Direct and indirect targets of carboxyatractyloside, including overlooked toxicity toward nucleoside diphosphate kinase (NDPK) and mitochondrial H+ leak.

CONTEXT: The toxicity of atractyloside/carboxyatractyloside is generally well recognized and commonly ascribed to the inhibition of mitochondrial ADP/ATP carriers, which are pivotal for oxidative phosphorylation. However, these glycosides may 'paralyze' additional target proteins. OBJECTIVE: This review presents many facts about atractyloside/carboxyatractyloside and their plant producers, such as Xanthium spp. (Asteraceae), named cockleburs. METHODS: Published studies and other information were obtained from databases, such as 'CABI - Invasive Species Compendium', 'PubMed', and 'The World Checklist of Vascular Plants', from 1957 to December 2022. The following major keywords were used: 'carboxyatractyloside', 'cockleburs', 'hepatotoxicity', 'mitochondria', 'nephrotoxicity', and 'Xanthium'. RESULTS: In the third decade of the twenty first century, public awareness of the severe toxicity of cockleburs is still limited. Such toxicity is often only perceived by specialists in Europe and other continents. Interestingly, cocklebur is among the most widely distributed invasive plants worldwide, and the recognition of new European stands of Xanthium spp. is provided here. The findings arising from field and laboratory research conducted by the author revealed that (i) some livestock populations may instinctively avoid eating cocklebur while grazing, (ii) carboxyatractyloside inhibits ADP/GDP metabolism, and (iii) the direct/indirect target proteins of carboxyatractyloside are ambiguous. CONCLUSIONS: Many aspects of the Xanthium genus still require substantial investigation/revision in the future, such as the unification of the Latin nomenclature of currently distinguished species, bur morphology status, true fruit (achene) description and biogeography of cockleburs, and a detailed description of the physiological roles of atractyloside/carboxyatractyloside and the toxicity of these glycosides, mainly toward mammals. Therefore, a more careful interpretation of atractyloside/carboxyatractyloside data, including laboratory tests using Xanthium-derived extracts and purified toxins, is needed.

Sensitivity of the aldehyde-induced and free fatty acid-induced activities of plant uncoupling protein to GTP is regulated by the ubiquinone reduction level.

Using isolated potato tuber mitochondria possessing uncoupling protein (StUCP), we found that, under non-phosphorylating conditions, the sensitivity of aldehyde (all trans-retinal or 4-hydroxy-2-nonenal)-induced and fatty acid (linoleic acid)-induced StUCP-mediated proton leaks to GTP is controlled by the endogenous ubiquinone (Q) reduction level. The action of StUCP activators was abolished by GTP only when Q was sufficiently oxidized, but no inhibitory effect was observed when Q was highly reduced. Thus, the Q reduction level-dependent regulation of StUCP inhibition functions independently of the type of UCP activation and could be an important physiological factor affecting the efficiency of UCP-catalyzed uncoupling in plant mitochondria.