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  2. NH4(+) triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

NH4(+) triggers the release of astrocytic lactate via mitochondrial pyruvate shunting

  • Proc Natl Acad Sci U S A. 2015 Sep 1;112(35):11090-5. doi: 10.1073/pnas.1508259112.
Rodrigo Lerchundi 1 Ignacio Fernández-Moncada 1 Yasna Contreras-Baeza 1 Tamara Sotelo-Hitschfeld 1 Philipp Mächler 2 Matthias T Wyss 2 Jillian Stobart 2 Felipe Baeza-Lehnert 3 Karin Alegría 3 Bruno Weber 2 L Felipe Barros 4
Affiliations

Affiliations

  • 1 Biological Laboratory, Centro de Estudios Científicos, 5110466 Valdivia, Chile; Universidad Austral de Chile, 5110566 Valdivia, Chile;
  • 2 Institute of Pharmacology and Toxicology, University of Zurich, 8057 Zurich, Switzerland; Neuroscience Center Zurich, Eidgenössische Technische Hochschule (ETH), and University of Zurich, 8057 Zurich, Switzerland.
  • 3 Biological Laboratory, Centro de Estudios Científicos, 5110466 Valdivia, Chile;
  • 4 Biological Laboratory, Centro de Estudios Científicos, 5110466 Valdivia, Chile; fbarros@cecs.cl.
Abstract

Neural activity is accompanied by a transient mismatch between local glucose and oxygen metabolism, a phenomenon of physiological and pathophysiological importance termed aerobic glycolysis. Previous studies have proposed glutamate and K(+) as the neuronal signals that trigger aerobic glycolysis in astrocytes. Here we used a panel of genetically encoded FRET sensors in vitro and in vivo to investigate the participation of NH4(+), a by-product of catabolism that is also released by active neurons. Astrocytes in mixed cortical cultures responded to physiological levels of NH4(+) with an acute rise in cytosolic lactate followed by lactate release into the extracellular space, as detected by a lactate-sniffer. An acute increase in astrocytic lactate was also observed in acute hippocampal slices exposed to NH4(+) and in the somatosensory cortex of anesthetized mice in response to i.v. NH4(+). Unexpectedly, NH4(+) had no effect on astrocytic glucose consumption. Parallel measurements showed simultaneous cytosolic pyruvate accumulation and NADH depletion, suggesting the involvement of mitochondria. An inhibitor-stop technique confirmed a strong inhibition of mitochondrial pyruvate uptake that can be explained by mitochondrial matrix acidification. These results show that physiological NH4(+) diverts the flux of pyruvate from mitochondria to lactate production and release. Considering that NH4(+) is produced stoichiometrically with glutamate during excitatory neurotransmission, we propose that NH4(+) behaves as an intercellular signal and that pyruvate shunting contributes to aerobic lactate production by astrocytes.

Keywords

FLII12Pglu700μΔ6; laconic; mitoSypHer; peredox; pyronic.

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