Mitochondrial DNA and the STING pathway are required for hepatic stellate cell activation.
Hepatology
; 78(5): 1448-1461, 2023 11 01.
Article
em En
| MEDLINE
| ID: mdl-37013923
ABSTRACT
BACKGROUND AND AIMS:
TGF-ß induces multiple structural and functional changes in quiescent HSCs, including an increase in proliferation, mitochondrial mass, and matrix deposition. HSC transdifferentiation requires significant bioenergetic capacity, and it is not known how TGF-ß-mediated transcriptional upregulation is coordinated with the bioenergetic capacity of HSCs. APPROACH ANDRESULTS:
Mitochondria are key bioenergetic organelles, and here, we report that TGF-ß induces release of mitochondrial DNA (mtDNA) from healthy HSCs through voltage-dependent anion channels (VDACs), with the formation of an mtDNA-CAP on the external mitochondrial membrane. This stimulates organization of cytosolic cyclic GMP-AMP synthase (cGAS) onto the mtDNA-CAP and subsequent activation of the cGAS-STING-IRF3 pathway. TGF-ß is unable to induce conversion of HSCs from a quiescent to a transdifferentiated phenotype in the absence of mtDNA, VDAC, or stimulator of interferon genes (STING). Transdifferentiation by TGF-ß is blocked by a STING inhibitor, which also reduces liver fibrosis prophylactically and therapeutically.CONCLUSIONS:
We have identified a pathway that requires the presence of functional mitochondria for TGF-ß to mediate HSC transcriptional regulation and transdifferentiation and therefore provides a key link between bioenergetic capacity of HSCs and signals for transcriptional upregulation of genes of anabolic pathways.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
DNA Mitocondrial
/
Fator de Crescimento Transformador beta
/
Células Estreladas do Fígado
/
Proteínas de Membrana
Limite:
Humans
Idioma:
En
Revista:
Hepatology
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos