Acetoacetate protects macrophages from lactic acidosis-induced mitochondrial dysfunction by metabolic reprograming.
Acetoacetates
/ pharmacology
Acidosis, Lactic
/ drug therapy
Cellular Reprogramming
Energy Metabolism
Gene Expression
Humans
Hydrogen-Ion Concentration
Lactic Acid
/ metabolism
Macrophages
/ drug effects
Metabolic Engineering
Mitochondria
/ metabolism
Mitophagy
Protective Agents
/ pharmacology
Tumor Microenvironment
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 12 2021
08 12 2021
Historique:
received:
07
10
2019
accepted:
09
11
2021
entrez:
9
12
2021
pubmed:
10
12
2021
medline:
11
1
2022
Statut:
epublish
Résumé
Lactic acidosis, the extracellular accumulation of lactate and protons, is a consequence of increased glycolysis triggered by insufficient oxygen supply to tissues. Macrophages are able to differentiate from monocytes under such acidotic conditions, and remain active in order to resolve the underlying injury. Here we show that, in lactic acidosis, human monocytes differentiating into macrophages are characterized by depolarized mitochondria, transient reduction of mitochondrial mass due to mitophagy, and a significant decrease in nutrient absorption. These metabolic changes, resembling pseudostarvation, result from the low extracellular pH rather than from the lactosis component, and render these cells dependent on autophagy for survival. Meanwhile, acetoacetate, a natural metabolite produced by the liver, is utilized by monocytes/macrophages as an alternative fuel to mitigate lactic acidosis-induced pseudostarvation, as evidenced by retained mitochondrial integrity and function, retained nutrient uptake, and survival without the need of autophagy. Our results thus show that acetoacetate may increase tissue tolerance to sustained lactic acidosis.
Identifiants
pubmed: 34880237
doi: 10.1038/s41467-021-27426-x
pii: 10.1038/s41467-021-27426-x
pmc: PMC8655019
doi:
Substances chimiques
Acetoacetates
0
Protective Agents
0
Lactic Acid
33X04XA5AT
acetoacetic acid
4ZI204Y1MC
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7115Informations de copyright
© 2021. The Author(s).
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