Mitochondrial stress activates YAP/TAZ through RhoA oxidation to promote liver injury

Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1; also known as TAZ) are the main effectors of the Hippo pathway and their dysregulation contributes to diseases in tissues including the liver. Although mitochondria are capable of transmitting signals to...

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Published in:	Cell death & disease 2024-01, Vol.15 (1), p.51-51, Article 51
Main Authors:	Kwon, Ari, Lee, Na Young, Yu, Jae-Hyun, Choi, Myeung Gi, Park, Jeongwoo, Koo, Ja Hyun
Format:	Article
Language:	eng
Subjects:	Acetaminophen Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Dephosphorylation Hepatocytes Intracellular Signaling Peptides and Proteins - metabolism Liver Liver - metabolism Mitochondria Oxidation Retrograde transport RhoA protein Signal Transduction Transcriptomics YAP-Signaling Proteins Yes-associated protein
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Summary:	Yes-associated protein (YAP) and WW domain-containing transcription regulator protein 1 (WWTR1; also known as TAZ) are the main effectors of the Hippo pathway and their dysregulation contributes to diseases in tissues including the liver. Although mitochondria are capable of transmitting signals to change transcriptomic landscape of diseased hepatocytes, such retrograde signaling and the related nuclear machinery are largely unknown. Here, we show that increased YAP activity is associated with mitochondrial stress during liver injury; and this is required for secondary inflammation, promoting hepatocyte death. Mitochondrial stress inducers robustly promoted YAP/TAZ dephosphorylation, nuclear accumulation, and target gene transcription. RNA sequencing revealed that the majority of mitochondrial stress transcripts required YAP/TAZ. Mechanistically, direct oxidation of RhoA by mitochondrial superoxide was responsible for PP2A-mediated YAP/TAZ dephosphorylation providing a novel physiological input for the Hippo pathway. Hepatocyte-specific Yap/Taz ablation suppressed acetaminophen-induced liver injury and blunted transcriptomic changes associated with the pathology. Our observations uncover unappreciated pathway of mitochondrial stress signaling and reveal YAP/TAZ activation as the mechanistic basis for liver injury progression.
ISSN:	2041-4889 2041-4889