본문 바로가기
KERD
논문KCI 등재

Involvement of Mrs3/4 in Mitochondrial Iron Transport and Metabolism in Cryptococcus neoformans

2

조회

0

다운로드

0

인용

0

참고문헌

키워드

주제분류생물학

초록

Mitochondria play a vital role in iron uptake and metabolism in pathogenic fungi, and also influence virulence and drug tolerance. However, the regulation of iron transport within the mitochondria of Cryptococcus neoformans, a causative agent of fungal meningoencephalitis in immunocompromised individuals, remains largely uncharacterized. In this study, we identified and functionally characterized Mrs3/4, a homolog of the Saccharomyces cerevisiae mitochondrial iron transporter, in C. neoformans var. grubii. A strain expressing an Mrs3/4-GFP fusion protein was generated, and the mitochondrial localization of the fusion protein was confirmed. Moreover, a mutant lacking the MRS3/4 gene was constructed; this mutant displayed significantly reduced mitochondrial iron and cellular heme accumulation. In addition, impaired mitochondrial iron-sulfur cluster metabolism and altered expression of genes required for iron uptake at the plasma membrane were observed in the mrs3/4 mutant, suggesting that Mrs3/4 is involved in iron import and metabolism in the mitochondria of C. neoformans. Using a murine model of cryptococcosis, we demonstrated that an mrs3/4 mutant is defective in survival and virulence. Taken together, our study suggests that Mrs3/4 is responsible for iron import in mitochondria and reveals a link between mitochondrial iron metabolism and the virulence of C. neoformans.

Abstract

Mitochondria play a vital role in iron uptake and metabolism in pathogenic fungi, and also influence virulence and drug tolerance. However, the regulation of iron transport within the mitochondria of Cryptococcus neoformans, a causative agent of fungal meningoencephalitis in immunocompromised individuals, remains largely uncharacterized. In this study, we identified and functionally characterized Mrs3/4, a homolog of the Saccharomyces cerevisiae mitochondrial iron transporter, in C. neoformans var. grubii. A strain expressing an Mrs3/4-GFP fusion protein was generated, and the mitochondrial localization of the fusion protein was confirmed. Moreover, a mutant lacking the MRS3/4 gene was constructed; this mutant displayed significantly reduced mitochondrial iron and cellular heme accumulation. In addition, impaired mitochondrial iron-sulfur cluster metabolism and altered expression of genes required for iron uptake at the plasma membrane were observed in the mrs3/4 mutant, suggesting that Mrs3/4 is involved in iron import and metabolism in the mitochondria of C. neoformans. Using a murine model of cryptococcosis, we demonstrated that an mrs3/4 mutant is defective in survival and virulence. Taken together, our study suggests that Mrs3/4 is responsible for iron import in mitochondria and reveals a link between mitochondrial iron metabolism and the virulence of C. neoformans.

참고문헌 (39)

