PMID- 36959514
OWN - NLM
STAT- MEDLINE
DCOM- 20230329
LR  - 20240427
IS  - 2522-5812 (Electronic)
IS  - 2522-5812 (Linking)
VI  - 5
IP  - 3
DP  - 2023 Mar
TI  - Loss of fatty acid degradation by astrocytic mitochondria triggers 
      neuroinflammation and neurodegeneration.
PG  - 445-465
LID - 10.1038/s42255-023-00756-4 [doi]
AB  - Astrocytes provide key neuronal support, and their phenotypic transformation is 
      implicated in neurodegenerative diseases. Metabolically, astrocytes possess low 
      mitochondrial oxidative phosphorylation (OxPhos) activity, but its 
      pathophysiological role in neurodegeneration remains unclear. Here, we show that 
      the brain critically depends on astrocytic OxPhos to degrade fatty acids (FAs) 
      and maintain lipid homeostasis. Aberrant astrocytic OxPhos induces lipid droplet 
      (LD) accumulation followed by neurodegeneration that recapitulates key features 
      of Alzheimer's disease (AD), including synaptic loss, neuroinflammation, 
      demyelination and cognitive impairment. Mechanistically, when FA load overwhelms 
      astrocytic OxPhos capacity, elevated acetyl-CoA levels induce astrocyte 
      reactivity by enhancing STAT3 acetylation and activation. Intercellularly, 
      lipid-laden reactive astrocytes stimulate neuronal FA oxidation and oxidative 
      stress, activate microglia through IL-3 signalling, and inhibit the biosynthesis 
      of FAs and phospholipids required for myelin replenishment. Along with LD 
      accumulation and impaired FA degradation manifested in an AD mouse model, we 
      reveal a lipid-centric, AD-resembling mechanism by which astrocytic mitochondrial 
      dysfunction progressively induces neuroinflammation and neurodegeneration.
CI  - (c) 2023. The Author(s), under exclusive licence to Springer Nature Limited.
FAU - Mi, Yashi
AU  - Mi Y
AD  - Center for Innovation in Brain Science, University of Arizona Health Sciences, 
      Tucson, AZ, USA.
FAU - Qi, Guoyuan
AU  - Qi G
AD  - Center for Innovation in Brain Science, University of Arizona Health Sciences, 
      Tucson, AZ, USA.
FAU - Vitali, Francesca
AU  - Vitali F
AD  - Center for Innovation in Brain Science, University of Arizona Health Sciences, 
      Tucson, AZ, USA.
AD  - Department of Neurology, College of Medicine Tucson, University of Arizona, 
      Tucson, AZ, USA.
FAU - Shang, Yuan
AU  - Shang Y
AD  - Center for Innovation in Brain Science, University of Arizona Health Sciences, 
      Tucson, AZ, USA.
FAU - Raikes, Adam C
AU  - Raikes AC
AUID- ORCID: 0000-0002-1609-6727
AD  - Center for Innovation in Brain Science, University of Arizona Health Sciences, 
      Tucson, AZ, USA.
FAU - Wang, Tian
AU  - Wang T
AUID- ORCID: 0000-0003-1867-5850
AD  - Center for Innovation in Brain Science, University of Arizona Health Sciences, 
      Tucson, AZ, USA.
AD  - Department of Neurology, College of Medicine Tucson, University of Arizona, 
      Tucson, AZ, USA.
FAU - Jin, Yan
AU  - Jin Y
AD  - Center of Translational Science, Florida International University, Port St. 
      Lucie, FL, USA.
FAU - Brinton, Roberta D
AU  - Brinton RD
AUID- ORCID: 0000-0001-8450-772X
AD  - Center for Innovation in Brain Science, University of Arizona Health Sciences, 
      Tucson, AZ, USA.
AD  - Department of Neurology, College of Medicine Tucson, University of Arizona, 
      Tucson, AZ, USA.
AD  - Department of Pharmacology, College of Medicine Tucson, University of Arizona, 
      Tucson, AZ, USA.
AD  - Graduate Interdisciplinary Program in Neuroscience, University of Arizona, 
      Tucson, AZ, USA.
FAU - Gu, Haiwei
AU  - Gu H
AD  - Center of Translational Science, Florida International University, Port St. 
      Lucie, FL, USA.
FAU - Yin, Fei
AU  - Yin F
AUID- ORCID: 0000-0002-5996-2410
AD  - Center for Innovation in Brain Science, University of Arizona Health Sciences, 
      Tucson, AZ, USA. feiyin@arizona.edu.
AD  - Department of Pharmacology, College of Medicine Tucson, University of Arizona, 
      Tucson, AZ, USA. feiyin@arizona.edu.
AD  - Graduate Interdisciplinary Program in Neuroscience, University of Arizona, 
      Tucson, AZ, USA. feiyin@arizona.edu.
LA  - eng
GR  - P30 AG072980/AG/NIA NIH HHS/United States
GR  - R21 AG072561/AG/NIA NIH HHS/United States
GR  - P01 AG026572/AG/NIA NIH HHS/United States
GR  - RF1 AG068175/AG/NIA NIH HHS/United States
GR  - U54 AG054345/AG/NIA NIH HHS/United States
GR  - U54 AG054349/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20230323
PL  - Germany
TA  - Nat Metab
JT  - Nature metabolism
JID - 101736592
RN  - 0 (Fatty Acids)
SB  - IM
CIN - Nat Metab. 2023 Mar;5(3):362-363. PMID: 36959513
MH  - Mice
MH  - Animals
MH  - *Neuroinflammatory Diseases
MH  - Astrocytes/metabolism
MH  - *Alzheimer Disease/metabolism
MH  - Fatty Acids/metabolism
MH  - Mitochondria/metabolism
PMC - PMC10202034
MID - NIHMS1886953
COIS- COMPETING INTERESTS The authors declare no competing interests.
EDAT- 2023/03/25 06:00
MHDA- 2023/03/29 06:05
PMCR- 2023/09/23
CRDT- 2023/03/24 00:31
PHST- 2022/06/19 00:00 [received]
PHST- 2023/02/03 00:00 [accepted]
PHST- 2023/03/29 06:05 [medline]
PHST- 2023/03/25 06:00 [pubmed]
PHST- 2023/03/24 00:31 [entrez]
PHST- 2023/09/23 00:00 [pmc-release]
AID - 10.1038/s42255-023-00756-4 [pii]
AID - 10.1038/s42255-023-00756-4 [doi]
PST - ppublish
SO  - Nat Metab. 2023 Mar;5(3):445-465. doi: 10.1038/s42255-023-00756-4. Epub 2023 Mar 
      23.