The mitochondrial permeability transition in cell death: a common mechanism in necrosis, apoptosis and autophagy

Abstract

Using confocal microscopy, onset of the mitochondrial permeability transition (MPT) in individual mitochondria within living cells can be visualized by the redistribution of the cytosolic fluorophore, calcein, into mitochondria. Simultaneously, mitochondria release membrane potential-indicating fluorophores like tetramethylrhodamine methylester. The MPT occurs in several forms of necrotic cell death, including oxidative stress, pH-dependent ischemia/reperfusion injury and Ca2+ ionophore toxicity. Cyclosporin A (CsA) and trifluoperazine block the MPT in these models and prevent cell killing, showing that the MPT is a causative factor in necrotic cell death. During oxidative injury induced by t-butylhydroperoxide, onset of the MPT is preceded by pyridine nucleotide oxidation, mitochondrial generation of reactive oxygen species, and an increase of mitochondrial free Ca2+, all changes that promote the MPT. During tissue ischemia, acidosis develops. Because of acidotic pH, anoxic cell death is substantially delayed. However, when pH is restored to normal after reperfusion (reoxygenation at pH 7.4), cell death occurs rapidly (pH paradox). This killing is caused by pH-dependent onset of the MPT, which is blocked by reperfusion at acidotic pH or with CsA. In isolated mitochondria, toxicants causing Reye's syndrome, such as salicylate and valproate, induce the MPT. Similarly, salicylate induces a CsA-sensitive MPT and killing of cultured hepatocytes. These in vitro findings suggest that the MPT is the pathophysiological mechanism underlying Reye's syndrome in vivo. Kroemer and coworkers proposed that the MPT is a critical event in the progression of apoptotic cell death. Using confocal microscopy, the MPT can be directly documented during tumor necrosis factor-alpha induced apoptosis in hepatocytes. CsA blocks this MPT and prevents apoptosis. The MPT does not occur uniformly during apoptosis. Initially, a small proportion of mitochondria undergo the MPT, which increases to nearly 100% over 1-3 h. A technique based on fluorescence resonance energy transfer can selectively reveal mitochondrial depolarization. After nutrient deprivation, a small fraction of mitochondria spontaneously depolarize and enter an acidic lysosomal compartment, suggesting that the MPT precedes the normal process of mitochondrial autophagy. A model is proposed in which onset of the MPT to increasing numbers of mitochondria within a cell leads progressively to autophagy, apoptosis and necrotic cell death.

Impairing the bioenergetic status and the biogenesis of mitochondria triggers mitophagy in yeast

“…As a matter of fact, a similar description of mitophagy preceding cell death was observed in mammals, where selective removal of mitochondria was reported to target nonfunctional organelles when the apoptotic programme was blocked at a postmitochondrial stage 14,[17][18][19] (after the release of apoptogenic factors from the organelles), or when mitochondria carry deleterious DNA mutations. 38 Whether this mitochondrial degradation results from direct lysosomal uptake 18,38 or from autophagosomal sequestration 15,17 is still unclear, but under these conditions, mitophagy would control the scavenging of damaged mitochondria.…”

“…Recent studies report that type II PCD (autophagy) could substitute for defective type I PCD (apoptosis), suggesting (i) that autophagy could be physiologically triggered by other means besides nutritional stress, and (ii) that autophagy could be an alternative to apoptosis. 14,15 It has therefore become essential to characterise the interactions (if any) between type I and type II PCD. During apoptosis, mitochondria are acknowledged as a central element; recently, some reports have suggested the involvement of mitochondria in autophagy also.…”

Ubiquitous mitochondrial creatine kinase downregulated in oral squamous cell carcinoma

“…Prolonged opening of the PTP leads to the previously mentioned effects, exposes cytosol to the contents of the mitochondria, and culminates in cell death (Debatin et al, 2002;Newmeyer and Ferguson-Miller, 2003). Interestingly, mitochondrial permeability transition can lead to both apoptosis and necrosis (Lemasters et al, 1998). CKMT1 is located in the intermembrane space and also interacts with VDAC -ANT complexes (Marzo et al, 1998).…”

Morphology of mitochondrial permeability transition: Morphometric volumetry in apoptotic cells

“…The mitochondrial permeability transition (MPT) refers to an increase in the permeability of the inner mitochondrial membrane caused by nonselective agents, in apoptotic and necrotic cells (Lemasters et al, 1998). This condition is associated with membrane depolarization and collapse of the transmembrane potential (⌬⌿m).…”