The malate-aspartate shuttle supports thermogenic lipid mobilization in brown adipocytes.

Authors

Michaela Veliova, Caroline M Ferreira, Katrina P Montales, Francisco Villalobos, Alexandra J Brownstein, Rebeca Acín-Pérez, Gabrielly S Ferreira, Anthony E Jones, Linsey Stiles, Ajit S Divakaruni, Marc Liesa, Orian S Shirihai, Marcus F Oliveira

Published in

The FEBS journal. Volume 293. Issue 15. Pages 4489-4507. Epub Feb 18, 2026.

Abstract

Brown adipose tissue (BAT) plays a central role in thermogenesis by coupling fatty acid oxidation to heat production. Efficient BAT thermogenic activity requires enhanced glycolytic flux, which in turn depends on continuous regeneration of cytosolic NAD⁺ to sustain glyceraldehyde-3-phosphate dehydrogenase activity. This regeneration is mediated by three main pathways: lactate dehydrogenase, the glycerol-3-phosphate shuttle (GPSh), and the malate-aspartate shuttle (MASh). We previously showed that inhibition of the mitochondrial pyruvate carrier increases energy expenditure in brown adipocytes via MASh activation. However, the specific contribution of MASh to BAT energy metabolism remains poorly defined. Here, we show that MASh is functional and directly regulates lipid metabolism in BAT. Enzymatic activities of cytosolic and mitochondrial malate dehydrogenases and glutamic-oxaloacetic transaminases in BAT were comparable to those in the liver. Using a reconstituted system of isolated BAT mitochondria and cytosolic MASh enzymes, we demonstrated that extra-mitochondrial NADH is efficiently reoxidized in a glutamate-dependent manner via MASh. Genetic silencing of the mitochondrial carriers critical to MASh, namely the oxoglutarate carrier (Ogc) and aspartate-glutamate carrier (Aralar1), had no apparent effects on respiratory rates. However, silencing either Ogc or Aralar1 led to the accumulation of small lipid droplets and impaired norepinephrine-induced lipolysis. Taken together, our data indicate a novel role of MASh in regulating BAT lipid homeostasis with potential implications to body energy expenditure and thermogenesis.

PMID:
41704162
Bibliographic data and abstract were imported from PubMed on 15 Sep 2026.

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