  1. Desnos-Ollivier M, "Cryptococcosis serotypes impact outcome and provide evidence of Cryptococcus neoformans speciation", mBio, 6, pp.e00311~ (2015)
  2. Vartivarian SE, "Regulation of cryptococcal capsular polysaccharide by iron", J. Infect. Dis, 167, pp.186~190 (1993)
  3. Jacobson ES, "Ferrous iron uptake in Cryptococcus neoformans", Infect. Immun, 66, pp.4169~4175 (1998)
  4. Jung WH, "Iron acquisition in the human fungal pathogen Cryptococcus neoformans", Curr. Opin. Microbiol, 16, pp.686~691 (2013)
  5. Caza M, "The Sec1", Munc18(SM)protein Vps45 is involved in iron uptake, mitochondrial function and virulence in the pathogenic fungus Cryptococcus neoformans, 2018, pp.14, e1007220~
  6. Saikia S, "Role of ferric reductases in iron acquisition and virulence in the fungal pathogen Cryptococcus neoformans", Infect. Immun, 82, pp.839~850 (2014)
  7. Pierrel F, "Metal Ion availability in mitochondria", Biometals, 20, pp.675~682 (2007)
  8. Rouault TA, "Iron-sulphur cluster biogenesis and mitochondrial iron homeostasis", Nat. Rev. Mol. Cell. Biol, 6, pp.345~351 (2005)
  9. Richardson DR, "Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol", Proc. Natl. Acad. Sci. USA, 107, pp.10775~10782 (2010)
  10. Napier I, "Iron trafficking in the mitochondrion : novel pathways revealed by disease", Blood, 105, pp.1867~1874 (2005)
  11. Hausmann A, "Cellular and mitochondrial remodeling upon defects in iron-sulfur protein biogenesis", J. Biol. Chem, 283, pp.8318~8330 (2008)
  12. Levi S, "The role of iron in mitochondrial function", Biochim. Biophys. Acta, 1790, pp.629~636 (2009)
  13. Lange H, "Mechanism of iron transport to the site of heme synthesis inside yeast mitochondria", J. Biol. Chem, 274, pp.18989~18996 (1999)
  14. Lill R, "Maturation of iron-sulfur proteins in eukaryotes : mechanisms, connected processes, and diseases", Annu. Rev. Biochem, 77, pp.669~700 (2008)
  15. Craig EA, "A specialized mitochondrial molecular chaperone system : a role in formation of Fe", S centers, 2002, pp.59, 1658~1665
  16. Foury F, "Deletion of the mitochondrial carrier genes MRS3 and MRS4 suppresses mitochondrial iron accumulation in a yeast frataxin-deficient strain", J. Biol. Chem, 277, pp.24475~24483 (2002)
  17. Zhang Y, "Frataxin and mitochondrial carrier proteins, Mrs3p and Mrs4p, cooperate in providing iron for heme synthesis", J. Biol. Chem, 280, pp.19794~19807 (2005)
  18. Kispal G, "The mitochondrial proteins Atm1p and Nfs1p are essential for biogenesis of cytosolic Fe", S proteins, 1999, pp.18, 3981~3989
  19. Lill R, "The role of mitochondria and the CIA machinery in the maturation of cytosolic and nuclear iron-sulfur proteins", Eur. J. Cell. Biol, 94, pp.280~291 (2015)
  20. Do E, "The mitochondrial ABC transporter Atm1 plays a role in iron metabolism and virulence in the human fungal pathogen Cryptococcus neoformans", Med. Mycol, 56, pp.458~468 (2018)
  21. Jung WH, "Role of ferroxidases in iron uptake and virulence of Cryptococcus neoformans", Eukaryotic Cell, 8, pp.1511~1520 (2009)
  22. Toffaletti DL, "Gene transfer in Cryptococcus neoformans by use of biolistic delivery of DNA", J. Bacteriol, 175, pp.1405~1411 (1993)
  23. Sambrook J, "Molecular cloning: a laboratory manual, Vol. 1", pp.6.33~6.58 (2001), CSHL press
  24. Daum G, "Import of proteins into mitochondria. Cytochrome b2 and cytochrome c peroxidase are located in the intermembrane space of yeast mitochondria", J. Biol. Chem., 257, pp.13028~13033 (1982)
  25. Gregg C, "Purification of mitochondria from yeast cells", J. Vis. Exp, 30, pp.1417~ (2009)
  26. Shi Y, "Human ISD11 is essential for both iron–sulfur cluster assembly and maintenance of normal cellular iron homeostasis", Hum. Mol. Genet, 18, pp.3014~3025 (2009)
  27. Kim J, "A defect in iron uptake enhances the susceptibility of Cryptococcus neoformans to azole antifungal drugs", Fungal Genet. Biol, 49, pp.955~966 (2012)
  28. Jung WH, "Iron regulation of the major virulence factors in the AIDS-associated pathogen Cryptococcus neoformans", PLoS Biol, 4, pp.e410~ (2006)
  29. Hu G, "A putative P-type ATPase, Apt1, is involved in stress tolerance and virulence in Cryptococcus neoformans", Eukaryot. Cell, 9, pp.74~83 (2010)
  30. Xu N, "Identification and functional characterization of mitochondrial carrier Mrs4 in Candida albicans", FEMS Yeast Res, 12, pp.844~858 (2012)
  31. Nyhus KJ, "Role of mitochondrial carrier protein Mrs3", 4 in iron acquisition and oxidative stress resistance of Cryptococcus neoformans, 2002, pp.40, 581~591
  32. Claros MG, "Computational method to predict mitochondrially imported proteins and their targeting sequences", Eur. J. Biochem, 241, pp.779~786 (1996)
  33. Jung WH, "Iron source preference and regulation of iron uptake in Cryptococcus neoformans", PLoS Pathog, 4, pp.e45~ (2008)
  34. Murakami K, "Inactivation of aconitase in yeast exposed to oxidative stress", Biochem. Mol. Biol. Int, 41, pp.481~486 (1997)
  35. Do E, "Leu1 plays a role in iron metabolism and is required for virulence in Cryptococcus neoformans", Fungal Genet. Biol, 75, pp.11~19 (2015)
  36. Do E, "The lysine biosynthetic enzyme Lys4 influences iron metabolism, mitochondrial function and virulence in Cryptococcus neoformans", Biochem. Biophys. Res. Commun, 477, pp.706~711 (2016)
  37. Froschauer EM, "The yeast mitochondrial carrier proteins Mrs3p", Mrs4p mediate iron transport across the inner mitochondrial membrane, 2009, pp.1788, 1044~1050
  38. Muhlenhoff U, "A specific role of the yeast mitochondrial carriers MRS3", 4p in mitochondrial iron acquisition under iron-limiting conditions, 2003, pp.278, 40612~40620
  39. Long N, "A Putative mitochondrial iron transporter MrsA in Aspergillus fumigatus plays important roles in azole-, oxidative stress responses and virulence", Front. Microbiol, 7, pp.716~ (2016)

관련 논문AI추천

Acidic pH Reduces Fluconazole Susceptibility in Cryptococcus neoformans by Altering Iron Uptake and Enhancing Ergosterol BiosynthesisCho Yong-Joon, Jung Won Hee, Kim Donghyeun, Kronstad James W., Shin Junghum한국미생물·생명공학회 · Journal of Microbiology and Biotechnology2025 · 제35권 Siderophore Biosynthesis and Transport Systems in Model and Pathogenic Fungi정원희, Choi Sohyeong, Kronstad James W.한국미생물·생명공학회 · Journal of Microbiology and Biotechnology2024 · 제34권 제8호The 14-3-3 Gene Function of Cryptococcus neoformans Is Required for its Growth and VirulenceAmbrose Jong, Chun-Hua Wu, Hiro Shimada, Jennifer Liu, Jingbo Li, Kyung J. Kwon-Chung, Rob Fante, Sheng-He Huang, Xiaowei Fu, Yun C. Chang한국미생물·생명공학회 · Journal of Microbiology and Biotechnology2016 · 제26권 제5호동물병원성 뇌수막염 유발 곰팡이 Cryptococcus neoformans의 Pathogenomic Signaling Network 연구와 항곰팡이제 개발고영준, 권유원, 나한나, 반용선한국미생물·생명공학회 · 한국미생물·생명공학회지2010 · 제38권 제1호Novel Approaches for Efficient Antifungal Drug Action이동건, 이희정한국미생물·생명공학회 · Journal of Microbiology and Biotechnology2018 · 제28권 제11호Functional Roles of Dnl4, DNA Ligase IV, in DNA Damage Stress in a Radiation-resistant Fungus, Cryptococcus neoformans김진홍, 배형우, 우소연, 이승식, 정경한, 정광우, 정문수, 정병엽(사)한국방사선산업학회 · 방사선산업학회지2025 · 제19권 제3호

이 간행물의 다른 논문 (13건)