Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition
del Prado, Lucia (Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC))
Jaraíz-Rodríguez, Myriam (Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC))
Agro, Mauro (Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC))
Zamora-Dorta, Marcos (Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC))
Azpiazu, Natalia (Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC))
Calleja, Manuel (Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC))
Lopez-Manzaneda, Mario (Hôpital de la Pitié Salpêtrière. Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP)
de Juan-Sanz, Jaime (Hôpital de la Pitié Salpêtrière. Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP)
Fernández-Rodrigo, Alba (Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC))
Esteban, José A. (Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC))
Girona, Mònica (Universitat Autònoma de Barcelona. Institut de Neurociències)
Quintana Romero, Albert (Universitat Autònoma de Barcelona. Institut de Neurociències)
Balsa, Eduardo (Instituto Universitario de Biología Molecular - IUBM (Universidad Autónoma de Madrid))

Data:	2024
Resum:	Deficiencies in the electron transport chain (ETC) lead to mitochondrial diseases. While mutations are distributed across the organism, cell and tissue sensitivity to ETC disruption varies, and the molecular mechanisms underlying this variability remain poorly understood. Here we show that, upon ETC inhibition, a non-canonical tricarboxylic acid (TCA) cycle upregulates to maintain malate levels and concomitant production of NADPH. Our findings indicate that the adverse effects observed upon CI inhibition primarily stem from reduced NADPH levels, rather than ATP depletion. Furthermore, we find that Pyruvate carboxylase (PC) and ME1, the key mediators orchestrating this metabolic reprogramming, are selectively expressed in astrocytes compared to neurons and underlie their differential sensitivity to ETC inhibition. Augmenting ME1 levels in the brain alleviates neuroinflammation and corrects motor function and coordination in a preclinical mouse model of CI deficiency. These studies may explain why different brain cells vary in their sensitivity to ETC inhibition, which could impact mitochondrial disease management. Mitochondrial diseases caused by ETC deficiencies affect cells differently. Here, the authors show that ETC inhibition activates a non-canonical TCA cycle to maintain NADPH levels, which explains the differential sensitivity observed between astrocytes and neurons.
Ajuts:	European Commission 948478
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Mechanisms of disease ; Molecular medicine
Publicat a:	Nature communications, Vol. 15 (october 2024) , ISSN 2041-1723

DOI: 10.1038/s41467-024-52968-1
PMID: 39375345

18 p, 1.7 MB

El registre apareix a les col·leccions:
Articles > Articles de recerca
Articles > Articles publicats