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Ubiquitin Subproteome of Brain Mitochondria and Its Changes Induced by Experimental Parkinsonism and Action of Neuroprotectors

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Abstract

The review summarizes the data of our research and published studies on the ubiquitination of brain mitochondrial proteins and its changes during the development of experimental parkinsonism and administration of the neuroprotector isatin (indole-2,3-dione) with special attention to the mitochondrial ubiquitin-conjugating system and location of ubiquitinated proteins in these organelles. Incubation of brain mitochondrial fraction with biotinylated ubiquitin in vitro resulted in the incorporation of biotinylated ubiquitin in both mitochondrial and mitochondria-associated proteins. According to the interactome analysis, the identified non-ubiquitinated proteins are able to form tight complexes with ubiquitinated proteins or their partners and components of mitochondrial membranes, in which interactions of ubiquitin chains with the ubiquitin-binding protein domains play an important role. The studies of endogenous ubiquitination in the total brain mitochondrial fraction of C57Bl mice performed in different laboratories have shown that mitochondrial proteins represent about 30% of all ubiquitinated proteins. However, comparison of brain subproteomes of mitochondrial ubiquitinated proteins reported in the literature revealed significant differences both in their composition and involvement of identified ubiquitinated proteins in biological processes listed in the Gene Ontology database. The development of experimental parkinsonism in C57Bl mice induced by a single-dose administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) resulted in a decrease in the total number of mitochondrial ubiquitinated proteins and increase in the number of oxidized mitochondrial proteins containing the ubiquitin signature (K-ε-GG). Comparison of ubiquitinated proteins associated with the mouse brain mitochondrial fraction and mouse brain mitochondrial proteins bound to the proteasome ubiquitin receptor (Rpn10 subunit) did not reveal any common proteins. This suggests that ubiquitination of brain mitochondrial proteins is not directly related to their degradation in the proteasomes. Proteomic profiling of brain isatin-binding proteins identified enzymes involved in the ubiquitin-conjugating system functioning. Mapping of the identified isatin-binding proteins to known metabolic pathways indicates their participation in the parkin (E3 ubiquitin ligase)-associated pathway (CH000000947). The functional links involving brain mitochondrial ubiquitinated proteins were found only in the group of animals with the MPTP-induced parkinsonism, but not in animals treated with MPTP/isatin or isatin only. This suggests that the neuroprotective effect of isatin may be associated with the impaired functional relationships of proteins targeted to subsequent degradation.

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Abbreviations

GO:

Gene Ontology database

MAO:

monoamine oxidase

MPTP:

neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

PPI:

protein—protein interaction

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Funding

Analysis of literature data was supported by the Russian Foundation for Basic Research (project no. 19-015-00073), the interactome analysis using the STRING open-access software was performed within the framework of the Program of Fundamental Scientific Research of the State Academies of Sciences for 2013–2020.

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Authors and Affiliations

  1. Department of Proteomic Research, Institute of Biomedical Chemistry, 119121, Moscow, Russia

    O. A. Buneeva, A. T. Kopylov & A. E. Medvedev

  2. Faculty of Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    M. V. Medvedeva

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  1. O. A. Buneeva
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  2. M. V. Medvedeva
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  3. A. T. Kopylov
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  4. A. E. Medvedev
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Correspondence to M. V. Medvedeva.

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The authors declare no conflict of interest.

Compliance with ethical standards

Experiments on the interactome analysis performed during the preparation of this review did not involve people and animals as research objects.

Published in Russian in Biokhimiya, 2019, Vol. 84, No. 11, pp. 1683–1700.

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Buneeva, O.A., Medvedeva, M.V., Kopylov, A.T. et al. Ubiquitin Subproteome of Brain Mitochondria and Its Changes Induced by Experimental Parkinsonism and Action of Neuroprotectors. Biochemistry Moscow 84, 1359–1374 (2019). https://doi.org/10.1134/S0006297919110117

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