ilyamazunin



Personal Websites

Ilya Mazunin

My research focuses on understanding the relationship between aneuploidy and mitochondrial DNA quality and quantity, and methods of oocyte rejuvenation by boosting mitochondria functioning. My current interests also include the modification of CRISPR/Cas systems for mitochondrial DNA editing. I also have a great collaboration in the field of human genetics with a focus on mitochondrial genetics.

 

  1. Tofilo, M., Voronova, N., Nigmatullina, L., Kuznetsova, E., Timonina, V., Efimenko, B., Tugunkhujaev, O., Avdeichik, S., Ansar, M., Popadin, K., Kirillova, A., Mazunin, I. Live birth of a healthy child in a couple with identical mtDNA carrying a pathogenic c.471_477delTTTAAAAinsG variant in the MOCS2 gene (2023) Genes 14(3), 720 (doi: 10.3390/genes14030720)
  2. Ri, M., Ree, N., Oreshkov, S., Tofilo, M., Kirillova, A., Zvereva, I., Gunbin, K., Yurov, V., Salumets, A., Woods, D.C., Khrapko, K., Fellay, J., Tilly, J.L., Mazunin, I., Popadin, K. Aneuploidy in human embryos is associated with a maternal age-independent increase in mitochondrial DNA content and an enrichment of ultra-rare mitochondrial DNA variants https://www.biorxiv.org/content/10.1101/2022.10.14.512116v2.full.pdf
  3. Mikhailova, A.A., Shamanskiy, V., Ushakova, K., Mikhailova, A.G., Oreshkov, S., Knorre, D., Tretiakov, E.O., Overdevest, J.B., Lukowski, S.W., Liuo, C-W., Lin, T-K., Kunz, W., Reymond, A., Mazunin, I., Bazykin, G.A., Gunbin, K., Fellay, J., Tanaka, M., Khrapko, K., Popadin, K. Risk of mitochondrial deletions is affected by the global secondary structure of the human mitochondrial genome  (2023) BMC Biology (in press) https://www.biorxiv.org/content/10.1101/603282v4.full.pdf
  4. Korchivaya, E., Silaeva, Y., Mazunin., I., Volodyaev, I. The mitochondrial challenge: disorders and prevention strategies (2023) BioSystems (doi: 10.1016/j.biosystems.2022.104819)
  5. Mikhaylova, A.G., Mikhailova, A.A., Ushakova, K., Tretiakov, E.O., Illushchenko, D., Shamansky, V., Lobanova., V.,  Kozenkov, I., Efimenko, B., Yurchenko, A.A., Kozenkova, E., Zdobnov, E., Makeev, V., Yurov, V., Tanaka, M., Gostimskaya, I., Fleischmann, Z., Annis, S., Franco, M., Wasko, K., Denisov, S., Kunz, W., Knorre, D., Mazunin, I., Nikolaev, S., Fellay, J., Reymond, A., Khrapko, K., Gunbin, K., Popadin, K. A mitochondria-specific mutational signature of aging: increased rate of A>G substitutions on a heavy strand (2022) Nucleic Acids Research, 50(18), 10264-10277,  doi: 10.1093/nar/gkac779
  6. Vasilev, R., Gunitseva, N., Shebanova, R., Korzhenkov, A., Vlaskina, A., Evteeva, M., Polushkina, I., Nikitchina, N., Toshchakov, S., Kamenski, P., Patrushev, M., Mazunin, I. Targeted modification of mammalian DNA by a novel Type V Cas12a endonuclease from Ruminococcus bromii (2022) International Journal of Molecular Sciences, Volume 23, Issue 16, 9289, doi: 10.3390/ijms23169289
