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Molecular phylogenetic analyses of the mitochondrial ADP-ATP carriers: the Plantae/Fungi/Metazoa trichotomy revisited.

ABSTRACT: We investigated the basal phylogeny of eukaryotes through analyses of sequences from the ADP-ATP mitochondrial carrier, a transmembrane protein that is stable in function across eukaryote kingdoms. The ADP-ATP data strongly suggest the grouping of Plantae and Fungi to the exclusion of Metazoa. We implemented several procedures to avoid pervasive analytical artifacts such as erroneous alignment, random rooting, long branch attraction, and misidentification of noisy characters. The quest of an eukaryote tree that would be largely consistent across multiple loci might be essentially illusory because of differential lineage sorting, horizontal gene transfer, and the chimeric nature of early eukaryotes. Better understanding of these evolutionary parameters, requiring separate phylogenetic analyses of multiple independent loci, is fundamental for resolution of the modes of emergence and evolution of the major eukaryote lineages.

SUBMITTER: Loytynoja A

PROVIDER: S-EPMC56939 | biostudies-literature | 2001 Aug

REPOSITORIES: biostudies-literature

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Molecular phylogenetic analyses of the mitochondrial ADP-ATP carriers: the Plantae/Fungi/Metazoa trichotomy revisited.

Löytynoja A A Milinkovitch M C MC

Proceedings of the National Academy of Sciences of the United States of America 20010821 18

We investigated the basal phylogeny of eukaryotes through analyses of sequences from the ADP-ATP mitochondrial carrier, a transmembrane protein that is stable in function across eukaryote kingdoms. The ADP-ATP data strongly suggest the grouping of Plantae and Fungi to the exclusion of Metazoa. We implemented several procedures to avoid pervasive analytical artifacts such as erroneous alignment, random rooting, long branch attraction, and misidentification of noisy characters. The quest of an euk ...[more]

PMID: 11517311

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Project description:An increasing number of commonly prescribed drugs are known to interfere with mitochondrial function, causing cellular toxicity, but the underlying mechanisms are largely unknown. Although often not considered, mitochondrial transport proteins form a significant class of potential mitochondrial off-targets. So far, most drug interactions have been reported for the mitochondrial ADP/ATP carrier (AAC), which exchanges cytosolic ADP for mitochondrial ATP. Here, we show inhibition of cellular respiratory capacity by only a subset of the 18 published AAC inhibitors, which questions whether all compound do indeed inhibit such a central metabolic process. This could be explained by the lack of a simple, direct model system to evaluate and compare drug-induced AAC inhibition. Methods: For its development, we have expressed and purified human AAC1 (hAAC1) and applied two approaches. In the first, thermostability shift assays were carried out to investigate the binding of these compounds to human AAC1. In the second, the effect of these compounds on transport was assessed in proteoliposomes with reconstituted human AAC1, enabling characterization of their inhibition kinetics. Results: Of the proposed inhibitors, chebulinic acid, CD-437 and suramin are the most potent with IC50-values in the low micromolar range, whereas another six are effective at a concentration of 100 μM. Remarkably, half of all previously published AAC inhibitors do not show significant inhibition in our assays, indicating that they are false positives. Finally, we show that inhibitor strength correlates with a negatively charged surface area of the inhibitor, matching the positively charged surface of the substrate binding site. Conclusion: Consequently, we have provided a straightforward model system to investigate AAC inhibition and have gained new insights into the chemical compound features important for inhibition. Better evaluation methods of drug-induced inhibition of mitochondrial transport proteins will contribute to the development of drugs with an enhanced safety profile.

Dataset Information

Molecular phylogenetic analyses of the mitochondrial ADP-ATP carriers: the Plantae/Fungi/Metazoa trichotomy revisited.

Publications

Molecular phylogenetic analyses of the mitochondrial ADP-ATP carriers: the Plantae/Fungi/Metazoa trichotomy revisited.

Similar Datasets

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