mitochondrial respiration

Mitochondrial respiration-IN-3, a fluorine derivative of Dalfopristin, possesses cell membrane permeability and exhibits the capability to inhibit mitochondrial translation in glioblastoma stem cells. This compound is utilized in cancer research [1].

Mitochondrial respiration-IN-1 hydrobromide (compound 49) is a potent mitochondrial inhibitor (IC50 = 8.8 mg mL) and significantly reduces mitochondrial respiration in platelets [1].

Mitochondrial respiration-IN-2, a fluorine derivative of Virginiamycin M1, inhibits the mitochondrial translation of glioblastoma stem cells [1].

Imeglimin hydrochloride (EMD 387008 hydrochloride) prevents human endothelial cell death by inhibiting mitochondrial permeability transition without inhibiting mitochondrial respiration.

(S)-Malic acid ((S)-2-Hydroxysuccinic acid) is a tart-tasting organic dicarboxylic acid found in many sour foods, such as apples, and contributes to the sourness of green apples and tartness of wine, although its concentration decreases with fruit ripeness (wikipedia). In its ionized form, it is called malate, an intermediate in the TCA cycle alongside fumarate, and can be formed from pyruvate through anaplerotic reactions. In humans, malic acid is derived from food sources and synthesized in the body via the citric acid cycle in mitochondria, playing a crucial role in energy production under both aerobic and anaerobic conditions. Under aerobic conditions, malate is oxidized to oxaloacetate, providing reducing equivalents via the malate-aspartate redox shuttle, while during anaerobic conditions, its simultaneous reduction to succinate and oxidation to oxaloacetate removes excess reducing equivalents, reversing hypoxia’s inhibition of glycolysis and energy production. Studies on rats have shown that tissue malate depletes following exhaustive physical activity, suggesting that malic acid deficiency may cause physical exhaustion. Administering malic acid to rats has been shown to elevate mitochondrial malate, increasing mitochondrial respiration and energy production.

Boscalid is a broad-spectrum carboxamide fungicide that inhibits fungal respiration by binding to the ubiquinone site of mitochondrial complex II/succinate dehydrogenase.1It suppresses mycelial growth ofS. minorby 87 to 100% and ofS. sclerotiorumby 77 to 100% when used at a concentration of 1 μg/ml.2In field studies, boscalid applied at 5.6 μg/cm2provides 55.5 and 30.4% disease control for lettuce drop caused byS. minorandS. sclerotiorum, respectively. It decreases cell viability of mouse primary cortical neurons following long-term exposure but is not cytotoxic (LC50= >100 μM for acute and continuous exposure). Formulations containing boscalid have been used in agriculture to prevent fungal growth on crops. 1.Wang, Y., Duan, Y., Wang, J., et al.A new point mutation in the iron-sulfur subunit of succinate dehydrogenase confers resistance to boscalid in Sclerotinia sclerotiorumMol. Plant Pathol.16(7)653-661(2015) 2.Matheron, M.E., and Porchas, M.Activity of boscalid, fenhexamid, fluazinam, fludioxonil, and vinclozolin on growth of Sclerotinia minor and S. sclerotiorum and development of lettuce dropPlant Dis.88(6)665-668(2004)

1-Hexanol (hexan-1-ol) is a natural product.1-Hexanol, a primary alcohol, is a surfactant that can be employed in industrial processes to enhance interfacial properties[1]. 1-Hexanol uncouples mitochondrial respiration by a non-protonophoric mechanism[2].

Mitochondrial fusion promoter M1, a modulator of mitochondrial dynamics, enhances mitochondrial function and cellular respiration, and has shown efficacy in reducing brain and cardiac damage in rats suffering from cardiac ischemia/reperfusion injury.

Aumitin, a diaminopyrimidine-based autophagy inhibitor, dose-dependently inhibits starvation- and rapamycin-induced autophagy with IC50s of 0.12 μM and 0.24 μM, respectively [1], and also inhibits mitochondrial respiration by targeting complex I.

CCI-006, a selective inhibitor and chemosensitizer for MLL-rearranged leukemia cells, disrupts mitochondrial respiration. This action leads to irreversible mitochondrial depolarization and triggers a pro-apoptotic unfolded protein response in specific MLL-r leukemia cells.

