2. Academic Validation
  3. OPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulation

OPA1 mutations in dominant optic atrophy: domain-specific defects in mitochondrial fusion and apoptotic regulation

  • J Transl Med. 2025 Apr 24;23(1):471. doi: 10.1186/s12967-025-06471-w.
Kexuan Zhang 1 2 3,  Wenqing Zhang 1,  Lin Zhang 1,  Xiaorong Hou 4,  Runyi Tian 2,  Zhengmao Hu 2,  Lili Yin 5 6 7,  Zhonghua Hu 8 9 10 11 12
Affiliations

Affiliations

  • 1 Department of Critical Care Medicine, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, 87 Xiangya Rd, Changsha, 410008, Hunan, China.
  • 2 Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410008, Hunan, China.
  • 3 Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha, 410008, Hunan, China.
  • 4 Department of Neurology, The Third Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
  • 5 Department of Ophthalmology, Shanghai Fourth People's Hospital, Tongji University, Shanghai, 200434, China. yll1444@alumni.sjtu.edu.cn.
  • 6 Department of Ophthalmology, Shanghai First People's Hospital), Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China. yll1444@alumni.sjtu.edu.cn.
  • 7 Department of Ophthalmology, Zunyi First People's Hospital, The Third Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China. yll1444@alumni.sjtu.edu.cn.
  • 8 Department of Critical Care Medicine, Institute of Molecular Precision Medicine and Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, 87 Xiangya Rd, Changsha, 410008, Hunan, China. huzhonghua@csu.edu.cn.
  • 9 Center for Medical Genetics and Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410008, Hunan, China. huzhonghua@csu.edu.cn.
  • 10 National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. huzhonghua@csu.edu.cn.
  • 11 Hunan Provincial Clinical Research Center for Critical Care Medicine, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China. huzhonghua@csu.edu.cn.
  • 12 MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha, 410008, Hunan, China. huzhonghua@csu.edu.cn.
PMID: 40275276 DOI: 10.1186/s12967-025-06471-w
Abstract

Background: Autosomal dominant optic atrophy (ADOA), a leading common inherited optic neuropathy, arises from progressive retinal ganglion cell degeneration, often linked to OPA1 mutations. OPA1, a mitochondrial GTPase, regulates mitochondrial fusion, crista structure, and Apoptosis. While GTPase-related dysfunction is well-studied, the role of Other OPA1 domains in ADOA pathology remains unclear.

Methods: To investigate ADOA-linked OPA1 mutations, we assessed mitochondrial morphology, membrane potential, cytochrome c release, and cell viability in primary cortical neurons and N2a cells expressing OPA1 wild-type or mutant constructs. RNA Sequencing and structural predictions (SWISS-MODEL) provided insights into molecular pathways and structural impacts.

Results: Two ADOA-associated mutations were characterized: V465F (GTPase β-fold) and V560F (BSE α-helix). Both mutations impaired mitochondrial fusion and cell survival under apoptotic stimuli. Notably, the BSE-located V560F mutation caused greater deficits in membrane potential maintenance, earlier Apoptosis, and distinct molecular pathway changes compared to V465F.

Conclusions: This study highlights the domain-specific impacts of OPA1 mutations on mitochondrial function and ADOA pathology, revealing unique roles of the BSE domain in Apoptosis regulation and mitochondrial integrity. These findings provide insights into ADOA mechanisms and potential therapeutic targets.

Keywords

Apoptosis; Autosomal dominant optic atrophy (ADOA); Bundle signaling element (BSE); GTPase activity; Mitochondrial dynamics; OPA1 mutations.

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