Mitochondrial Permeability Transition in Cardiac Cell Injury and Death

Abstract

Mitochondria can serve as the arbiter of cell fate in response to stress. Mitochondrial permeability transition (MPT) is characterized by permeabilization of an otherwise relatively impermeable mitochondrial inner membrane and appears to have a major role in ischemia/reperfusion (I/R) injury in myocardial infarction and stroke. After I/R, the fate of the cell is determined by the extent of MPT. If minimal, the cell may recover; if moderate, the cell may undergo programmed cell death; if severe, the cell may die from necrosis due to inadequate energy production. After reviewing the role of MPT in disease, we examine the signaling and metabolic networks that regulate MPT. We then conclude with some of the challenges in future MPT research.

Glyceraldehyde-3-phosphate Dehydrogenase (GAPDH) Phosphorylation by Protein Kinase Cδ (PKCδ) Inhibits Mitochondria Elimination by Lysosomal-like Structures following Ischemia and Reoxygenation-induced Injury

“…HL1 cells were subcultured at high density (typically a 1:3 split) on 10-cm 2 plates or glass coverslips pre-coated with 0.02% gelatin and 25 g/ml of fibronectin (Sigma). HL1 cell culture medium was replaced daily to maintain their differentiated cardiomyocyte phenotype and contractile activity.…”

“…or Atg5 cells were grown to confluence in 10-or 25-cm 2 dishes, or to 90% subconfluence on glass coverslips in 6-well plates and I/R-induced injury was performed as described (25) Briefly, cells were rinsed twice with phosphate-buffered saline (PBS), followed by the addition of ischemia mimetic solution (125 mM NaCl, 8 mM KCl, 1.2 mM KH 2 PO 4 , 1.25 mM MgSO 4 , 1.2 mM CaCl 2 , 6.25 mM NaHCO 3 , 5 mM sodium lactate, 20 mM HEPES, pH 6.6) and placing the cells in hypoxic pouches (GasPak EZ Anaerobe Gas Generating Pouch System with indicator, BD Biosciences). After 2.5 h of simulated ischemia, reperfusion injury was initiated by removing the ischemia buffer and immediately replacing with pre-warmed normoxic Krebs-Henseleit solution (110 mM NaCl, 4.7 mM KCl, 1.2 mM KH 2 PO 4 , 1.25 mM MgSO 4 , 1.2 mM CaCl 2 , 25 mM NaHCO 3 , 15 mM glucose, 20 mM HEPES, pH 7.4) and incubated at 95% room air, 5% CO 2 for 30 min or as indicated.…”

“…This ischemia-reoxygenation or reperfusion (I/R) 5 -induced injury is mediated by reactive oxygen species, generated primarily by damaged mitochondria, which leads to opening of the mitochondrial permeability transition pore and the onset of cell death by apoptosis and necrosis (1,2). Hence, ensuring proper elimination of damaged mitochondria is imperative to cell survival.…”

Molecular mechanism of preconditioning

“…If minimal, cell may recover; if moderate, cell may undergo apoptosis; if severe, the cell may die from necrosis due to inadequate energy production. The MPT inhibitors CsA and sanglifehrin A both protect the heart against reperfusion injury (18).…”

Schisandrin B Decreases the Sensitivity of Mitochondria to Calcium Ion-Induced Permeability Transition and Protects against Carbon Tetrachloride Toxicity in Mouse Livers

“…A growing body of evidence has accumulated suggesting the involvement of PT of the mitochondrial inner membrane in the pathogenesis of oxidant injury in various tissues. 6,7) One critical event of mitochondrial PT is the permeability of inner membrane to small ions and solutes with M.W.Ͻ1500 daltons, with the consequent large amplitude swelling of mitochondria. 8) Opening of mitochondrial PT pores plays an important role in regulating necrotic and apoptotic cell death.…”