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<p>Glycolysis is classically defined as a cytoplasmic process. Here, in our investigation of mitochondrial dysfunction in Retinitis Pigmentosa (RP), we report the unexpected discovery of a complete and functional glycolytic pathway operating inside mitochondria. Through CoIP-MS, polysome profiling, and [U-<sup>13</sup>C] glucose isotope tracing, we demonstrate that key glycolytic enzymes are locally translated and metabolically active within the organelle. Mechanistically, we show that the VWA8-PHB2-GRP75 complex is responsible for anchoring these enzymes, thereby sustaining intra-mitochondrial glycolysis and preserving mitochondrial function by regulating NAD+ levels and reactive oxygen species (ROS) homeostasis. In vivo, Vwa8 knockout in both mice and zebrafish abolishes this metabolic safeguard, leading to RP-like phenotypes that can be partially rescued by reactivating mitochondrial glycolysis. Collectively, these findings redefine the spatial compartmentalization of glucose metabolism and establish mitochondrial glycolysis as a therapeutic target for mitochondrial diseases.</p>

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Intra-mitochondrial glycolysis maintains mitochondrial function and underlies the pathogenesis of retinitis pigmentosa

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月12日

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  • Linghui Kong,
  • Jiajian Liang,
  • Dan Liu,
  • Shanshan Jia,
  • Hui Gu,
  • Yiwen He,
  • Wenting Luo,
  • Songying Cao,
  • Yizhang Dong,
  • Chao Yang,
  • Minghui Liao,
  • Guojia Wan,
  • Bo Du,
  • Dongxue Ding,
  • Wei Ma,
  • Xiaowei Wei,
  • Anhua Wu,
  • Zhengwei Yuan

摘要

Glycolysis is classically defined as a cytoplasmic process. Here, in our investigation of mitochondrial dysfunction in Retinitis Pigmentosa (RP), we report the unexpected discovery of a complete and functional glycolytic pathway operating inside mitochondria. Through CoIP-MS, polysome profiling, and [U-13C] glucose isotope tracing, we demonstrate that key glycolytic enzymes are locally translated and metabolically active within the organelle. Mechanistically, we show that the VWA8-PHB2-GRP75 complex is responsible for anchoring these enzymes, thereby sustaining intra-mitochondrial glycolysis and preserving mitochondrial function by regulating NAD+ levels and reactive oxygen species (ROS) homeostasis. In vivo, Vwa8 knockout in both mice and zebrafish abolishes this metabolic safeguard, leading to RP-like phenotypes that can be partially rescued by reactivating mitochondrial glycolysis. Collectively, these findings redefine the spatial compartmentalization of glucose metabolism and establish mitochondrial glycolysis as a therapeutic target for mitochondrial diseases.