Antimycin A4 is an active component of the antimycin A antibiotic complex that is more polar than antimycin A1 , antimycin A2 , and antimycin A3 . Antimycin A4 inhibits ATP-citrate lyase with a Ki value of 64.8 μM. The antimycin A complex is a mixture of antimycins A1, A2, A3, and A4 that demonstrates antifungal, insecticidal, nematocidal, and piscicidal properties. It blocks mitochondrial respiration and can deplete cellular levels of ATP via inhibition of complex III of the mitochondrial electron transport chain (ETC). Antimycin A prevents the transfer of electrons between the b-cytochromes and ubiquinone at the Q(inner) site of complex III. This results in the stabilization of the ubisemiquinone radical at the Q(outer) site of complex III, leading to increased production of superoxide. Antimycin A is widely used in research to shunt electron flow through the ETC to study the chemical details of oxygen respiration. Additionally, antimycin A has been shown to inhibit Bcl-2 and Bcl-xL proteins, inducing apoptosis.

GW604714X (2,4-Thiazolidinedione, 5-[[5-[6-(4-acetyl-1-piperazinyl)-3-nitro-2-pyridinyl]-2-fluorophenyl]methylene]-) were found to be potent inhibitors of mitochondrial respiration supported by pyruvate

Ninerafaxstat trihydrochloride shifts cellular metabolism to glucose oxidation from fatty acid oxidation. Ninerafaxstat trihydrochloride improves overall mitochondrial respiration and reduces fatty acid oxidation, thereby inhibiting the proliferation and growth of cancer cells.

SLU-PP-332 is a pan-estrogen receptor-related receptor (ERR) agonist with high affinity for ERRα, ERRβ, and ERRγ, exhibiting EC50 values of 98, 230, and 430 nM, respectively. SLU-PP-332 enhances mitochondrial function and cellular respiration, increases type IIa oxidized skeletal muscle fibers, and enhances exercise tolerance in skeletal muscle cell lines. It has potential applications in the study of metabolic diseases, improvement of muscle function, and amelioration of metabolic disorders and aging.

Compound 5C, referred to as Pkm2-in-4, is a selective PKM2 inhibitor (IC50 = 0.35 µM) that modulates pyruvate-dependent respiration and promotes mitochondrial H2O2 production rate and electron transport system coupling [1].

(±)9(10)-DiHOME, the diol derivative of (±)9(10)-EpOME—a cytochrome P450-derived epoxide of linoleic acid also known as leukotoxin—is formed through the action of soluble epoxide hydrolase (sEH) in neutrophils. It exhibits toxicity towards Sf21 cells expressing sEH as well as tolacZ-expressing control cells, differing from leukotoxin which only harms sEH-containing cells. Furthermore, combined exposure to 9(10)- and 12(13)-DiHOME leads to cell death in rabbit renal proximal tubule cells by disrupting mitochondrial respiration, and causes lung injury, respiratory distress, and mortality in mice, highlighting its role as a toxic lipid mediator. Specifically, 9(10)-DiHOME has been associated with acute respiratory distress syndrome (ARDS), a severe and often deadly complication in patients with major burns. Elevated levels of this compound have been detected in the bronchoalveolar lavage fluid (BALF) of women, but not men, with chronic obstructive pulmonary disease (COPD), and its levels are also increased in patients with allergic asthma, indicating its significance in respiratory conditions.

Tioxaprofen is a novel anti-mycotic drug effective against Trichophyton mentagrophytes and T. rubrum, and it acts as a potent uncoupling agent of mitochondrial respiration [1].

Picoxystrobin, a prominent primary strobilurin fungicide, is extensively utilized for efficient plant disease management. By obstructing electron transfer at the Qo center of cytochrome b and c1, picoxystrobin effectively halts mitochondrial respiration[1].

Mito-apocynin (C11) is a mitochondria-targeting antioxidant that works by targeting and neutralizing reactive oxygen species (ROS) produced during cellular respiration. Triphenylphosphonium bromide has been found to be effective in preventing mitochondrial dysfunction, which is a major cause of the aging process and various diseases. It has anti-inflammatory, anti-apoptotic and antioxidant activities.

Azoxystrobin (Bankit) is a broad-spectrum fungicide. Azoxystrobin induces ROS production, cell apoptosis and mitochondrial respiration by blocking electron transfer between cytochromes b and c1.

