Opening of the Mitochondrial Permeability Transition Pore Causes Depletion of Mitochondrial and Cytosolic NAD+and Is a Causative Event in the Death of Myocytes in Postischemic Reperfusion of the…

By F. Di Lisa, R. Menabò, M. Canton, M. Barile, P. Bernardi. Journal of Biological Chemistry, 2001

681 citations recorded by the source corpus.

The opening of the mitochondrial permeability transition pore (PTP) has been suggested to play a key role in various forms of cell death, but direct evidence in intact tissues is still lacking. We found that in the rat heart, 92% of NAD+glycohydrolase activity is associated with mitochondria. This activity was not modified by the addition of Triton X-100, although it was abolished by mild treatment with the protease Nagarse, a condition that did not affect the energy-linked properties of mitochondria. The addition of Ca2+ to isolated rat heart mitochondria resulted in a profound decrease in their NAD+ content, which followed mitochondrial swelling. Cyclosporin A(CsA), a PTP inhibitor, completely prevented NAD+ depletion but had no effect on the glycohydrolase activity. Thus, in isolated mitochondria PTP opening makes NAD+ available for its enzymatic hydrolysis. Perfused rat hearts subjected to global ischemia for 30 min displayed a 30% decrease in tissue NAD+ content, which was not modified by extending the duration of ischemia. Reperfusion resulted in a more severe reduction of both total and mitochondrial contents of NAD+, which could be measured in the coronary effluent together with lactate dehydrogenase. The addition of 0.2 μm CsA or of its analogue MeVal-4-Cs (which does not inhibit calcineurin) maintained higher NAD+ contents, especially in mitochondria, and significantly protected the heart from reperfusion damage, as shown by the reduction in lactate dehydrogenase release. Thus, upon reperfusion after prolonged ischemia, PTP opening in the heart can be documented as a CsA-sensitive release of NAD+, which is then partly degraded by glycohydrolase and partly released when sarcolemmal integrity is compromised. These results demonstrate that PTP opening is a causative event in reperfusion damage of the heart.

Subfields: Molecular Biology, Pathology and Forensic Medicine, Surgery

View Paper: https://www.semanticscholar.org/paper/3b9e97e67908a5808e3b590384bb65d1efabfc80

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Citations in the corpus

Mitochondrial α-Ketoglutarate Dehydrogenase Complex Generates Reactive Oxygen Species (2004, background): “Furthermore, rat brain mitochondria contain 5 nmol of total NAD/mg protein (C. Chinopoulos, unpublished observations) similar to the amount found in mitochondria from other tissues (3–7 nmol of total NAD/mg mitochondrial protein) (Tischler et al., 1977; Di Lisa et al., 2001).”
Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning, and Postconditioning (2007, background): “Evidence favors mPTP opening causing cell death by necrosis (Di Lisa et al., 2001), although it has been proposed that either apoptosis or necrosis might be precipitated, depending on the extent of mPTP opening (Halestrap et al., 2004).”
CD38 dictates age-related NAD decline and mitochondrial dysfunction through a SIRT3-dependent mechanism (2016, neutral): “It has been shown that cellular stress can induce the opening of the mitochondrial transition pore, causing swelling of the mitochondria, loss of membrane potential, and leakage of mitochondrial matrix components such as NAD and NADH (Di Lisa et al., 2001).”
Mitochondrial permeability transition pore opening during myocardial reperfusion--a target for cardioprotection. (2004, background): “This drawback can be overcome by the use of CsA analogues that are without effect on calcineurin such as [MeAla(6)]CsA and 4-methyl-val-CsA and by SfA [6,18,19].”
PINK1-Associated Parkinson's Disease Is Caused by Neuronal Vulnerability to Calcium-Induced Cell Death (2009, background): “…promote cell death: (1) PTP opening will further increase ROS production in the mitochondria, (2) PTP opening will result in reduced rate of maximal respiration through pyridine nucleotide depletion (Di Lisa et al., 2001), and (3) PTP opening will cause cytochrome c release and neuronal apoptosis.”
Necrosis: a specific form of programmed cell death? (2003, background): “[101] F.”