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Comprehensive phenotypic assessment of nonsense mutations in mitochondrial ND5 in mice

홍성호|성제경|Kim Jieun|Kim Hae-Rim|이성현|Lee Su Bin|Lee Hyunji|Park Seul Gi|Kim Eun-Kyoung|Lim Soo-Yeon|Kim Kyoungmi|Kim Sanghun|Cho Sang-Mi|Ju Sungjin|Kim Sol Pin|Jeong Tae Young|Oh Yeji|Han Seunghun|Lee Taek Chang|Kim Hyoung-Chin|Yoon Won Kee|An Tae Hyeon|Oh Kyoung-Jin|Nam Ki-Hoan
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2024.12|Experimental and Molecular Medicine|제56권 |pp. 2395-2408|DOI 10.1038/s12276-024-01333-9

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주제분류생화학

초록

Mitochondrial dysfunction induced by mitochondrial DNA (mtDNA) mutations has been implicated in various human diseases. A comprehensive analysis of mitochondrial genetic disorders requires suitable animal models for human disease studies. While gene knockout via premature stop codons is a powerful method for investigating the unique functions of target genes, achieving knockout of mtDNA has been rare. Here, we report the genotypes and phenotypes of heteroplasmic MT-ND5 gene-knockout mice. These mutant mice presented damaged mitochondrial cristae in the cerebral cortex, hippocampal atrophy, and asymmetry, leading to learning and memory abnormalities. Moreover, mutant mice are susceptible to obesity and thermogenetic disorders. We propose that these mtDNA gene-knockdown mice could serve as valuable animal models for studying the MT-ND5 gene and developing therapies for human mitochondrial disorders in the future.

Abstract

Mitochondrial dysfunction induced by mitochondrial DNA (mtDNA) mutations has been implicated in various human diseases. A comprehensive analysis of mitochondrial genetic disorders requires suitable animal models for human disease studies. While gene knockout via premature stop codons is a powerful method for investigating the unique functions of target genes, achieving knockout of mtDNA has been rare. Here, we report the genotypes and phenotypes of heteroplasmic MT-ND5 gene-knockout mice. These mutant mice presented damaged mitochondrial cristae in the cerebral cortex, hippocampal atrophy, and asymmetry, leading to learning and memory abnormalities. Moreover, mutant mice are susceptible to obesity and thermogenetic disorders. We propose that these mtDNA gene-knockdown mice could serve as valuable animal models for studying the MT-ND5 gene and developing therapies for human mitochondrial disorders in the future.

참고문헌 (50)

