Palmitic Acid Opens a Novel Cyclosporin A-Insensitive Pore in the Inner Mitochondrial Membrane

Sultan, Aya; Sokolove, Patricia M.

doi:10.1006/abbi.2000.2194

Cited by 85 publications

(38 citation statements)

References 66 publications

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“…As shown in Fig. 4B, when mitochondria were preswollen with Ca 2+ , the addition of poly(ethylene glycol) having a molecular size of more than 4000 (PEG4000) caused increased turbidity of the mitochondrial suspension, reflecting induction of shrinkage of preswollen mitochondria; whereas those smaller than 1000 did not, as reported previously [16]. These results are thought to indicate that the mitochondrial membrane became permeable to the molecules smaller than a molecular size of 1500 by the Ca 2+ treatment.…”

Section: +supporting

confidence: 83%

Multiple effects of DiS‐C₃(5) on mitochondrial structure and function

Yamamoto¹,

Tachikawa²,

Terauchi³

et al. 2004

European Journal of Biochemistry

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3,3¢-Dipropyl-2,2¢-thiadicarbocyanine iodide [DiS-C 3 (5)], often used as a tracer dye to assess the mitochondrial membrane potential, was investigated in detail regarding its effects on the structure and function of isolated mitochondria. As reported previously, DiS-C 3 (5) had an inhibitory effect on NADH-driven mitochondrial electron transfer. On the contrary, in the presence of inorganic phosphate, DiS-C 3 (5) showed dose-dependent biphasic effects on mitochondria energized by succinate. At higher concentrations, such as 50 lM, DiS-C 3 (5) accelerated mitochondrial oxygen consumption. Measurements of the permeability of DiS-C 3 (5)-treated mitochondrial membranes to poly(ethylene glycol) and analysis of mitochondrial configuration by transmission electron microscopy revealed that the accelerating effect of DiS-C 3 (5) on mitochondrial oxygen consumption reflects the induction of the mitochondrial permeability transition (PT). When the mitochondrial PT was induced by DiS-C 3 (5), release of mitochondrial cytochrome c was observed, as in the case of the PT induced by Ca 2+. On the contrary, at a low concentration such as 5 lM, DiS-C 3 (5) showed an inhibitory effect on the latent oxygen consumption by mitochondria. This effect was shown to reflect inhibition of the PT induced by a low concentration of Ca 2+. Furthermore, in the absence of inorganic phosphate, DiS-C 3 (5) caused mitochondrial swelling. Under this condition, DiS-C 3 (5) caused changes in the membrane status of the mitochondria, but did not induce a release of mitochondrial cytochrome c.Keywords: cyanine dye; cytochrome c; DiS-C 3 (5); mitochondria; permeability transition.The mitochondrial inner membrane is highly impermeable even to small solutes and ions. However, under certain conditions, such as in the presence of Ca 2+ and inorganic phosphate (P i ), the inner mitochondrial membrane becomes permeable to solutes and ions up to 1500 Da. This phenomenon is referred to as the mitochondrial permeability transition (PT), and PT is believed to reflect the opening of a proteinaceous pore [1][2][3].In the field of biochemistry, cyanine dyes are often employed as an indicator dye to assess the mitochondrial membrane potential [4,5]. In our previous studies, we characterized the effects of cyanine dyes such as 2,2¢-{3-[2-(3-butyl-4-methyl-2-thiazolin-2-ylidene)ethylidene]propenylene}-bis(3-butyl-4-methyl thiazolinium iodide) [TriS-C 4 (5)] and 2,2¢-{3-[2-(3-heptyl-4-methyl-2-thiazolin-2-ylidene) ethylidene] propenylene}-bis(3-heptyl-4-methyl thiazolinium iodide) [TriS-C 7 (5)], both of which have three heterocylic groups, on mitochondrial structure and function. These cyanine dyes accelerated mitochondrial oxygen consumption only in the presence of P i in the incubation medium [6][7][8]. Furthermore, the accelerating effects of these cyanine dyes on the mitochondrial oxygen consumption were attributable mainly to the induction of the mitochondrial PT [9]. However, different from the classical PT induced by Ca , that induced by these cyanine dyes was o...

