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Subcellular fraction kidney proteomics in MGME1 knockout mice

ABSTRACT: Metabolic dysregulation can lead to inflammatory responses. Imbalanced nucleotide synthesis triggers the release of mitochondrial DNA (mtDNA) to the cytosol and an innate immune response by cGAS-STING signaling. However, how nucleotide deficiency drives mtDNA dependent inflammation has not been elucidated. Here, we show that nucleotide imbalance leads to an increased misincorporation of ribonucleotides into mtDNA during age-dependent renal inflammation in a mouse model lacking the mitochondrial exonuclease MGME1 and upon inhibition of pyrimidine synthesis in cells lacking the mitochondrial i-AAA protease YME1L. Similarly, reduced deoxyribonucleotide synthesis increases ribonucleotide content of mtDNA in cell cycle-arrested senescent cells. This leads to mtDNA release into the cytosol, cGAS-STING activation and the mtDNA-dependent senescence-associated secretory phenotype (SASP), which can be suppressed by exogenously added deoxyribonucleotides. Our results explain age- and mtDNA-dependent inflammatory responses by imbalanced nucleotide metabolism and highlight the sensitivity of mtDNA to aberrant ribonucleotide incorporation.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Kidney

SUBMITTER: Hendrik Nolte

LAB HEAD: Thomas Langer

PROVIDER: PXD053639 | Pride | 2025-07-25

REPOSITORIES: Pride

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			Action	DRS
	0255_RESULTS.zip	Other
	20231116_TT_TC_TL_EC_Perf15cm_30SPD_0255_WBePTxncEGd2_001_S2-A1_1_3002.d.zip	Other
	20231116_TT_TC_TL_EC_Perf15cm_30SPD_0255_WBePTxncEGd2_002_S2-A2_1_3003.d.zip	Other
	20231116_TT_TC_TL_EC_Perf15cm_30SPD_0255_WBePTxncEGd2_003_S2-A3_1_3004.d.zip	Other
	20231116_TT_TC_TL_EC_Perf15cm_30SPD_0255_WBePTxncEGd2_004_S2-A4_1_3005.d.zip	Other

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Project description:The goal of this analysis was to utilize microarray profiling to identify basal alterations in gene expression in response to TFAM depletion and mtDNA stress. 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, TFAM (transcription factor A,mitochondrial), regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined. Here we show that moderate mtDNA stress elicited by TFAM deficiency engages cytosolic antiviral signalling to enhance the expression of a subset of interferon-stimulated genes. Mechanistically, we find that aberrant mtDNA packaging promotes escape of mtDNA into the cytosol, where it engages the DNA sensor cGAS (also known as MB21D1) and promotes STING (also known as TMEM173)–IRF3-dependent signalling to elevate interferon-stimulated gene expression, potentiate type I interferon responses and confer broad viral resistance. Furthermore, we demonstrate that herpesviruses induce mtDNA stress, which enhances antiviral signalling 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 engage antiviral innate immunity. Murine embryonic fibroblasts were isolated from wild-type or Tfam+/- E13.5 littermate embryos. RNA from passage-matched wild-type and Tfam+/- MEF lines was extracted in duplicate and hybridized onto Affymetrix microarrays. Four arrays were performed in total with two technical replicates per genotype.

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Subcellular fraction kidney proteomics in MGME1 knockout mice

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