  7. Tofilo, M., Voskoboeva, E., Timonina, V., Staufner, C., Hoffmann, G., Poschl, J., Schlieben, L., Prokisch, H., Kholodov, D., Ladygin, S., Avdeichik, S., Mazunin, I. A new family with congenital myasthenic syndrome caused by compound heterozygous CHAT mutations (2022) Biomedical Journal of Scientific & Technical Research (BJSTR), doi: 10.26717/BJSTR.2022.44.007122
  8. Kirillova, A., Mazunin, I. Operation “mitochondrial wipeout” – clearing recipient mitochondria DNA during nuclear transfer (2022) Journal of Assisted Reproduction and Genetics, doi: 10.1007/s10815-022-02561-6
  9. Shebanova, R., Nikitchina, N., Shebanov, N., Mekler, V., Kuznedelov, K., Ulashchik, E., Vasilev, R., Sharko, O., Shmanai, V., Tarassov, I., Severinov, K., Entelis, N., Mazunin, I. Efficient target cleavage by Type V Cas12a effector programmed with split CRISPR RNA (2022) Nucleic Acids Research, 50(2), 1162-1173,  doi: 10.1093/nar/gkab1227
  10. Kirillova, A., Smitz, J.E.J., Sukhikh, G., Mazunin, I. The role of mitochondria in oocyte maturation. (2021) Cells, 10(9), 2484. doi: 10.3390/cells10092484
  11. Zakirova, E., Muzyka, V., Mazunin, I., Orishchenko, K. Natural and artificial mechanisms of mitochondrial genome elimination. (2021) Life, 11(2):76. doi: 10.3390/life11020076.
  12. Kenis, V., Melchenko, E., Mazunin, I., Pekkinen, M., Makitie, O. A new family with Epiphyseal chondrodysplasia type Miura (2021) American Journal of Medical Genetics Part A (DOI: 10.1002/ajmg.a.61923) 
  13. Zakirova, E., Vyatkin, Yu, Verechshagina, N., Muzyka, V., Mazunin, I., Orishchenko, K. Study of the effect the introduction of mitochondrial import determinants into the gRNA structure on the activity of the gRNA/SpCas9 complex in vitro (2020). Vavilov Journal of genetics and breeding, 24(5):512-518 (DOI: 10.18699/VJ20.643)
  14. Starikovskaya, E.B., Shalaurova, S.A., Dryomov, S.V., Nazhmidenova, A.M., Volodko, N.V., Bychkov, I.Y., Mazunin, I.O., Sukernik, R.I. Mitochondrial DNA variation of Leber’s Hereditary Optic Neuropathy (LHON) in Western Siberia (2019) Cells, 8, 1574 (DOI: 10.3390/cells8121574)
  15. Gazizova, I.R., Mazunin, I.O.,  Malishevskaya T.N., Kiseleva, O.A., Gadzhiev, A.M., Rindzhibal, Al-M. Mitochondrial DNA as a Factor of Glaucomous Optic Neuropathy’s Development Mechanism (2019) Oftalmologiya; 16(4), pp 479–486 (DOI: 10.18008/1816-5095-2019-4-479-486)
  16. Martemyanov, V., Bykov, R., Demenkova, M., Gninenko, Y., Romancev, S., Bolonin, I., Mazunin, I., Belousova, I., Akhanaev, Y., Pavlushin, S., Krasnoperova, P., Ilinsky, Y. Genetic Evidence of Broad Spreading of Lymantria dispar in the West Siberian Plain (2019) PLOS One (DOI: 10.1371/journal.pone.0220954)
  17. Skuratovskaia, D., Litvinova, L., Zatolokin, P., Vulf, M., Popadin, K., Mazunin, I. From Normal to Obesity and Back: The Associations between Mitochondrial DNA Copy Number, Gender, and Body Mass Index (2019) Cells, 8(5) (DOI: 10.3390/cells8050430)
