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<p>AGC1 deficiency is a rare, early-onset encephalopathy caused by mutations in the <i>SLC25A12</i> gene, encoding the mitochondrial aspartate/glutamate carrier isoform 1 (AGC1). Patients exhibit epileptic encephalopathy, cerebral hypomyelination, severe hypotonia, and global developmental delay. A hallmark biochemical feature of AGC1 deficiency is reduced brain N-acetylaspartate (NAA), a key metabolite involved in myelin lipid synthesis. However, the underlying mechanisms leading to the hypomyelinating phenotype remain unclear. In this study, we generated neuronal progenitors (NPs) derived from human-induced pluripotent stem cells (hiPSCs) of AGC1-deficient patients to investigate the metabolic and bioenergetic consequences of AGC1 loss. We demonstrated that AGC1-deficient NPs exhibit impaired proliferation, increased apoptosis, and a metabolic shift toward a hyperglycolytic phenotype due to defective mitochondrial pyruvate oxidation. RNA sequencing revealed downregulation of mitochondrial pyruvate carrier MPC1/2, limiting pyruvate-driven oxidative phosphorylation (OXPHOS) and reinforcing glycolysis as the primary energy source. Despite this metabolic shift, AGC1-deficient mitochondria retained the potential for OXPHOS when alternative anaplerotic substrates were provided. Notably, the administration of ketone bodies, in combination with glutamine, fully restored mitochondrial respiration, suggesting a mechanistic basis for the clinical improvements observed in AGC1-deficient patients undergoing ketogenic diet therapy. Our study highlights the importance of alternative metabolic pathways in maintaining neuronal energy homeostasis in AGC1 deficiency and offers insights into potential therapeutic strategies aimed at bypassing the mitochondrial pyruvate oxidation defect.</p>

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Combined ketone body and glutamine supplementation restores aerobic energy production in AGC1-deficient neuronal progenitors

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月15日

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  • Simona Nicole Barile,
  • Maria Chiara Magnifico,
  • Eleonora Poeta,
  • Felix Distelmaier,
  • Luigi Viggiano,
  • Nicola Balboni,
  • Michele Protti,
  • Sabrina Petralla,
  • Antonella Pignataro,
  • Giacomo Volpe,
  • Monica De Luise,
  • Massimo Bonora,
  • Marica Antonicelli,
  • Giorgia Babini,
  • Francesca Massenzio,
  • Vito Porcelli,
  • Eleonora Lama,
  • Roberto Arrigoni,
  • Isabella Pisano,
  • Veronica Addabbo,
  • Anna Campana,
  • Francesca Begnozzi,
  • Stewart A. Anderson,
  • Giuseppe Fiermonte,
  • Federico Manuel Giorgi,
  • Paolo Pinton,
  • Ferdinando Palmieri,
  • Giuseppe Gasparre,
  • Laura Mercolini,
  • Luigi Palmieri,
  • Douglas C. Wallace,
  • Julia Hentschel,
  • Barbara Monti,
  • Francesco Massimo Lasorsa

摘要

AGC1 deficiency is a rare, early-onset encephalopathy caused by mutations in the SLC25A12 gene, encoding the mitochondrial aspartate/glutamate carrier isoform 1 (AGC1). Patients exhibit epileptic encephalopathy, cerebral hypomyelination, severe hypotonia, and global developmental delay. A hallmark biochemical feature of AGC1 deficiency is reduced brain N-acetylaspartate (NAA), a key metabolite involved in myelin lipid synthesis. However, the underlying mechanisms leading to the hypomyelinating phenotype remain unclear. In this study, we generated neuronal progenitors (NPs) derived from human-induced pluripotent stem cells (hiPSCs) of AGC1-deficient patients to investigate the metabolic and bioenergetic consequences of AGC1 loss. We demonstrated that AGC1-deficient NPs exhibit impaired proliferation, increased apoptosis, and a metabolic shift toward a hyperglycolytic phenotype due to defective mitochondrial pyruvate oxidation. RNA sequencing revealed downregulation of mitochondrial pyruvate carrier MPC1/2, limiting pyruvate-driven oxidative phosphorylation (OXPHOS) and reinforcing glycolysis as the primary energy source. Despite this metabolic shift, AGC1-deficient mitochondria retained the potential for OXPHOS when alternative anaplerotic substrates were provided. Notably, the administration of ketone bodies, in combination with glutamine, fully restored mitochondrial respiration, suggesting a mechanistic basis for the clinical improvements observed in AGC1-deficient patients undergoing ketogenic diet therapy. Our study highlights the importance of alternative metabolic pathways in maintaining neuronal energy homeostasis in AGC1 deficiency and offers insights into potential therapeutic strategies aimed at bypassing the mitochondrial pyruvate oxidation defect.