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Grant support

We thank all the members of the Balsa laboratory for discussions regarding this project. This work was supported by grants to E.B. from the Spanish Government, Ministerio de Ciencia e Innovacion/Agencia Estatal de Investigacion (PID2019-110766GA-I00 and PID2022-137404OB-I00), European Research Council (ERC) under the European Union's Horizon 2020 research and innovation (ERC-2020-STG grant agreement n degrees 948478) and Fundacion CRIS contra el cancer (PR_EX_2022-01). A.Q. was supported by grant PID2020-114977RB-I00 funded by MICIU/AEI /10.13039/501100011033. M.Z. was supported in part by an FPI-UAM PhD fellowship. We also thank Cristina Ugalde for the 143B ND2, CytB, Cox2 and WT cybrid cell lines.

Analysis of institutional authors

Jaraiz-Rodriguez, MyriamAuthorAgro, MauroAuthorZamora-Dorta, MarcosAuthorDe Juan-Sanz JAuthorBalsa, EduardoCorresponding Author

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December 9, 2024
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Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition

Publicated to:Nature Communications. 15 (1): 8682- - 2024-10-07 15(1), DOI: 10.1038/s41467-024-52968-1

Authors: del Prado, Lucia; Jaraiz-Rodriguez, Myriam; Agro, Mauro; Zamora-Dorta, Marcos; Azpiazu, Natalia; Calleja, Manuel; Lopez-Manzaneda, Mario; de Juan-Sanz, Jaime; Fernandez-Rodrigo, Alba; Esteban, Jose A; Girona, Monica; Quintana, Albert; Balsa, Eduardo

Affiliations

Sorbonne Univ, Hop Pitie Salpetriere, AP HP, CNRS,Inst Cerveau Paris Brain Inst ICM,Inserm, Paris, France - Author
UAM, Ctr Biol Mol Severo Ochoa, CSIC, Madrid, Spain - Author
UAM, Dept Biol Mol, CSIC, Madrid, Spain - Author
Univ Autonoma Barcelona, Dept Cell Biol Physiol & Immunol, Bellaterra, Spain - Author
Univ Autonoma Barcelona, Inst Neurociencies, Bellaterra, Spain - Author
Univ Autonoma Madrid, Inst Univ Biol Mol IUBM, Madrid, Spain - Author
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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. 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.

Keywords

Adenosine triphosphateAdipose-tissueAnimalsAstrocytesBiosynthesisBrainCancerCitric acid cycleCompetitionDeficiencyDehydrogenaseDisease models, animalElectron transport complex iHumansMalatesMaleMalic acidMiceMice, inbred c57blMitochondriaMitochondrial diseasesMouse modelNadpNeuronNeuronsPyruvate carboxylaseRespiration

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Nature Communications due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2024 there are still no calculated indicators, but in 2023, it was in position 8/134, thus managing to position itself as a Q1 (Primer Cuartil), in the category Multidisciplinary Sciences. Notably, the journal is positioned above the 90th percentile.

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-18:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 10.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 9 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 7.25.
  • The number of mentions on the social network X (formerly Twitter): 15 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.
  • Assignment of a Handle/URN as an identifier within the deposit in the Institutional Repository: https://repositorio.uam.es/handle/10486/718700

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: France.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (del Prado, Lucia) and Last Author (BALSA MARTINEZ, EDUARDO).

the author responsible for correspondence tasks has been BALSA MARTINEZ, EDUARDO.