  1. Willis, E. J., "The powerhouse of the cell", Ultrastruct. Pathol, 16, pp.iii~vi (1992)
  2. Javadov, S., "Mitochondria in health and diseases", Cells, 9 (2020)[DOI]
  3. Wallace, D. C., "Mitochondrial DNA in aging and disease", Sci. Am, 277, pp.40~47 (1997)
  4. DiMauro, S., "Mitochondrial DNA mutations in human disease", Am. J. Med. Genet, 106, pp.18~26 (2001)
  5. Pittis, A. A., "Late acquisition of mitochondria by a host with chi maeric prokaryotic ancestry", Nature, 531, pp.101~104 (2016)
  6. Herzig, S., "Identification and functional expression of the mitochondrial pyruvate carrier", Science, 337, pp.93~96 (2012)
  7. Anderson, S., "Sequence and organization of the human mitochondrial genome", Nature, 290, pp.457~465 (1981)
  8. Schon, K. R., "Mito chondrial diseases : a diagnostic revolution", Trends Genet, 36, pp.702~717 (2020)
  9. Giacomello, M., "The cell biology of mitochondrial membrane dynamics", Nat. Rev. Mol. Cell Biol, 21, pp.204~224 (2020)
  10. Sharma, L. K., "Mitochondrial respiratory complex I: structure, function and implication in human diseases", Curr. Med. Chem, 16, pp.1266~1277 (2009)
  11. "MITOMAP: a human mitochondrial genome database", Nucleic Acids Res, 24, pp.177~179 (2019)
  12. Mok, B. Y., "A bacterial cytidine deaminase toxin enables CRISPR-free mito chondrial base editing", Nature, 583, pp.631~637 (2020)
  13. Cho, S. I., "Targeted A-to-G base editing in human mitochondrial DNA with programmable deaminases", Cell, 185, pp.1764~1776 (2022)
  14. Lee, S., "Enhanced mitochondrial DNA editing in mice using nuclear-exported TALE-linked deaminases and nucleases", Genome Biol, 23, pp.211~ (2022)
  15. Qi, X., "Precision modeling of mitochondrial disease in rats via DdCBE mediated mtDNA editing", Cell Discov, 7, pp.95~ (2021)
  16. Lee, H., "Mitochondrial DNA editing in mice with DddA-TALE fusion deami nases", Nat. Commun, 12, pp.1190~ (2021)
  17. Zaidi, A. A., "Bottleneck and selection in the germline and maternal age influence transmission of mitochondrial DNA in human pedigrees", Proc. Natl. Acad. Sci. USA, 116, pp.25172~25178 (2019)
  18. Chan, D. C., "Mitochondria : dynamic organelles in disease, aging, and develop ment", Cell, 125, pp.1241~1252 (2006)
  19. Ambekar, T., "Mitochondrial quality control : epigenetic signatures and ther apeutic strategies", Neurochem. Int, 148, pp.105095~ (2021)
  20. Shen, X., "Mitochondrial quality control in the brain : the physiological and pathological roles", Front. Neurosci, 16, pp.1075141~ (2022)
  21. Munday, D. C., "Quantitative proteomic analysis of A549 cells infected with human respiratory syncytial virus", Mol. Cell Proteom, 9, pp.2438~2459 (2010)
  22. Eichenbaum, H., "The hippocampus and declarative memory : cognitive mechan isms and neural codes", Behav. Brain Res, 127, pp.199~207 (2001)
  23. Eichenbaum, H., "Hippocampus : cognitive processes and neural representations that underlie declarative memory", Neuron, 44, pp.109~120 (2004)
  24. Murphy, R., "Clinical features, diag nosis and management of maternally inherited diabetes and deafness(MIDD)associated with the 3243A>G mitochondrial point mutation", Diabet. Med, 25, pp.383~399 (2008)
  25. Malecki, M. T., "Maternally inherited diabetes with deafness and obesity : body weight reduction response to treatment with insulin analogues", Rev. Diabet. Stud, 3, pp.205~207 (2006)
  26. Stadler, J. T., "Obesity-related changes in high-density lipoprotein metabolism and function", Int. J. Mol. Sci, 21 (2020)[DOI]
  27. Fenzl, A., "Brown adipose tissue and thermogenesis", Horm. Mol. Biol. Clin. Investig, 19, pp.25~37 (2014)
  28. Lei, Z., "Mitochondrial base editor induces substantial nuclear off-target mutations", Nature, 606, pp.804~811 (2022)
  29. Wei, Y., "Mitochondrial base editor DdCBE causes substantial DNA off-target editing in nuclear genome of embryos", Cell Discov, 8, pp.27~ (2022)
  30. Lee, S., "Precision mitochondrial DNA editing with high-fidelity DddA-derived base editors", Nat. Biotechnol, 41, pp.378~386 (2023)
  31. Martin, L. J., "Mitochondrial and cell death mechanisms in neurodegenerative diseases", Pharm. (Basel), 3, pp.839~915 (2010)
  32. Yin, F., "Energy metabolism and inflammation in brain aging and Alzheimer’sdisease", Free Radic. Biol. Med, 100, pp.108~122 (2016)
  33. Stefanatos, R., "The role of mitochondrial ROS in the aging brain", FEBS Lett, 592, pp.743~758 (2018)
  34. Claassen, D. O., "Cortical asymmetry in Parkinson’s disease : early susceptibility of the left hemisphere", Brain Behav, 6, pp.e00573~ (2016)
  35. Seo, J. H., "The mitochondrial unfoldase-peptidase complex ClpXP controls bioenergetics stress and metastasis", PLoS Biol, 14, pp.e1002507~ (2016)
  36. Bournat, J. C., "Mitochondrial dysfunction in obesity", Curr. Opin. Endocrinol. Diabetes Obes, 17, pp.446~452 (2010)
  37. Gregoire, F. M., "Understanding adipocyte differentiation", Physiol. Rev, 78, pp.783~809 (1998)
  38. Tormos, K. V., "Mitochondrial complex III ROS regulate adipocyte differ entiation", Cell Metab, 14, pp.537~544 (2011)
  39. Wang, C. H., "Mitochondrial dysfunction leads to impairment of insulin sensitivity and adiponectin secretion in adipocytes", FEBS J, 280, pp.1039~1050 (2013)
  40. Park, A., "Distinction of white, beige and brown adipocytes derived from mesenchymal stem cells", World J. Stem Cells, 6, pp.33~42 (2014)
  41. Filograna, R., "Mitochondrial DNA copy number in human disease: the more the better?", FEBS Lett, 595, pp.976~1002 (2021)
  42. Chinnery, P. F., "Accumulation of mito chondrial DNA mutations in ageing, cancer, and mitochondrial disease: is there a common mechanism?", Lancet, 360, pp.1323~1325 (2002)
  43. Rossignol, R., "Mitochondrial threshold effects", Biochem. J, 370, pp.751~762 (2003)
  44. Li, R., "Human mitochondrial leucyl-tRNA synthetase corrects mitochondrial dysfunctions due to the tRNALeu(UUR)A3243G mutation, asso ciated with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like symptoms and diabetes", Mol. Cell Biol, 30, pp.2147~2154 (2010)
  45. Suzuki, S., "Clinical features of diabetes mellitus with the mitochondrial DNA 3243(A-G)mutation in Japanese : maternal inheritance and mitochondria-related complications", Diabetes Res. Clin. Pract, 59, pp.207~217 (2003)
  46. Guillausseau, P. J., "Maternally inherited diabetes and deafness : a multicenter study", Ann. Intern. Med, 134, pp.721~728 (2001)
  47. de Wit, H. M., "MIDD or MELAS:that’s not the question MIDD evolving into MELAS : a severe phenotype of the m.3243A>G mutation due to paternal co-inheritance of type 2 diabetes and a high heteroplasmy level", Neth. J. Med, 70, pp.460~462 (2012)
  48. Wallace, D. C., "Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease", Cold Spring Harb. Perspect. Biol, 5, pp.a021220~ (2013)
  49. Kotrys, A. V., "Single-cell analysis reveals context-dependent, cell-level selection of mtDNA", Nature, 629, pp.458~466 (2024)
  50. Floros, V. I., "Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos", Nat. Cell Biol, 20, pp.144~151 (2018)

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