Small structural changes on a hydroquinone scaffold determine the complex I inhibition or uncoupling of tumoral oxidative phosphorylation

Urra, Félix A.; Córdova-Delgado, Miguel; Lapier, Michel; Orellana‐Manzano, Andrea; Acevedo-Arévalo, Luis; Pessoa‐Mahana, Hernán; González-Vivanco, Jaime M.; Martínez-Cifuentes, Maximiliano; Ramírez-Rodríguez, Oney; Millas-Vargas, Juan Pablo; Weiss-López, Boris; Pavani, Mario; Ferreira, Jorge; Araya‐Maturana, Ramiro

doi:10.1016/j.taap.2015.12.005

Cited by 31 publications

(31 citation statements)

References 60 publications

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“…3a). FR58P1a contains the hydroquinone scaffold FR58H8, which has a known effect on complex I-dependent respiration 26 , and a bromo hexanoyl (BHA) tail. To determine whether the effect of FR58P1a is mediated by these compounds after a potential intracellular hydrolysis, we isolated mitochondria from the highly oxidative TA3/Ha cells 26 and the effects of FR58H8, FR58P1a and BHA on respiration were determined.…”

Section: Resultsmentioning

confidence: 99%

“…FR58P1a contains the hydroquinone scaffold FR58H8, which has a known effect on complex I-dependent respiration 26 , and a bromo hexanoyl (BHA) tail. To determine whether the effect of FR58P1a is mediated by these compounds after a potential intracellular hydrolysis, we isolated mitochondria from the highly oxidative TA3/Ha cells 26 and the effects of FR58H8, FR58P1a and BHA on respiration were determined. When we compared the effect of FR58H8 and FR58P1a on respiration in state 3 u (in presence of FCCP) and state 4o (in presence of oligomycin), we found that both compounds increase mitochondrial respiration stimulated with glutamate/malate in state 4o, but only FR58H8 completely inhibited respiration in state 3 u at 50 µM (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Previously, we described an anti-cancer ortho -carbonyl substituted hydroquinone scaffold 55 that through small structural changes determines three types of compounds with mitochondrial action 26 . One of these types corresponds to compounds with dual action (inhibitors of complex I-dependent respiration and uncouplers of OXPHOS) whose ester derivatives and benzophenone, chromone and benzofuran scaffolds were used to screen the effect on these cells.…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondria were isolated from TA3/Ha ascites tumor cell line by fractional centrifugation as previously described 26 . Mitochondrial respiration was measured polarographically at 25 °C with a Clark electrode No.…”

Section: Methodsmentioning

confidence: 99%

“…Intracellular NAD(P)H levels were measured by auto-fluorescence using specific excitation and emission wavelengths of 340/428 nm as described 26 . Mitochondrial membrane potential (∆Ψm) and intracellular ROS levels in intact cells were determined by flow cytometry using the potentiometric probe tetramethylrhodamine methyl ester (TMRM, Molecular Probe) and dihydroethidium (DHE) probe, respectively.…”

Section: Methodsmentioning

confidence: 99%

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FR58P1a; a new uncoupler of OXPHOS that inhibits migration in triple-negative breast cancer cells via Sirt1/AMPK/β1-integrin pathway

Urra

Muñoz

Córdova-Delgado

et al. 2018

Sci Rep

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Highly malignant triple-negative breast cancer (TNBC) cells rely mostly on glycolysis to maintain cellular homeostasis; however, mitochondria are still required for migration and metastasis. Taking advantage of the metabolic flexibility of TNBC MDA-MB-231 cells to generate subpopulations with glycolytic or oxidative phenotypes, we screened phenolic compounds containing an ortho-carbonyl group with mitochondrial activity and identified a bromoalkyl-ester of hydroquinone named FR58P1a, as a mitochondrial metabolism-affecting compound that uncouples OXPHOS through a protonophoric mechanism. In contrast to well-known protonophore uncoupler FCCP, FR58P1a does not depolarize the plasma membrane and its effect on the mitochondrial membrane potential and bioenergetics is moderate suggesting a mild uncoupling of OXPHOS. FR58P1a activates AMPK in a Sirt1-dependent fashion. Although the activation of Sirt1/AMPK axis by FR58P1a has a cyto-protective role, selectively inhibits fibronectin-dependent adhesion and migration in TNBC cells but not in non-tumoral MCF10A cells by decreasing β1-integrin at the cell surface. Prolonged exposure to FR58P1a triggers a metabolic reprograming in TNBC cells characterized by down-regulation of OXPHOS-related genes that promote cell survival but comprise their ability to migrate. Taken together, our results show that TNBC cell migration is susceptible to mitochondrial alterations induced by small molecules as FR58P1a, which may have therapeutic implications.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%