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Experiment

Tfam CLAMS
Summary Data Summary
Investigator Shadel, Gerald
Description Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell
and is packaged into several hundred higher-order structures termed nucleoids.
The abundant mtDNA-binding protein, transcription factor A mitochondrial (TFAM),
regulates nucleoid architecture, abundance, and segregation. Complete mtDNA
depletion profoundly impairs oxidative phosphorylation (OXPHOS), triggering
calcium-dependent stress signaling and adaptive metabolic responses. However,
the cellular responses to mtDNA instability, a physiologically relevant stress
observed in many human diseases and aging, remain ill-defined. Here we show that
moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral
signaling to enhance the expression of a subset of interferon-stimulated genes
(ISG). Mechanistically, we have found that aberrant mtDNA packaging promotes
escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS and
promotes STING-IRF3-dependent signaling to elevate ISG expression, potentiate
type I interferon responses, and confer broad viral resistance. Furthermore, we
demonstrate that herpesviruses induce mtDNA stress, which potentiates antiviral
signaling and type I interferon responses during infection. Our results further
demonstrate that mitochondria are central participants in innate immunity,
identify mtDNA stress as a cell-intrinsic trigger of antiviral signaling, and
suggest that cellular monitoring of mtDNA homeostasis cooperates with canonical
virus sensing mechanisms to fully license antiviral innate immunity.

Applicable research area(s): Obesity, Metabolism
Status Completed
Public Release 7/1/2018
Animal Age Measured In: week(s) post-natal (w)
Flags has-data-flagSame StrainMetadataExperiment Description
Data Analysis
TypeCount
Animals32
Experimental Conditions2
Catalog Items1
Curation Info (# flags)3
Phenotype Assays15
Phenotype Measurements480
Histology Images0
Publications0


Animals
Strain NameCommon NameFemalesMalesUnknown
C57BL/6
0
16
0
B6.Cg-Tfamtm1.1Ncdl Tg(CAG-cre/Esr1*)5Amc/J
0
16
0

Animals/Strains
Experimental Factors
 Categorical Values
Name / AbbreviationDescription

Experimental Factor: Experimental Group

 Control
This animal belongs to the control group for the experiment.
 Experiment
This animal belongs to experimental group that is homozygous for gene manipulations.

Experimental Factor: Mouse Diet

 Research Diets - D12492
Rodent Diet with 34% Fat, 60% kcal from Fat
 Teklad - 2018
2018 Teklad Global 18% Protein Rodent Diet is a fixed formula, non-autoclavable diet manufactured with high quality ingredients and designed to support gestation, lactation, and growth of rodents. 2018 does not contain alfalfa, thus lowering the...
Experimental Factor (Units)
Experimental Group
Mouse Diet
Experimental Factor Values


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