  18. Skuratovskaia, D., Zatolokin, P., Vulf, M., Mazunin, I., Litvinova, L. Interrelation of chemerin and TNF-α with mtDNA copy number in adipose tissues and blood cells in obese patients with and without type 2 diabetes (2019) BMC Medical Genomics (DOI: 10.1186/s12920-019-0485-8)
  19. Litvinova, L., Zatolokin, P., Vulf, M., Mazunin, I., Skuratovskaia, D. The relationship between the mtDNA copy number in insulin-dependent tissues and markers of endothelial dysfunction and inflammation in obese patients (2019) BMC Medical Genomics (DOI: 10.1186/s12920-019- 0486-7)
  20. Bykov, R.A., Yudina, M.A., Gruntenko, N.E., Zakharov, I.K., Voloshina, M.A., Melashchenko, E.S., Danilova, M.V., Mazunin, I.O., Ilinsky, Y.Y. Prevalence and genetic diversity of Wolbachia endosymbiont and mtDNA in Palearctic populations of Drosophila melanogaster (2019) BMC Evolutionary Biology (DOI: 10.1186/s12862-019-1372-9)
  21. Verechshagina, N., Nikitchina, N., Yamada, Y., Harashima, H, Tanaka, M., Orishchenko, K., Mazunin, I. Future of human mitochondrial DNA editing technologies (2019) Mitochondrial DNA Part A: DNA Mapping, Sequencing, and Analysis, 30(2), pp. 214-221
  22. Mazunin I. Human mitochondrial genome surgery (2018) Genes & Cells (DOI: 10.23868/201811030)
  23. Verechshagina, N.A., Konstantinov, Y.M., Kamenski, P.A., Mazunin, I.O. Protein and nucleic acid import into mitochondria (2018) Biochemistry (Moscow), 83 (16), pp. 643-661.
  24. Mazunin, I.O., Volodko, N.V. Leber hereditary optic neuropathy (2018) Vestnik Oftalmologii, 134(2), pp. 92-97
  25. Skuratovskaia, D.A., Sofronova, J.K., Zatolokin, P .A., Popadin, K.Y ., Vasilenko, M.A., Litvinova, L.S., Mazunin, I.O. Additional evidence of the link between mtDNA copy number and the body mass index (2018) Mitochondrial DNA Part A: DNA Mapping, Sequencing, and Analysis, 29(8), pp. 1240-1244
  26. Skuratovskaia, D.A., Sofronova, J.K., Zatolokin, P .A., Vasilenko, M.A., Litvinova, L.S.,Mazunin, I.O. The association of the mitochondrial DNA OriB variants with metabolic syndrome (2017) Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry, 63 (6), pp. 533-538.
  27. Sofronova, J.K., Ilinsky, Y.Y., Orishchenko, K.E., Chupakhin, E.G., Lunev, E.A., Mazunin, I.O. Detection of mutations in mitochondrial DNA by droplet digital PCR (2016) Biochemistry (Moscow), 81 (10), pp. 1031-1037.
  28. Orishchenko, K.E., Sofronova, J.K., Chupakhin, E.G., Lunev, E.A., Mazunin, I.O. Delivery Cas9 into mitochondria (2016) Genes & Cells, XI (2), pp. 100-105
  29. Toshchakov, S.V., Korzhenkov, A.A., Samarov, N.I., Mazunin, I.O., Mozhey, O.I., Shmyr, I.S., Derbikova, K.S., Taranov, E.A., Dominova, I.N., Bonch-Osmolovskaya, E.A., Patrushev, M.V., Podosokorskaya, O.A., Kublanov, I.V. Complete genome sequence of and proposal of Thermofilum uzonense sp. nov. a novel hyperthermophilic crenarchaeon and emended description of the genus Thermofilum (2015) Standards in Genomic Sciences
  30. Mazunin, I.O., Levitskii, S.A., Patrushev, M.V., Kamenski, P.A. Mitochondrial matrix processes (2015) Biochemistry (Moscow), 80 (11), pp. 1418-1428.
