Mitochondrial lactate venting limits oxidative stress

  • Cell Metab. 2026 Jun 2;38(6):1130-1140.e6. doi: 10.1016/j.cmet.2026.02.020.
Daniela Rauseo  1 ,  Yasna Contreras-Baeza  1 ,  Mildreth Salazar  2 ,  Abigail J Galarza  2 ,  Sebastián Holtheuer-Gallardo  3 ,  Hugo Faurand  2 ,  Natali Cárcamo-Lemus  2 ,  Raibel Suárez  2 ,  Joel L Asenjo  4 ,  Alexandra von Faber-Castell  5 ,  Franco Silva  2 ,  Valentina Mora-González  6 ,  Jan Dernic  5 ,  Luca Ravotto  5 ,  Matthias T Wyss  5 ,  Felipe Baeza-Lehnert  7 ,  Iván Ruminot  3 ,  Carlos Alvarez-Navarro  8 ,  Alejandro San Martín  2 ,  Bruno Weber  5 ,  Pamela Y Sandoval  9 ,  L Felipe Barros  10
Affiliations
  • 1. Centro de Estudios Científicos-CECs, Valdivia, Chile; Facultad de Medicina, Universidad San Sebastián, Valdivia, Chile; Universidad Austral de Chile, Valdivia, Chile.
  • 2. Centro de Estudios Científicos-CECs, Valdivia, Chile; Facultad de Medicina, Universidad San Sebastián, Valdivia, Chile.
  • 3. Centro de Estudios Científicos-CECs, Valdivia, Chile; Facultad de Ciencias de la Rehabilitación y Calidad de Vida, Universidad San Sebastián, Valdivia, Chile.
  • 4. Universidad Austral de Chile, Valdivia, Chile.
  • 5. Institute of Pharmacology and Toxicology, University and ETH Zurich, Zurich, Switzerland; Neuroscience Center Zurich, ETH and University Zurich, Zürich, Switzerland.
  • 6. Instituto de Inmunología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile.
  • 7. Carl-Ludwig-Institute for Physiology, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
  • 8. Instituto de Inmunología, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile; Unidad de Proteómica, AUSTRAL-omics, Universidad Austral de Chile, Valdivia, Chile.
  • 9. Centro de Estudios Científicos-CECs, Valdivia, Chile; Facultad de Medicina, Universidad San Sebastián, Valdivia, Chile. Electronic address: [email protected].
  • 10. Centro de Estudios Científicos-CECs, Valdivia, Chile; Facultad de Medicina, Universidad San Sebastián, Valdivia, Chile. Electronic address: [email protected].
PMID: 41881014 DOI: 10.1016/j.cmet.2026.02.020
Abstract

Lactate has been proposed to enter mitochondria and fuel respiration, but this "intracellular lactate shuttle" remains controversial. Using genetically encoded lactate and redox sensors in cultured cells and neurons in vivo, we identify a dynamic lactate pool within the mitochondrial matrix that tracks extracellular and blood lactate and promotes lactylation of mitochondrial proteins. Lactate crosses the inner mitochondrial membrane through a saturable pathway that is partly sensitive to pharmacologic and genetic inhibition of the mitochondrial pyruvate carrier (MPC). Despite transport and matrix Lactate Dehydrogenase activity, lactate does not measurably energize the electron transport chain under the conditions tested. Instead, energized mitochondria can produce lactate from pyruvate, a response enhanced by hypoxia. Blocking MPC causes matrix lactate and H₂O₂ accumulation, revealing a rapid lactate-based "vent" that modulates matrix energy and Reactive Oxygen Species.

Keywords
genetically encoded fluorescent indicator; hypoxia; lactate; lactate dehydrogenase; membrane transport; metabolism; mitochondrial pyruvate carrier; monocarboxylate transporter; pyruvate; reactive oxygen species.
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