Hexafluoro is an inhibitor of DRP1 phosphorylation. Honokiol DCA stimulates a phenotype suggestive of respiration through mitochondrial normalization and demonstrates activity in Vemurafenib-resistant melanoma in vivo.

Cyanidin-3-O-arabinoside chloride has antioxidant activity. It reduces the peroxynitrite-induced suppression of mitochondrial respiration, DNA damage, PARS activation and vascular dysfunction in HUVECs.

Cefaloglycin (Cephaloglycin), an orally active, nephrotoxic β-lactam cephalosporin antibiotic, exhibits antibacterial activity primarily against Gram-Positive cocci, excluding enterococci. It impairs mitochondrial substrate uptake and respiration, underscoring its toxicity [1] [2] [3].

Dichloroacetate (DCA) is an inhibitor of all pyruvate dehydrogenase kinase (PDHK) isoforms, which are enzymes that phosphorylate and inhibit PDH in mitochondria. Inhibition of PDHK shifts cell metabolism from glycolysis to mitochondrial glucose oxidation, an effect that has relevance to cancer, type 2 diabetes, and other diseases. CAY10703 is a DCA trimer that is at least 10-fold more cytotoxic against leukemia cell lines than DCA. It is approximately 3-fold less cytotoxic than DCA against peripheral blood mononuclear cells from healthy blood donors. CAY10703 significantly reduces both basal and maximal respiration in leukemia cells. It is stable in vivo after subcutaneous inoculation, remaining in circulation for more than five hours after injection.

6-Benzylthioinosine, a broad-spectrum metabolic inhibitor, inhibits glucose uptake, decreases glycolysis and ATP concentration with minimal changes in ROS and mitochondrial respiration.

8-Azido-ADP (disodium) is a covalently bound inhibitor of mitochondrial adenine nucleotide translocation that prevents the ADP-induced 4 to 3 shift in mitochondrial respiration. Additionally, in a light-dependent reaction, 8-Azido-ADP (disodium) irreversibly inhibits adenine nucleotide exchange.

Z16078526 enhances thermogenesis in mice by inducing endogenous Ucp1 expression, promoting p38 MAPK phosphorylation, and stimulating lipolysis in primary mouse brown adipocytes. Additionally, it activates thermogenic gene expression and mitochondrial activity, specifically uncoupled respiration, in these cells.

ROCK-IN-4 is a potent ROCK inhibitor that maintains NO release capacity, reversibly depolymerizes F-actin, and blocks mitochondrial respiration in human trabecular meshwork (HTM) cells. ROCK-IN-4 can be utilized to study glaucoma or high intraocular pressure.

Honokiol DCA is an inhibitor of DRP1 phosphorylation. Honokiol DCA stimulates a phenotype suggestive of respiration through mitochondrial normalization and demonstrating activity in Vemurafenib-resistant melanoma in vivo.

Piericidin B is a bacterial metabolite that has been found inS. mobaraensisand has insecticidal and antimicrobial activities.1,2,3It inhibits NADH oxidase activity in isolated bovine heart mitochondria and inhibits respiration in isolated rat liver mitochondria and isolated cockroach (P. americana) muscle mitochondria.2,3Topical application of piericidin B (4 μg/insect) induces mortality in 87.5% of houseflies (M. domestica).1It induces 93.3, 100, and 100% mortality in rice stem borer (C. simples), silkworm (B. mori), and green caterpillar (P. rapae) larvae, respectively, when applied at respective concentrations of 60, 4.8, and 96 μg/larva. Piericidin B is active against the fungiT. asteroides,T. rubrum,M. gypseum, andC. neoforms(MICs = 20, 10, 20, and 2 μg/ml, respectively), as well as the bacteriaM. luteusandP. vulgaris(MICs = 50 and 100 μg/ml, respectively). 1.Takahashi, N., Suzuki, A., Kimura, Y., et al.Isolation, structure and physiological activities of piericidin B, natural Insecticide produced by a StreptomycesAgr. Biol. Chem.32(9)1115-1122(1968) 2.Jeng, M., Hall, C., Crane, F.L., et al.Inhibition of mitochondrial electron transport by piericidin A and related compoundsBiochemistry7(4)1311-1322(1968) 3.Mitsui, T., Fukami, J.-I., Fukunaga, K., et al.Studies on piericidin. I. : Effects of piericidin A and B on mitochondrial electron transport in insect muscle comparing with rotenoneSci. Insect Control34(3)126-134(1969)