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<p>Choroideremia (CHM) is a hereditary retinal degenerative disorder characterized by progressive dysfunction of the retinal pigment epithelium (RPE) and photoreceptors with no available therapy. Despite the recognized genetic basis of CHM, the metabolic pathways driving disease progression remain poorly defined. By investigating REP-1 deficiency in CHM disease, our study reveals a previously unrecognized role for REP-1 in regulating GLUT-1 and GLUT-4 membrane trafficking, controlling glucose uptake, and reprograming mitochondrial metabolism toward lipid oxidation. This chronic metabolic shift results in reduced glycolytic flux, elevated oxidative stress, and compromised ATP production, culminating in a progressive retinal dystrophy. Notably, pharmacological restoration of GLUT trafficking via leptin administration re-established glucose uptake and mitochondrial function, rescuing cellular energetics both in vitro and in vivo. These findings establish REP-1 as a key regulator of retinal metabolic homeostasis and suggest that targeting glucose–lipid metabolic rewiring may represent a novel therapeutic strategy for CHM and related retinal dystrophies.</p><p></p>

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REP-1 deficiency induces aberrant mitochondrial metabolic rewiring from glycolysis to lipid oxidation in CHM disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月30日

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  • Sara Buonocore,
  • Giuliana Giamundo,
  • Chiara Barone,
  • Iolanda Carratù,
  • Giovanna Trinchese,
  • Giovanni Andrea Vitale,
  • Gianluca Fasciolo,
  • Marcello Ziaco,
  • Paola Venditti,
  • Angelo Fontana,
  • Maria Pina Mollica,
  • Dario Antonini,
  • Ivan Conte

摘要

Choroideremia (CHM) is a hereditary retinal degenerative disorder characterized by progressive dysfunction of the retinal pigment epithelium (RPE) and photoreceptors with no available therapy. Despite the recognized genetic basis of CHM, the metabolic pathways driving disease progression remain poorly defined. By investigating REP-1 deficiency in CHM disease, our study reveals a previously unrecognized role for REP-1 in regulating GLUT-1 and GLUT-4 membrane trafficking, controlling glucose uptake, and reprograming mitochondrial metabolism toward lipid oxidation. This chronic metabolic shift results in reduced glycolytic flux, elevated oxidative stress, and compromised ATP production, culminating in a progressive retinal dystrophy. Notably, pharmacological restoration of GLUT trafficking via leptin administration re-established glucose uptake and mitochondrial function, rescuing cellular energetics both in vitro and in vivo. These findings establish REP-1 as a key regulator of retinal metabolic homeostasis and suggest that targeting glucose–lipid metabolic rewiring may represent a novel therapeutic strategy for CHM and related retinal dystrophies.