Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition
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.
Authors
- Alba Fernández‐Rodrigo (ORCID: https://orcid.org/0000-0003-3834-0687)
- Marcos Zamora-Dorta
- Albert Quintana (ORCID: https://orcid.org/0000-0003-1674-7160)
- Jaime de Juan‐Sanz (ORCID: https://orcid.org/0000-0002-1212-5623)
- Mauro Agrò (ORCID: https://orcid.org/0000-0002-3476-5410)
- Myriam Jaraíz-Rodríguez (ORCID: https://orcid.org/0000-0002-9908-3541)
- Natalia Azpiazu (ORCID: https://orcid.org/0000-0002-1085-2341)
- Eduardo Balsa (ORCID: https://orcid.org/0000-0002-6836-7023)
- José A. Esteban (ORCID: https://orcid.org/0000-0002-3759-3300)
- Mario López-Manzaneda (ORCID: https://orcid.org/0000-0002-1366-4143)
- Manuel Calleja (ORCID: https://orcid.org/0000-0003-3608-8289)
- Mònica Girona
- Lucia del Prado (ORCID: https://orcid.org/0000-0003-1270-7495)
Institutions
- Universitat Autònoma de Barcelona (ES)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Sorbonne Université (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Pitié-Salpêtrière Hospital (FR)
- Centro de Biología Molecular Severo Ochoa (ES)
- Institut du Cerveau (FR)
- Universidad Autónoma de Madrid (ES)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-07
- DOI
- https://doi.org/10.1038/s41467-024-52968-1
- Citations
- 9
- Primary Topic
- Mitochondrial Function and Pathology
- Type
- article
- Field-Weighted Citation Impact
- 2.10
Funders
- European Commission
- Ministerio de Ciencia e Innovación
- Agencia Estatal de Investigación