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La acetilcoenzima citosólica A es un metabolito de señalización para controlar la mitofagia
Yifan Zhang1,2, Xiao Shen1,2, Yuan Shen1,2
1Fudan University Shanghai Cancer Center & School of Basic Medical Sciences & Institutes of Biomedical Sciences; Cancer Institutes; Key Laboratory of Breast Cancer in Shanghai; Shanghai Key Laboratory of Radiation Oncology; The Shanghai Key Laboratory of Medical Epigenetics; State Key Laboratory of Brain Function and Disorders, School of Basic Medical Sciences, Fudan University, Shanghai, China.
Nature
|November 12, 2025
Resumen
El ayuno reduce el acetil-CoA citosólico (AcCoA), desencadenando la mitofagia a través de NLRX1. La suplementación con acetato invierte esto, revelando AcCoA como una señal metabólica clave que vincula el estado de los nutrientes con la mitofagia.
Área de la Ciencia:
- Biología celular
- Regulación del metabolismo
- La autofagia
Sus antecedentes:
- El acetil-CoA (AcCoA) es fundamental para el metabolismo de los nutrientes y el ciclo del ácido tricarboxílico.
- El estado nutricional, como el ayuno, regula dinámicamente los niveles de AcCoA y las vías metabólicas.
- La mitofagia, la degradación selectiva de las mitocondrias, juega un papel en la homeostasis celular.
Objetivo del estudio:
- Investigar el papel del AcCoA citosólico en la regulación de la mitofagia.
- Identificar los mecanismos moleculares que vinculan los niveles de AcCoA con la mitofagia.
- Para explorar el potencial terapéutico de dirigirse al eje AcCoA-mitophagy.
Principales métodos:
- Ayuno a corto plazo e inhibición farmacológica de las enzimas metabólicas clave (ACLY, SLC25A1, ACSS2) para reducir el AcCoA citosólico.
- Suplementación con acetato para contrarrestar la reducción de AcCoA.
- Disrupción genética de NLRX1 (miembro de la familia de receptores similares a NOD X1).
- Experimentos in vitro e in vivo para evaluar la mitofagia.
- Ensayos bioquímicos para el estudio de las interacciones proteína-proteína (NLRX1-AcCoA).
Principales resultados:
- La reducción de los niveles citosólicos de AcCoA, inducida por el ayuno o la inhibición de la enzima, desencadena la mitofagia.
- La suplementación con acetato contrarresta eficazmente la mitofagia inducida por la reducción de AcCoA.
- NLRX1 es esencial para la mediación de la mitofagia en respuesta a la disminución de la AcCoA citosólica.
- NLRX1 se une directamente al AcCoA citosólico, regulando su conformación e interacción con el LC3.
- La vía AcCoA-NLRX1 está implicada en la mitofagia inducida por los inhibidores de KRAS y la resistencia a los fármacos.
Conclusiones:
- El AcCoA citosólico actúa como un metabolito de señalización que conecta el metabolismo de los nutrientes con la mitofagia a través de su receptor NLRX1.
- El eje AcCoA-NLRX1 representa un nuevo mecanismo metabólico que contribuye a la resistencia al inhibidor KRAS.
- Dirigirse a esta vía puede ofrecer estrategias terapéuticas para las enfermedades metabólicas y el tratamiento del cáncer.
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