  31. Patrushev, M.V., Mazunin, I.O., Vinogradova, E.N., Kamenski, P.A. Mitochondrial fission and fusion (2015) Biochemistry (Moscow), 80 (11), pp. 1457-1464.
  32. Sokhonevich, N.A., Yurova, K.A., Gutsol, A.A., Khaziakhmatova, O.G., Mazunin, I.O., Litvinova, L.S. Effects of Immunoregulatory Cytokines (IL-2, IL-7, and IL-15) on Expression of Gfi1 and U2afll4 Genes in T Cells at Different Stages of Differentiation (2015) Bulletin of Experimental Biology and Medicine, 4 p.
  33. Patrushev, M.V., Kamenski, P.A., Mazunin, I.O. Mutations in mitochondrial DNA and approaches for their correction (2014) Biochemistry (Moscow), 79 (11), pp. 1151-1160.
  34. Mozheĭ, O.I., Zatolokin, P.A., Vasilenko, M.A., Litvinova, L.S., Kirienkova, E.V., Mazunin, I.O. Evaluating the mitochondrial dna copy number in leukocytes and adipocytes from metabolic syndrome patients: pilot study (2014) Molecular Biology, 48 (4), pp. 677-681.
  35. Litvinova, L.S., Kirienkova, E.V., Mazunin, I.O., Vasilenko, M.A., Fattakhov, N.S. Pathogenesis of insulin resistance in metabolic obesity (2014) Biochemistry (Moscow) Supplement Series B: Biomedical Chemistry, 8 (3), pp. 192-202.
  36. Litvinova, L.S., Mazunin, I.O., Gutsol, A.A., Sokhonevich, N.A., Khaziakhmatova, O.G., Kofanova, K.A. Dose-response effect of steroid hormones on Gfi1 and U2af1l4 gene expression in T lymphocytes at different stages of differentiation (2013) Molecular Biology, 47 (4), pp. 572- 580.
  37. Sukernik, R.I., Volodko, N.V., Mazunin, I.O., Eltsov, N.P., Dryomov, S.V., Starikovskaya, E.B. Mitochondrial genome diversity in the tubalar, even, and ulchi: Contribution to prehistory of native siberians and their affinities to native americans (2012) American Journal of Physical Anthropology, 148 (1), pp. 123-138.
  38. Sukernik, R.I., Volodko, N.V., Mazunin, I.O., Eltsov, N.P., Starikovskaya, E.B. The genetic history of Russian old settlers of polar northeastern Siberia (2010) Russian Journal of Genetics, 46 (11), pp. 1386-1394.
  39. Mazunin, I.O., Volodko, N.V., Starikovskaya, E.B., Sukernik, R.I. Mitochondrial genome and human mitochondrial diseases (2010) Molecular Biology, 44 (5), pp. 665-681.
  40. Mazunin, I.O. Modern concepts of the mitochondrial structure and functions (2010) Russian Journal of Genetics, 46 (9), pp. 1100-1101.
  41. Eltsov, N.P., Volodko, N.V., Starikovskaya, E.B., Mazunin, I.O., Sukernik, R.I. The role of natural selection in the evolution of mitochondrial haplogroups in Northeastern Eurasia (2010) Russian Journal of Genetics, 46 (9), pp. 1105-1107.
  42. Volodko, N.V., Starikovskaya, E.B., Mazunin, I.O., Eltsov, N.P., Naidenko, P.V., Wallace, D.C., Sukernik, R.I. Mitochondrial Genome Diversity in Arctic Siberians, with Particular Reference to the Evolutionary History of Beringia and Pleistocenic Peopling of the Americas (2008) American Journal of Human Genetics, 82 (5), pp. 1084-1100.

