ArticleNature communications2024
Compensatory activity of the PC-ME1 metabolic axis underlies differential sensitivity to mitochondrial complex I inhibition.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed.
- Genetic modulation of NAD(P)H homeostasis reveals distinct redox-coupled metabolic vulnerabilities.Nature metabolism · 2026Article
- Metabolic circuitry of NADH buffering reveals a vulnerability in redox-adaptive cancer cells.Innovation (Cambridge (Mass.)) · 2026Article
- Specific FbioRxiv : the preprint server for biology · 2026Article
- Mitochondrial complex I deficiency-associated diseases and models.Cellular and molecular life sciences : CMLS · 2026Review
- Induced pluripotent stem cells from a transgenic minipig model of Huntington's disease reveal early metabolic changes.Disease models & mechanisms · 2026Article
- Perturbation of NAD(P)H metabolism with theScience advances · 2026Article
- Changes in the brain [NADFrontiers in aging neuroscience · 2026Review
- Effects of aging and anti-aging dietary restriction on regulators of the [NADPH]/[NADPFree radical biology & medicine · 2025Review
- Redox Cascade in Chicken Skeletal Muscle: SELENOT Suppression in Selenium Deficiency Triggers Disulfidptosis via mtROS-NADPH Dysregulation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Tissue-specific modulation of NADH consumption as an anti-aging intervention in Drosophila.bioRxiv : the preprint server for biology · 2025Article
- Glioinflammation: disease-associated microglia and astrocytes in psychiatric disorders, neurodegeneration, and senescence.Frontiers in cellular neuroscience · 2025Review
Corrections and comments
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Authors and funding
13 authors.
Funding
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.
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Registered trials
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