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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.

The brain is a highly metabolic organ, composed of multiple cell classes, that controls crucial functions of the body. Although neurons have traditionally been the main protagonist, astrocytes have gained significant attention over the last decade. In this regard, astrocytes are a type of glial cells that have recently emerged as critical regulators of central nervous system (CNS) function and play a significant role in maintaining brain energy metabolism. However, in certain scenarios, astrocyte behavior can go awry, which poses a significant threat to brain integrity and function. This is definitively the case for mutations that turn normal astrocytes and astrocytic precursors into gliomas, an aggressive type of brain tumor. In addition, healthy astrocytes can interact with tumor cells, becoming part of the tumor microenvironment and influencing disease progression. In this review, we discuss the recent evidence suggesting that disturbed metabolism in astrocytes can contribute to the development and progression of fatal human diseases such as cancer. Emphasis is placed on detailing the molecular bases and metabolic pathways of this disease and highlighting unique metabolic vulnerabilities that can potentially be exploited to develop successful therapeutic opportunities.