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Caffeic acid and caffeine attenuate toxicity associated with malonic or methylmalonic acid exposure in Drosophila melanogaster

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Abstract

The deficiency in the activity of the mitochondrial enzyme methylmalonyl-CoA mutase (MCM, EC 5.4.99.2) leads to a condition called methylmalonic academia, which is characterised by the accumulation of methylmalonic (MMA), malonic (MA) or other organic acids. Importantly, we have recently found that supplementation with Ilex paraguariensis aqueous extract offered protection against toxicity associated with MMA or MA exposure to Drosophila melanogaster. Of note, caffeic acid (CA) and caffeine (CAF) were the major phytochemicals found in our Ilex paraguariensis crude extract. Therefore, here, we have exploited CA and/or CAF to test the hypothesis that supplementation with the isolated compounds (either alone or combined) could exert a protective effect against MMA or MA-induced toxicity in flies. Therefore, flies were exposed to MA (5 mM) or MMA (5 mM) and concomitantly treated with CA (1.39 μg/mL), CAF (1.27 μg/mL) or CA + CAF for 10 days for survival, and for 4 days for behavioural and biochemical assays. CA, CAF and CA + CAF treatments completely abolished the mortality associated with either MMA or MA exposure. Moreover, CA and CAF, either alone or combined, completely abolished behavioural changes, and completely protect against changes in thiobarbituric acid reactive substances (TBARS) levels, catalase (CAT) activity and MTT reduction ability, associated with MA or MMA exposure. In turn, CAF restored SOD activity in the head of flies exposed to MA or MMA. However, CA and CAF (either alone or combined) significantly decreased acetylcholinesterase (AChE) activity per se, while CAF alone protected from changes in AChE activity (in head tissue) associated with MA or MMA. Finally, CA and/or CAF were able to protect from a decrease in glucose and triglyceride levels associated with both MA and MMA exposures in haemolymph. Together, our data confirm the hypothesis that supplementation with CA and/or CAF offers protection against detrimental changes associated with MMA or MA exposure in flies, being responsible, at least in part, for the protective effect of I. paraguariensis crude extract which was reported previously.

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Acknowledgements

The authors are also grateful to FAPERGS, CNPq, FINEP, INCT-EN and UNIPAMPA.

Funding

This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior–Brasil (CAPES)–Finance Code 001. Additional financial support was given by CNPq/FAPERGS/DECIT/SCTIE-MS/PRONEM #16/2551-0000248-7 and CNPq scholarship (#301807/2018-3).

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  1. Campus Uruguaiana, Programa de Pós-Graduação em Bioquímica (PPGBioq), Universidade Federal do Pampa, Campus Uruguaiana BR-472 Km 7, Uruguaiana, RS, CEP 97500-970, Brazil

    José Luiz Portela, Matheus Chimelo Bianchini, Daniel H. Roos, Daiana Silva de Ávila & Robson Luiz Puntel

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  1. José Luiz Portela
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JLP and RLP conceived and designed research. JLP, MCB and RLP conducted experiments. DHR, DSA and RLP analysed data. JLP, DHR, DSA and RLP wrote the manuscript. The authors declare that all data were generated in-house and that no paper mill was used. All authors read and approved the manuscript.

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Correspondence to Robson Luiz Puntel.

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Portela, J.L., Bianchini, M.C., Roos, D.H. et al. Caffeic acid and caffeine attenuate toxicity associated with malonic or methylmalonic acid exposure in Drosophila melanogaster. Naunyn-Schmiedeberg's Arch Pharmacol 394, 227–240 (2021). https://doi.org/10.1007/s00210-020-01974-3

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