Your browser doesn't support javascript.
loading
Sumoylation of methionine adenosyltransferase alpha 1 promotes mitochondrial dysfunction in alcohol-associated liver disease.
Floris, Andrea; Chandla, Swati; Lim, Youngyi; Barbier-Torres, Lucia; Seth, Karina; Khangholi, Arash; Li, Tony W H; Robison, Aaron; Murray, Ben J; Lee, Sion; Matsuda, Michitaka; Murali, Ramachandran; Tomasi, Maria Lauda; Lu, Shelly C.
Afiliación
  • Floris A; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Chandla S; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Lim Y; Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Barbier-Torres L; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Seth K; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Khangholi A; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Li TWH; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Robison A; Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Murray BJ; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Lee S; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Matsuda M; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Murali R; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Tomasi ML; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
  • Lu SC; Department of Medicine, Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Hepatology ; 80(1): 102-118, 2024 Jul 01.
Article en En | MEDLINE | ID: mdl-38100286
ABSTRACT
BACKGROUND AND

AIMS:

Methionine adenosyltransferase alpha1 (MATα1) is responsible for the biosynthesis of S-adenosylmethionine in normal liver. Alcohol consumption enhances MATα1 interaction with peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), which blocks MATα1 mitochondrial targeting, resulting in lower mitochondrial MATα1 content and mitochondrial dysfunction in alcohol-associated liver disease (ALD) in part through upregulation of cytochrome P450 2E1. Conversely, alcohol intake enhances SUMOylation, which enhances cytochrome P450 2E1 expression. MATα1 has potential SUMOylation sites, but whether MATα1 is regulated by SUMOylation in ALD is unknown. Here, we investigated if MATα1 is regulated by SUMOylation and, if so, how it impacts mitochondrial function in ALD. APPROACH AND

RESULTS:

Proteomics profiling revealed hyper-SUMOylation of MATα1, and prediction software identified lysine 48 (K48) as the potential SUMOylation site in mice (K47 in humans). Experiments with primary hepatocytes, mouse, and human livers revealed that SUMOylation of MAT1α by SUMO2 depleted mitochondrial MATα1. Furthermore, mutation of MATα1 K48 prevented ethanol-induced mitochondrial membrane depolarization, MATα1 depletion, and triglyceride accumulation. Additionally, CRISPR/CRISPR associated protein 9 gene editing of MATα1 at K48 hindered ethanol-induced MATα1-PIN1 interaction, degradation, and phosphorylation of MATα1 in vitro. In vivo, CRISPR/CRISPR associated protein 9 MATα1 K48 gene-edited mice were protected from ethanol-induced fat accumulation, liver injury, MATα1-PIN1 interaction, mitochondrial MATα1 depletion, mitochondrial dysfunction, and low S-adenosylmethionine levels.

CONCLUSIONS:

Taken together, our findings demonstrate an essential role for SUMOylation of MATα1 K48 for interaction with PIN1 in ALD. Preventing MATα1 K48 SUMOylation may represent a potential treatment strategy for ALD.
Asunto(s)
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sumoilación / Hepatopatías Alcohólicas / Metionina Adenosiltransferasa Límite: Animals / Humans / Male Idioma: En Revista: Hepatology Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sumoilación / Hepatopatías Alcohólicas / Metionina Adenosiltransferasa Límite: Animals / Humans / Male Idioma: En Revista: Hepatology Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos