MoCox6 is a regulator of mitophagy and a druggable target in Magnaporthe oryzae

  • Nat Microbiol. 2026 Jun;11(6):1662-1676. doi: 10.1038/s41564-026-02329-z.
Ming-Hua Wu  1  2  3  4 ,  Ya-Nan Lv  1 ,  Hui Li  5 ,  Hui Qian  6 ,  Yun-Yun Wei  7 ,  Yun-Ran Zhang  3 ,  Shuang Liang  2 ,  Xue-Ming Zhu  2 ,  Jian-Ping Lu  5 ,  Maurizio Del Poeta  8  9  10  11 ,  Zong-Hua Wang  12 ,  Yong-Hwan Lee  13 ,  Naweed I Naqvi  14 ,  Richard A Wilson  15 ,  Daniel J Klionsky  16 ,  Fu-Cheng Lin  17  18  19 ,  Xiao-Hong Liu  20
Affiliations
  • 1. State Key Laboratory for Quality and Safety of Agro-Products, Zhejiang Provincial Key Laboratory of Agricultural Microbiomics, Institute of Biotechnology, Zhejiang University, Hangzhou, China.
  • 2. State Key Laboratory for Quality and Safety of Agro-Products, Zhejiang Provincial Key Laboratory of Agricultural Microbiomics, Key Laboratory of Agricultural Microbiome (MARA), Institute of Plant Protection and Microbiology, Zhejiang Academy of Agricultural Sciences, Hangzhou, China.
  • 3. Xianghu Laboratory, Hangzhou, China.
  • 4. National Key Laboratory of Non-Food Biomass Energy Technology, National Engineering Research Center for Non-Food Biorefinery, Institute of Biological Science and Technology, Guangxi Academy of Sciences, Nanning, China.
  • 5. College of Life Sciences, Zhejiang University, Hangzhou, China.
  • 6. College of Plant Protection, Shandong Agricultural University, Taian, China.
  • 7. College of Biology and Environmental Engineering, Zhejiang Shuren University, Hangzhou, China.
  • 8. Department of Microbiology and Immunology, Stony Brook University, Stony Brook, NY, USA.
  • 9. Institute of Chemical Biology and Drug Discovery, Stony Brook University, Stony Brook, NY, USA.
  • 10. Division of Infectious Diseases, School of Medicine, Stony Brook University, Stony Brook, NY, USA.
  • 11. Northport VA Medical Center, Northport, NY, USA.
  • 12. Institute of Oceanography, Minjiang University Fuzhou, Fujian, China.
  • 13. Department of Agricultural Biotechnology and Global Plant Immunity Research Center, Seoul National University Seoul, Seoul, Republic of Korea.
  • 14. Temasek Life Sciences Laboratory, and the National University of Singapore, Singapore, Singapore.
  • 15. Department of Plant Pathology, University of Nebraska-Lincoln, Lincoln, NE, USA.
  • 16. Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA.
  • 17. State Key Laboratory for Quality and Safety of Agro-Products, Zhejiang Provincial Key Laboratory of Agricultural Microbiomics, Institute of Biotechnology, Zhejiang University, Hangzhou, China. [email protected].
  • 18. State Key Laboratory for Quality and Safety of Agro-Products, Zhejiang Provincial Key Laboratory of Agricultural Microbiomics, Key Laboratory of Agricultural Microbiome (MARA), Institute of Plant Protection and Microbiology, Zhejiang Academy of Agricultural Sciences, Hangzhou, China. [email protected].
  • 19. Xianghu Laboratory, Hangzhou, China. [email protected].
  • 20. State Key Laboratory for Quality and Safety of Agro-Products, Zhejiang Provincial Key Laboratory of Agricultural Microbiomics, Institute of Biotechnology, Zhejiang University, Hangzhou, China. [email protected].
PMID: 42009759 DOI: 10.1038/s41564-026-02329-z
Abstract

Mitophagy is a selective autophagic process that maintains cellular homeostasis by degrading damaged mitochondria and is a promising Antifungal target. However, few inner mitochondrial membrane (IMM) regulators of Mitophagy are known. Here we identify cytochrome c oxidase subunit 6 (MoCox6) as an IMM regulator in Magnaporthe oryzae that binds MoAtg5 and MoAtg14 following outer mitochondrial membrane rupture to mediate Mitophagy. MoSirt5 regulates this process by desuccinylating MoCox6 at K144. Structural analysis revealed that residue D95 at the MoSirt5-MoCox6 interface mediates the dual role of MoCox6 in Mitophagy and mitochondrial metabolic competence. Deletion of the COX6 gene significantly reduced vegetative growth and virulence in both M. oryzae and Alternaria alternata. Through high-throughput screening, we identified a small-molecule compound, Pan-RAS-IN-1, which targets MoCox6 to inhibit Mitophagy, thereby suppressing M. oryzae virulence. Pan-RAS-IN-1 exhibits broad-spectrum Antifungal activity, and its application to rice Plants significantly suppressed rice blast incidence.

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