Mechanism of action of agents which uncouple oxidative phosphorylation: Direct correlation between protoncarrying and respiratory-releasing properties using rat liver mitochondria

Cunarro, Julia; Weiner, Michael W.

doi:10.1016/0005-2728(75)90106-1

Cited by 101 publications

(35 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We think it possible that the observed shift of some of the mitochondria to a lighter density in the presence of the CCCP inhibitor (resulting in a second peak of imported protein in fraction 1 that is not seen in the absence of inhibitor) may reflect the swelling of some of the well sealed mitochondria. CCCP-induced swelling of actively respiring mitochondria has been reported previously (51) in other systems.…”

Section: Cytochrome C 1 Is Imported Into Mitochondria In the Absence mentioning

confidence: 79%

Trypanosoma brucei Cytochromec1 Is Imported into Mitochondria Along an Unusual Pathway

Priest¹,

Hajduk

2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

In most eukaryotic organisms, cytochrome c 1 is encoded in the nucleus, translated on cytosolic ribosomes, and directed to its final destination in the mitochondrial inner membrane by a bipartite, cleaved, amino-terminal presequence. However, in the kinetoplastids and euglenoids, the cytochrome c 1 protein has been shown to lack a cleaved presequence; a single methionine is removed from the amino terminus upon maturation, and the sequence upstream of the heme-binding site is generally shorter than that of the other eukaryotic homologs. We have used a newly developed mitochondrial protein import assay system from Trypanosoma brucei to demonstrate that the T. brucei cytochrome c 1 protein is imported along a non-conservative pathway similar to that described for the inner membrane carrier proteins of other organisms. This pathway requires external ATP and an external protein receptor but is not absolutely dependent on a membrane potential or on ATP hydrolysis in the mitochondrial matrix. We propose the cytochrome c 1 import in T. brucei is a two-step process first involving a membrane potential independent translocation across the outer mitochondrial membrane followed by heme attachment and a membrane potential-dependent insertion into the inner membrane.

show abstract

Section: Cytochrome C 1 Is Imported Into Mitochondria In the Absence mentioning

confidence: 79%

Trypanosoma brucei Cytochromec1 Is Imported into Mitochondria Along an Unusual Pathway

Priest¹,

Hajduk

2003

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The following day, the cells were treated with PEP005 or 200 M carbonyl cyanide m-chlorophenylhydrazone (Sigma, St. Louis, MO; Refs. 26,27). PEP005 and carbonyl cyanide m-chlorophenylhydrazone were dissolved in 100% acetone and diluted in complete medium; the acetone concentration in the medium did not exceed 1%.…”

Section: Methodsmentioning

confidence: 99%

Antitumor Activity of 3-Ingenyl Angelate

et al. 2004

View full text Add to dashboard Cite

Options for skin cancer treatment currently include surgery, radiotherapy, topical chemotherapy, cryosurgery, curettage, and electrodessication. Although effective, surgery is costly and unsuitable for certain patients. Radiotherapy can leave a poor cosmetic effect, and current chemotherapy is limited by low cure rates and extended treatment schedules. Here, we describe the preclinical activity of a novel topical chemotherapeutic agent for the treatment of skin cancer, 3-ingenyl angelate (PEP005), a hydrophobic diterpene ester isolated from the plant Euphorbia peplus. Three daily topical applications of 42 nmol (18 g) of PEP005 cured a series of s.c. mouse tumors (B16 melanoma, LK2 UV-induced squamous cell carcinoma, and Lewis lung carcinoma; n ‫؍‬ >14 tumors/group) and human tumors (DO4 melanoma, HeLa cervical carcinoma, and PC3 and DU145 prostate carcinoma; n ‫؍‬ >4 tumors/group) previously established (5-10 mm 3 ) on C57BL/6 or Foxn1 nu mice. The treatment produced a mild, short-term erythema and eschar formation but, ultimately, resulted in excellent skin cosmesis. The LD 90 for PEP005 for a panel of tumor cell lines was 180 -220 M. Electron microscopy showed that treatment with PEP005 both in vitro (230 M) and in vivo (42 nmol) rapidly caused swelling of mitochondria and cell death by primary necrosis. 51 Cr release, uptake of propidium iodide, and staining with the mitochondria dye JC1, revealed that PEP005 (230 M) treatment of tumor cells in vitro resulted in a rapid plasma membrane perturbation and loss of mitochondrial membrane potential. PEP005 thus emerges as a new topical anti-skin cancer agent that has a novel mode of action involving plasma membrane and mitochondrial disruption and primary necrosis, ultimately resulting in an excellent cosmetic outcome.