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Section: +supporting

confidence: 83%

Multiple effects of DiS‐C₃(5) on mitochondrial structure and function

Yamamoto¹,

Tachikawa²,

Terauchi³

et al. 2004

European Journal of Biochemistry

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“…Furthermore, exogenous palmitate, which is a major fatty acid produced by the PLA 1 activity of iPLA 2 ␥, restored iPLA 2 ␥ Ϫ/Ϫ hepatic mitochondrial swelling, mimicking that observed in WT control mitochondria. Palmitate has been previously proposed to activate both CsA-sensitive and CsA-insensitive pores in rat liver mitochondria (58,59). In this study, we found that palmitate-induced swelling in iPLA 2 ␥ Ϫ/Ϫ liver mitochondria is largely reversible by CsA.…”

Section: Discussionsupporting

confidence: 59%

Genetic Ablation of Calcium-independent Phospholipase A2γ (iPLA2γ) Attenuates Calcium-induced Opening of the Mitochondrial Permeability Transition Pore and Resultant Cytochrome c Release

Moon

Jenkins

Kiebish

et al. 2012

Journal of Biological Chemistry

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“…18,[37][38][39] Such observations have led to the proposal that MPT pores have two open conductance modes: regulated and unregulated. 18 Regulated MPT pore opening occurs after low level chemical induction, requires mitochondrial Ca 2ϩ uptake, and is inhibited by CsA.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

et al. 2004

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Acetaminophen overdose causes massive hepatic failure via mechanisms involving glutathione depletion, oxidative stress, and mitochondrial dysfunction. The ultimate target of acetaminophen causing cell death remains uncertain, and the role of apoptosis in acetaminophen-induced cell killing is still controversial. Our aim was to evaluate the mitochondrial permeability transition (MPT) as a key factor in acetaminophen-induced necrotic and apoptotic killing of primary cultured mouse hepatocytes. After administration of 10 mmol/L acetaminophen, necrotic killing increased to more than 49% and 74%, respectively, after 6 and 16 hours. MPT inhibitors, cyclosporin A (CsA), and NIM811 temporarily decreased necrotic killing after 6 hours to 26%, but cytoprotection was lost after 16 hours. Confocal microscopy revealed mitochondrial depolarization and inner membrane permeabilization approximately 4.5 hours after acetaminophen administration. CsA delayed these changes, indicative of the MPT, to approximately 11 hours after acetaminophen administration. Apoptosis indicated by nuclear changes, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and caspase-3 activation also increased after acetaminophen administration. Fructose (20 mmol/L, an adenosine triphosphategenerating glycolytic substrate) plus glycine (5 mmol/L, a membrane stabilizing amino acid) prevented nearly all necrotic cell killing but paradoxically increased apoptosis from 37% to 59% after 16 hours. In the presence of fructose plus glycine, CsA decreased apoptosis and delayed but did not prevent the MPT. In conclusion, after acetaminophen a CsA-sensitive MPT occurred after 3 to 6 hours followed by a CsA-insensitive MPT 9 to 16 hours after acetaminophen. The MPT then induces ATP depletion-dependent necrosis or caspase-dependent apoptosis as determined, in part, by ATP availability from glycolysis.

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Palmitic Acid Opens a Novel Cyclosporin A-Insensitive Pore in the Inner Mitochondrial Membrane

Cited by 85 publications

References 66 publications

Multiple effects of DiS‐C₃(5) on mitochondrial structure and function

Multiple effects of DiS‐C₃(5) on mitochondrial structure and function

Genetic Ablation of Calcium-independent Phospholipase A2γ (iPLA2γ) Attenuates Calcium-induced Opening of the Mitochondrial Permeability Transition Pore and Resultant Cytochrome c Release

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

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Palmitic Acid Opens a Novel Cyclosporin A-Insensitive Pore in the Inner Mitochondrial Membrane

Cited by 85 publications

References 66 publications

Multiple effects of DiS‐C3(5) on mitochondrial structure and function

Multiple effects of DiS‐C3(5) on mitochondrial structure and function

Genetic Ablation of Calcium-independent Phospholipase A2γ (iPLA2γ) Attenuates Calcium-induced Opening of the Mitochondrial Permeability Transition Pore and Resultant Cytochrome c Release

Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes

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Multiple effects of DiS‐C₃(5) on mitochondrial structure and function

Multiple effects of DiS‐C₃(5) on mitochondrial structure and function