Compensatory Activity of the PC-ME1 Metabolic Axis Underlies Differential Sensitivity to Mitochondrial Complex I Inhibition

Overview

Journal Nat Commun

Specialty Biology

Date 2024 Oct 7

PMID 39375345

Authors

Lucia Del Prado

Myriam Jaraiz-Rodriguez

Mauro Agro

Marcos Zamora-Dorta

Natalia Azpiazu

Manuel Calleja

Mario Lopez-Manzaneda

Jaime de Juan-Sanz

Alba Fernandez-Rodrigo

Jose A Esteban

Monica Girona

Albert Quintana

Eduardo Balsa

Affiliations

Soon will be listed here.

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.

Citing Articles

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