show abstract

“…Given the known mode of action of uncouplers as transmembrane proton carriers (5,24) none. When this plastoquinone function was inhibited, electron flow to ferredoxin stopped unless proton translocation was restored by the addition of an uncoupler.…”

Section: Resultsmentioning

confidence: 99%

Proton transport in photooxidation of water: A new perspective on photosynthesis

Arnon

Tsujimoto

Tang

1981

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The currently prevalent concept of the generation of photosynthetic reducing power in oxygen-evolving cells envisions a linear (noncyclic) electron flow from water to ferredoxin (and thence to NADP+) that requires the collaboration of photosystems I and 11 (PSI and PSII) joined by plastoquinone and other electron carriers (the Z scheme). The essence of the Z scheme is that only PSI can reduce ferredoxin-i.e., that, after being energized to an intermediate reducing potential by PSII, electrons from water are transported via plastoquinone to PSI which energizes the electrons to their ultimate reducing potential adequate for the reduction of ferredoxin. Basic to the Z scheme is the function of plastoquinone as the obligatory link in electron transport from PSIl to PSI. However, we have found that, when plastoquinone function was inhibited, ferredoxin was photoreduced by water without the collaboration of PSI. We now report evidence for an important function of plastoquinone in the translocation of protons liberated inside the thylakoid membrane by photooxidation of water. When the oxygenic photoreduction (i.e., by water) of ferredoxin was blocked by plastoquinone inhibitors, dibromothymoquinone or dinitrophenol ether of iodonitrothymol, the photoreduction of ferredoxin was restored by each of four chemically diverse uncouplers, similar only in their ability to facilitate proton movement across membranes. Similar results were obtained for the oxygenic reduction of NADP'. Our results suggest that the light-induced electron flow from water cannot be maintained unless the simultaneously liberated protons are removed from inside the membrane via plastoquinone. The new evidence is embodied in a concept of an oxygenic photosystem for photosynthetic electron and proton transport, which we propose as an alternative to the Z scheme, to account for photoreduction offerredoxin-NADP+ by water and the coupled oxygenic (formerly noncyclic) ATP formation without involving PSI. The role of the anoxygenic photosystem (formerly called PSI) is ATP formation by cyclic photophosphorylation.Photooxidation of water, 2H20-) 4 e-+ 4H + 02, is a key reaction in plant photosynthesis. Aside from its all-important by-product, oxygen, the liberated electrons eventually reduce ferredoxin (1, 2) and then NADP+ (3), thereby accounting for photosynthetic reducing power; the liberated protons contribute to the protonmotive force (4, 5) which accounts for the ("noncyclic") ATP formation that is coupled to NADP+ reduction (6).Photooxidation of water takes place inside the thylakoid membranes (7). These contain two photocenters identified with photosystems I and II (PSI and PSII) and a chain of carriers responsible for the transport ofelectrons and protons within and across the membrane. According to the now-prevalent concepts embodied in the so-called Z scheme (8, 9), PSII photooxidizes water but cannot reduce ferredoxin because it can energize the released electrons only to an intermediate potential; the electrons are transported from PSII t...

show abstract

Mechanism of action of agents which uncouple oxidative phosphorylation: Direct correlation between protoncarrying and respiratory-releasing properties using rat liver mitochondria

Cited by 101 publications

References 31 publications

Trypanosoma brucei Cytochromec1 Is Imported into Mitochondria Along an Unusual Pathway

Trypanosoma brucei Cytochromec1 Is Imported into Mitochondria Along an Unusual Pathway

Antitumor Activity of 3-Ingenyl Angelate

Proton transport in photooxidation of water: A new perspective on photosynthesis

Contact Info

Product

Resources

About