PMID- 34039599
OWN - NLM
STAT- MEDLINE
DCOM- 20220415
LR  - 20240214
IS  - 2375-2548 (Electronic)
IS  - 2375-2548 (Linking)
VI  - 7
IP  - 22
DP  - 2021 May
TI  - Elevated type I interferon responses potentiate metabolic dysfunction, 
      inflammation, and accelerated aging in mtDNA mutator mice.
LID - 10.1126/sciadv.abe7548 [doi]
LID - eabe7548
AB  - Mitochondrial dysfunction is a key driver of inflammatory responses in human 
      disease. However, it remains unclear whether alterations in mitochondria-innate 
      immune cross-talk contribute to the pathobiology of mitochondrial disorders and 
      aging. Using the polymerase gamma (POLG) mutator model of mitochondrial DNA 
      instability, we report that aberrant activation of the type I interferon (IFN-I) 
      innate immune axis potentiates immunometabolic dysfunction, reduces health span, 
      and accelerates aging in mutator mice. Mechanistically, elevated IFN-I signaling 
      suppresses activation of nuclear factor erythroid 2-related factor 2 (NRF2), 
      which increases oxidative stress, enhances proinflammatory cytokine responses, 
      and accelerates metabolic dysfunction. Ablation of IFN-I signaling attenuates 
      hyperinflammatory phenotypes by restoring NRF2 activity and reducing aerobic 
      glycolysis, which combine to lessen cardiovascular and myeloid dysfunction in 
      aged mutator mice. These findings further advance our knowledge of how 
      mitochondrial dysfunction shapes innate immune responses and provide a framework 
      for understanding mitochondria-driven immunopathology in POLG-related disorders 
      and aging.
CI  - Copyright (c) 2021 The Authors, some rights reserved; exclusive licensee American 
      Association for the Advancement of Science. No claim to original U.S. Government 
      Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 
      (CC BY-NC).
FAU - Lei, Yuanjiu
AU  - Lei Y
AUID- ORCID: 0000-0002-7486-4261
AD  - Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas 
      A&M University, Bryan, TX, USA.
FAU - Guerra Martinez, Camila
AU  - Guerra Martinez C
AUID- ORCID: 0000-0001-6116-9182
AD  - Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas 
      A&M University, Bryan, TX, USA.
FAU - Torres-Odio, Sylvia
AU  - Torres-Odio S
AUID- ORCID: 0000-0002-0008-0798
AD  - Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas 
      A&M University, Bryan, TX, USA.
FAU - Bell, Samantha L
AU  - Bell SL
AUID- ORCID: 0000-0002-5453-3203
AD  - Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas 
      A&M University, Bryan, TX, USA.
FAU - Birdwell, Christine E
AU  - Birdwell CE
AD  - Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas 
      A&M University, Bryan, TX, USA.
FAU - Bryant, Joshua D
AU  - Bryant JD
AUID- ORCID: 0000-0001-6668-1409
AD  - Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas 
      A&M University, Bryan, TX, USA.
FAU - Tong, Carl W
AU  - Tong CW
AUID- ORCID: 0000-0003-2479-2498
AD  - Department of Medical Physiology, College of Medicine, Texas A&M University, 
      Bryan, TX, USA.
FAU - Watson, Robert O
AU  - Watson RO
AUID- ORCID: 0000-0003-4976-0759
AD  - Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas 
      A&M University, Bryan, TX, USA.
FAU - West, Laura Ciaccia
AU  - West LC
AUID- ORCID: 0000-0002-8303-3582
AD  - Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas 
      A&M University, Bryan, TX, USA.
FAU - West, A Phillip
AU  - West AP
AUID- ORCID: 0000-0003-2884-6895
AD  - Department of Microbial Pathogenesis and Immunology, College of Medicine, Texas 
      A&M University, Bryan, TX, USA. awest@tamu.edu.
LA  - eng
GR  - R01 AI145287/AI/NIAID NIH HHS/United States
GR  - R01 HL145534/HL/NHLBI NIH HHS/United States
GR  - P30 ES029067/ES/NIEHS NIH HHS/United States
GR  - R01 AI125512/AI/NIAID NIH HHS/United States
GR  - R01 HL148153/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20210526
PL  - United States
TA  - Sci Adv
JT  - Science advances
JID - 101653440
RN  - 0 (DNA, Mitochondrial)
RN  - 0 (Interferon Type I)
RN  - 0 (NF-E2-Related Factor 2)
SB  - IM
CIN - Lab Anim (NY). 2021 Jul;50(7):167. PMID: 34188231
MH  - Aging/genetics/metabolism
MH  - Animals
MH  - *DNA, Mitochondrial/genetics/metabolism
MH  - Inflammation/genetics/metabolism
MH  - *Interferon Type I/metabolism
MH  - Mice
MH  - Mitochondria/genetics/metabolism
MH  - Mutation
MH  - NF-E2-Related Factor 2/genetics/metabolism
PMC - PMC8153723
EDAT- 2021/05/28 06:00
MHDA- 2022/04/16 06:00
PMCR- 2021/05/26
CRDT- 2021/05/27 05:49
PHST- 2020/09/11 00:00 [received]
PHST- 2021/04/08 00:00 [accepted]
PHST- 2021/05/27 05:49 [entrez]
PHST- 2021/05/28 06:00 [pubmed]
PHST- 2022/04/16 06:00 [medline]
PHST- 2021/05/26 00:00 [pmc-release]
AID - 7/22/eabe7548 [pii]
AID - abe7548 [pii]
AID - 10.1126/sciadv.abe7548 [doi]
PST - epublish
SO  - Sci Adv. 2021 May 26;7(22):eabe7548. doi: 10.1126/sciadv.abe7548. Print 2021 May.