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<p>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 <i>c</i> oxidase subunit 6 (MoCox6) as an IMM regulator in <i>Magnaporthe oryzae</i> 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 <i>COX6</i> gene significantly reduced vegetative growth and virulence in both <i>M</i>. <i>oryzae</i> and <i>Alternaria alternata</i>. Through high-throughput screening, we identified a small-molecule compound, Pan-RAS-IN-1, which targets MoCox6 to inhibit mitophagy, thereby suppressing <i>M</i>. <i>oryzae</i> virulence. Pan-RAS-IN-1 exhibits broad-spectrum antifungal activity, and its application to rice plants significantly suppressed rice blast incidence.</p>

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

  • 期刊论文

  • 发表日期：

    2026年4月20日

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  • 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

摘要

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.