Control of mitochondrial swelling by Mg2+?the relation of ion transport to structural changes

Dow, Dorothy S.; Walton, Kenneth G.; Fleischer, Sidney

doi:10.1007/bf01516287

Cited by 16 publications

(5 citation statements)

References 39 publications

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“…Mitochondrial respiration, using freshly isolated mitochondria, was measured by oxygen consumption using an oxygen electrode (YSI International) and oxygen consumption chamber (Gilson). Assay medium contained 40 m M KCl, 50 m M mannitol, 50 m M sucrose, 0.5 m M disodium EDTA, 10 m M HEPES, 5 m M MgCl 2 , and 10 m M K 2 HPO 4 , pH 7.4 (Dow et al, 1970). In these respiratory studies, control brain mitochondria routinely had respiratory control ratios of ≥4 with glutamate and malate as substrates.…”

Section: Methodsmentioning

confidence: 99%

4‐Hydroxy‐2(E)‐Nonenal Inhibits CNS Mitochondrial Respiration at Multiple Sites

Picklo

Amarnath

McIntyre

et al. 1999

Journal of Neurochemistry

144

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A destructive cycle of oxidative stress and mitochondrial dysfunction is proposed in neurodegenerative disease. Lipid peroxidation, one outcome of oxidative challenge, can lead to the formation of 4-hydroxy-2(E )-nonenal (HNE), a lipophilic alkenal that forms stable adducts on mitochondrial proteins. In this study, we characterized the effects of HNE on brain mitochondrial respiration. We used whole rat brain mitochondria and concentrations of HNE comparable to those measured in patients with Alzheimer's disease. Our results showed that HNE inhibited respiration at multiple sites. Complex I-linked and complex II-linked state 3 respirations were inhibited by HNE with IC 50 values of ϳ200 M HNE. Respiration was apparently diminished owing to the inhibition of complex III activity. In addition, complex II activity was reduced slightly. The lipophilicity and adduction characteristics of HNE were responsible for the effects of HNE on respiration. The inhibition of respiration was not prevented by N-acetylcysteine or aminoguanidine. Studies using mitochondria isolated from porcine cerebral cortex also demonstrated an inhibition of complex I-and complex II-linked respiration. Thus, in neurodegenerative disease, oxidative stress may impair mitochondrial respiration through the production of HNE.

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Section: Methodsmentioning

confidence: 99%

4‐Hydroxy‐2(E)‐Nonenal Inhibits CNS Mitochondrial Respiration at Multiple Sites

Picklo

Amarnath

McIntyre

et al. 1999

Journal of Neurochemistry

144

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“…NO/GMP signaling is compartmentalized to principal cells in the main fluid-secreting segment of tubules, containing the electrogenic vacuolar H ϩ -ATPase (V-ATPase) pump (11), which energizes fluid transport. Furthermore, electrophysiological studies suggest that cGMP signaling modulates V-ATPase activity (6), suggesting that cGMP signaling may regulate ion transport in tubules.…”

mentioning

confidence: 99%

Ectopic Expression of Bovine Type 5 Phosphodiesterase Confers a Renal Phenotype in Drosophila

Broderick

Kean

Dow

et al. 2004

Journal of Biological Chemistry

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cGMP signaling regulates epithelial fluid transport by Drosophila Malpighian (renal) tubules. In order to directly evaluate the importance of cGMP-degrading phosphodiesterases (PDEs) in epithelial transport, bovine PDE5 (a bona fide cGMP-PDE), was ectopically expressed in vivo. Transgenic UAS-PDE5 Drosophila were generated, and PDE5 expression was driven in specified tubule cells in vivo by cell-specific GAL4 drivers. Targeted expression was verified by PCR and Western blotting. Immunolocalization of PDE5 in tubule confirmed specificity of expression and demonstrated localization to the apical plasma membrane. GAL4/UAS-PDE5 tubules exhibit increased cG-PDE activity and reduced basal cGMP levels compared with control lines. We show that wild-type and control tubules are sensitive to the PDE5-specific inhibitor sildenafil and that GAL4/UAS-PDE5 tubules display enhanced sensitivity to sildenafil, compared with controls. cGMP content in GAL4/UAS-PDE5 tubules is restored to control levels by treatment with sildenafil. Thus bovine PDE5 retains cGMP-degrading activity and inhibitor sensitivity when expressed in Drosophila. Expression of PDE5 in tubule principal cells results in an epithelial phenotype, reducing rates of basal and cGMP-/Cardioaccelatory peptide 2b (CAP 2b )-stimulated fluid transport. Furthermore, inhibition of PDE5 activity by sildenafil restores basal and cGMP-stimulated fluid transport rates to control levels. However, corticotrophin releasing factorlike-stimulated transport, which is activated by cAMP signaling, was unaffected, confirming that only cGMPstimulated signaling events in tubule are compromised by overexpression of PDE5. Successful ectopic expression of a vertebrate cG-PDE in Drosophila has shown that cG-PDE has a critical role in tubule function in vivo and that cG-PDE function is conserved across evolution. The transgene also provides a generic tool for the analysis of cGMP signaling in Drosophila.

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“…D. melanogaster tubules, which constitute an important genetic model for transporting epithelia (22), display increased fluid transport rates when stimulated by either exogenous cGMP, which enters tubule cells via a cyclic nucleotide transporter (23), nitric oxide (NO), or neuropeptide (capa)-generated NO/cGMP (24 -27). NO-and capa-stimulated cGMP signaling is compartmentalized to principal cells in the main, fluid-secreting segment of tubules (27,28), containing the electrogenic vacuolar H ϩ -ATPase (V-ATPase) (29), which energizes fluid transport. Electrophysiological studies show that cGMP signaling modulates V-ATPase activity (25), suggesting that cGMP signaling may regulate ion transport in tubules.…”

mentioning

confidence: 99%