATP used for membrane repair and ion pumping. The mitochondrial Ca2+ handling is important in removing Ca2+ from the cytosol since the mitochondria are able to take up substantial amounts of Ca2+. However, if a certain threshold is exceeded, mitochondria undergo a so-called permeability transition (MPT), release their Ca2+, undergo swelling and become uncoupled. MPT has been shown to be due to the opening of large pore allowing passage of substances with a M(R) < 1500. Data are presented showing by electron microscopy swelling of mitochondria in cells in perfused liver before other gross morphological changes have taken place. There are a number of factors lowering the threshold for Ca2+ in inducing the MPT: inorganic phosphate, pro-oxidants that oxidize membrane SH-groups, oxidation of NAD(P)H and GSH, while a protective effect is exerted by Mg2+, ADP (and ATP), some antioxidants, carnitine, decrease in pH, and cyclosporin A that binds to cyclophilin. The potential benefit of these in minimizing reperfusion-induced tissue damage is discussed.
Insights
Mitochondrial dysfunction during ischemia-reperfusion injury involves calcium overload, leading to permeability transition and cell damage. Factors like phosphate and oxidants lower the threshold for this transition, while magnesium and cyclosporin A offer protection.
Area of Science:
- Cell Biology
- Biochemistry
- Pathophysiology
Background:
- Ischemia-reperfusion (I/R) injury is a significant clinical problem.
- Mitochondrial dysfunction plays a critical role in I/R pathophysiology.
- Cellular ATP and pH levels decrease during ischemia, while ion concentrations change.
Purpose of the Study:
- To review mitochondrial dysfunction during ischemia-reperfusion.
- To discuss the role of mitochondrial calcium handling and permeability transition in I/R injury.
- To explore factors influencing the mitochondrial permeability transition and their therapeutic potential.
Main Methods:
- Literature review of mitochondrial dysfunction in I/R.
- Electron microscopy to visualize mitochondrial swelling.
- Analysis of factors affecting mitochondrial permeability transition (MPT).
Main Results:
- Ischemia leads to decreased ATP and pH, increased membrane permeability, and elevated cytosolic Na+ and Ca2+.
- Reperfusion can further increase Ca2+ levels, potentially triggering MPT.
- MPT involves the opening of a large pore, leading to mitochondrial swelling and uncoupling.
- Factors like inorganic phosphate and pro-oxidants lower the MPT threshold, while Mg2+, ADP/ATP, and cyclosporin A are protective.
Conclusions:
- Mitochondrial calcium overload and subsequent permeability transition are key events in I/R injury.
- Understanding factors that modulate MPT offers potential therapeutic targets for minimizing tissue damage.
- Electron microscopy confirms mitochondrial swelling precedes other morphological changes in I/R.