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<p>Prion diseases are lethal neurodegenerative disorders marked by mitochondrial impairment, oxidative stress, and neuronal apoptosis. Our previous work identified optic atrophy protein 1 (OPA1) as a promising point of intervention, yet the underlying mechanisms are poorly understood. In the present work, we showed that OPA1-mediated protection depends on ATP synthase activity and oligomerization. In N2a cells, PrP<sup>106−126</sup> exposure reduced the protein expression levels of OPA1 and key ATP synthase subunits, including the catalytic subunit ATP5A and the oligomerization-associated subunit ATP5k, whereas OPA1 overexpression attenuated this downregulation. Additionally, OPA1 overexpression preserved mitochondrial morphology and cristae structure, alleviated mitochondrial dysfunction, limited oxidative stress, and suppressed mitochondria-dependent apoptotic signaling. Importantly, these protective effects were abolished by pharmacological inhibition of ATP synthase or genetic silencing of ATP5k. Collectively, these results demonstrate that ATP synthase activity and oligomerization are indispensable for OPA1-mediated protection against prion-induced mitochondrial dysfunction, oxidative stress, and neuronal apoptosis, thereby providing novel mechanistic insights and identifying avenues for therapeutic intervention in prion diseases.</p>

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OPA1 Requires ATP Synthase Activity and Oligomerization to Mitigate Prion-Induced Mitochondrial Dysfunction, Oxidative Stress, and Neuronal Apoptosis

  • 期刊论文

  • 发表日期：

    2026年1月1日

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  • Wei Wu,
  • Xixi Zhang,
  • Mingyue Jiang,
  • Deming Zhao,
  • Lifeng Yang,
  • Ning Ma

摘要

Prion diseases are lethal neurodegenerative disorders marked by mitochondrial impairment, oxidative stress, and neuronal apoptosis. Our previous work identified optic atrophy protein 1 (OPA1) as a promising point of intervention, yet the underlying mechanisms are poorly understood. In the present work, we showed that OPA1-mediated protection depends on ATP synthase activity and oligomerization. In N2a cells, PrP106−126 exposure reduced the protein expression levels of OPA1 and key ATP synthase subunits, including the catalytic subunit ATP5A and the oligomerization-associated subunit ATP5k, whereas OPA1 overexpression attenuated this downregulation. Additionally, OPA1 overexpression preserved mitochondrial morphology and cristae structure, alleviated mitochondrial dysfunction, limited oxidative stress, and suppressed mitochondria-dependent apoptotic signaling. Importantly, these protective effects were abolished by pharmacological inhibition of ATP synthase or genetic silencing of ATP5k. Collectively, these results demonstrate that ATP synthase activity and oligomerization are indispensable for OPA1-mediated protection against prion-induced mitochondrial dysfunction, oxidative stress, and neuronal apoptosis, thereby providing novel mechanistic insights and identifying avenues for therapeutic intervention in prion diseases.