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

Ming Hua Wu; Ya Nan Lv; Hui Li; Hui Qian; Yun Yun Wei; Yun Ran Zhang; Shuang Liang; Xue Ming Zhu; Jian Ping Lu; Maurizio Del Poeta; Zong Hua Wang; Yong Hwan Lee; Naweed I. Naqvi; Richard A. Wilson; Daniel J. Klionsky; Fu Cheng Lin; Xiao Hong Liu

doi:10.1038/s41564-026-02329-z

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

Ming Hua Wu
, Ya Nan Lv
, Hui Li
, Hui Qian
, Yun Yun Wei
, Yun Ran Zhang
, Shuang Liang
, Xue Ming Zhu
, Jian Ping Lu
, Maurizio Del Poeta
, Zong Hua Wang
, Yong Hwan Lee
, Naweed I. Naqvi
, Richard A. Wilson
, Daniel J. Klionsky
, Fu Cheng Lin
, Xiao Hong Liu

Zhejiang University
Zhejiang Academy of Agricultural Sciences
Xianghu Laboratory
Guangxi Academy of Agricultural Sciences
Shandong Agricultural University
Zhejiang Shuren University
Minjiang University
Seoul National University
National University of Singapore
University of Nebraska-Lincoln
University of Michigan, Ann Arbor

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English
Pages (from-to)	1662-1676
Number of pages	15
Journal	Nature Microbiology
Volume	11
Issue number	6
DOIs	https://doi.org/10.1038/s41564-026-02329-z
State	Published - Jun 2026

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Wu, M. H., Lv, Y. N., Li, H., Qian, H., Wei, Y. Y., Zhang, Y. R., Liang, S., Zhu, X. M., Lu, J. P., Del Poeta, M., Wang, Z. H., Lee, Y. H., Naqvi, N. I., Wilson, R. A., Klionsky, D. J., Lin, F. C., & Liu, X. H. (2026). MoCox6 is a regulator of mitophagy and a druggable target in Magnaporthe oryzae. Nature Microbiology, 11(6), 1662-1676. https://doi.org/10.1038/s41564-026-02329-z

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title = "MoCox6 is a regulator of mitophagy and a druggable target in Magnaporthe oryzae",

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.",

author = "Wu, \{Ming Hua\} and Lv, \{Ya Nan\} and Hui Li and Hui Qian and Wei, \{Yun Yun\} and Zhang, \{Yun Ran\} and Shuang Liang and Zhu, \{Xue Ming\} and Lu, \{Jian Ping\} and \{Del Poeta\}, Maurizio and Wang, \{Zong Hua\} and Lee, \{Yong Hwan\} and Naqvi, \{Naweed I.\} and Wilson, \{Richard A.\} and Klionsky, \{Daniel J.\} and Lin, \{Fu Cheng\} and Liu, \{Xiao Hong\}",

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature Limited 2026.",

year = "2026",

month = jun,

doi = "10.1038/s41564-026-02329-z",

language = "English",

volume = "11",

pages = "1662--1676",

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AU - Wu, Ming Hua

AU - Lv, Ya Nan

AU - Li, Hui

AU - Qian, Hui

AU - Wei, Yun Yun

AU - Zhang, Yun Ran

AU - Liang, Shuang

AU - Zhu, Xue Ming

AU - Lu, Jian Ping

AU - Del Poeta, Maurizio

AU - Wang, Zong Hua

AU - Lee, Yong Hwan

AU - Naqvi, Naweed I.

AU - Wilson, Richard A.

AU - Klionsky, Daniel J.

AU - Lin, Fu Cheng

AU - Liu, Xiao Hong

PY - 2026/6

Y1 - 2026/6

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105036076707

U2 - 10.1038/s41564-026-02329-z

DO - 10.1038/s41564-026-02329-z

M3 - Article

C2 - 42009759

AN - SCOPUS:105036076707

SN - 2058-5276

VL - 11

SP - 1662

EP - 1676

JO - Nature Microbiology

JF - Nature Microbiology

IS - 6

ER -

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

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