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PC-ME1 代谢轴的代偿活性是导致对线粒体复合物 I 抑制的敏感性差异的基础。

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

机构信息

Departamento de Biología Molecular and Centro de Biología Molecular Severo Ochoa (UAM-CSIC), Madrid, Spain.

Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, APHP, Hôpital de la Pitié Salpêtrière, Paris, France.

出版信息

Nat Commun. 2024 Oct 7;15(1):8682. doi: 10.1038/s41467-024-52968-1.

DOI:10.1038/s41467-024-52968-1
PMID:39375345
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11458614/
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.

摘要

电子传递链 (ETC) 的缺陷会导致线粒体疾病。虽然突变分布在整个生物体中，但细胞和组织对 ETC 破坏的敏感性存在差异，而这种变异性的分子机制仍知之甚少。在这里，我们表明，在 ETC 抑制后，非经典的三羧酸 (TCA) 循环上调以维持苹果酸水平和伴随的 NADPH 产生。我们的发现表明，CI 抑制后观察到的不良影响主要源于 NADPH 水平降低，而不是 ATP 耗竭。此外，我们发现丙酮酸羧化酶 (PC) 和 ME1，即协调这种代谢重编程的关键介质，在星形胶质细胞中与神经元相比选择性表达，并为它们对 ETC 抑制的差异敏感性奠定基础。在 CI 缺乏的临床前小鼠模型中，增加大脑中的 ME1 水平可减轻神经炎症并纠正运动功能和协调性。这些研究可以解释为什么不同的脑细胞对 ETC 抑制的敏感性不同，这可能会影响线粒体疾病的管理。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a9de/11458614/cdab9c796df1/41467_2024_52968_Fig7_HTML.jpg
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