Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition

Lucia Prado, Myriam Jaraíz-Rodríguez, Mauro Agro, Marcos Zamora-Dorta, Natalia Azpiazu, Manuel Calleja, Mario Lopez-Manzaneda, Jaime Juan-Sanz, Alba Fernández-Rodrigo, José A. Esteban, Mònica Girona, Albert Quintana and Eduardo Balsa ()
Additional contact information
Lucia Prado: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC)
Myriam Jaraíz-Rodríguez: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC)
Mauro Agro: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC)
Marcos Zamora-Dorta: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC)
Natalia Azpiazu: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC)
Manuel Calleja: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC)
Mario Lopez-Manzaneda: Hôpital de la Pitié Salpêtrière
Jaime Juan-Sanz: Hôpital de la Pitié Salpêtrière
Alba Fernández-Rodrigo: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC)
José A. Esteban: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC)
Mònica Girona: Physiology and Immunology, Universitat Autònoma de Barcelona
Albert Quintana: Physiology and Immunology, Universitat Autònoma de Barcelona
Eduardo Balsa: Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC)

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52968-1

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