2010 PhD in Molecular Genetics

Institute of Chemical Biology and Fundamental Medicine, Novosibirsk, Russia.

Thesis title:  “Analysis of the variability of mitochondrial DNA of Tubalars of the Altai Mountains and the Evens tribes of Eastern Siberia.”

Thesis supervisor: Prof Rem Sukernik.

2006 MS in Biology

Chelyabinsk State University, Chelyabinsk, Russia

Thesis title: “The influence of radiation on the formation of left-handedness.”






Using low-coverage, whole-genome sequences of trophectoderm biopsies from human blastocyst-stage embryos, we analyzed the relationship between chromosomal abnormalities and mitochondrial (mt) DNA dynamics. Comparing aneuploid and euploid embryos in cohort studies, we found that mtDNA content in aneuploid embryos was significantly higher than that in euploid embryos. This outcome was confirmed through intrafamilial analyses of embryos with matched parents and in vitro fertilization cycles, and it occurred independent of maternal age. Additional human population-based studies uncovered a higher abundance of ultra-rare mtDNA variants located in never-altered positions in the human population in aneuploid compared to euploid embryos in both cohort- and family-based analyses. This maternal age-independent association of increased mtDNA content and aneuploidy in human embryos may reflect a novel mechanism of purifying selection against potentially deleterious mtDNA variants, which arise from germline or early developmental mtDNA damaging events, that occurs in human embryos prior to implantation (Ri et al. https://www.biorxiv.org/content/10.1101/2022.10.14.512116v2.full.pdf).

 

CRISPR RNAs (crRNAs) that direct target DNA cleavage by Type V Cas12a nucleases consist of constant repeat-derived 5′-scaffold moiety and variable 3′-spacer moieties. We demonstrated that removal of most of the 20-nucleotide scaffold has only a slight effect on in vitro target DNA cleavage by a Cas12a ortholog from Acidaminococcus sp. (As-Cas12a) (Shebanova et al. 2022, NAR). In fact, residual cleavage was observed even in the presence of a 20-nucleotide crRNA spacer moiety only. In addition to dsDNA target cleavage, AsCas12a programmed with split crRNAs also catalyzed specific ssDNA target cleavage and non-specific ssDNA degradation (collateral activity). V-A effector nucleases from Francisella novicida (Fn-Cas12a) and Lachnospiraceae bacterium (LbCas12a) were also functional with split crRNAs. Thus, the ability of V-A effectors to use split crRNAs appears to be a general property. Another discovery made during the project was the identification of a new ortholog, which we named CRISPR/RbCas12a. It turned out that the RbCas12a nuclease is a more effective editor compared to the commonly used AsCas12a (Vasilev et al. 2022, IJMS). The ability to split guide RNAs that program Cas12 into two parts, of which only one corresponds to the target, while the other one is constant, simplifies both genome editing and diagnostic applications and drastically increases the ability to multiplex. It also makes it possible to specifically target the editor to mitochondria, something that has not been achieved before. This opens up ways to treat mitochondrial genetic diseases, including many age-associated diseases. 

 

Despite its high mutation rate and its association with numerous diseases, the mutagenesis of the mtDNA is not well understood. We hypothesized that the mtDNA mutational spectrum is linked to species-specific life-history traits. We analyzed the mtDNA mutational spectra of hundreds of mammalian species and found that variations in the spectra are correlated with the species-specific generation length. Our findings suggest that the mtDNA mutational signature (A>G substitutions on the heavy chain of mtDNA) reflects oxidative damage associated with aging and longevity (Mikhailova et al. 2022, NAR). Further analysis of mtDNA mutagenesis in cold- and warm-blooded vertebrates, as well as different types of human cancer, supports the universality of our findings, indicating that the mtDNA mutational spectrum – previously not understood or interpretable – is a natural marker of the level of aerobic metabolism in different tissues and species.

Two related BioRxives are under review: “A mitochondrial mutational signature of temperature in ectothermic and endothermic vertebrates” (https://www.biorxiv.org/content/10.1101/2020.07.25.221184v2) and “Mammalian mitochondrial mutational spectrum as a hallmark of cellular and organismal aging” (https://www.biorxiv.org/content/10.1101/589168v3).


Mitochondrial direct nucleotide repeats are involved in the development of mitochondrial somatic deletions, which are associated with common age-related traits such as neurodegeneration and sarcopenia. Disrupting these nucleotide repeats can mitigate their harmful effect, reducing the rate of somatic mitochondrial deletions and promoting healthy aging. This mechanism may explain the higher prevalence of centenarians among Japanese individuals with the disrupted common repeat in the mitochondrial genome (Mikhailova et al., 2019). We suggest that the positive properties of certain mitochondrial haplogroups, such as D4a, could potentially be utilized in mitochondrial donation techniques.