Mitochondrial general control of amino acid synthesis 5 like 1 promotes nonalcoholic steatohepatitis development through ferroptosis‐induced formation of neutrophil extracellular traps

Abstract

Background Mitochondria play central roles in metabolic diseases including nonalcoholic steatohepatitis (NASH). However, how mitochondria regulate NASH progression remains largely unknown. Our previous findings demonstrate that mitochondrial general control of amino acid synthesis 5 like 1 (GCN5L1) is associated with mitochondrial metabolism. Nevertheless, the roles of GCN5L1 in NASH are unclear. Aims and methods The GCN5L1 expression was detected in the fatty livers of NASH patients and animals. Hepatocyte‐specific GCN5L1 deficiency or overexpression mice were used to induce NASH models by feeding with a high‐fat/high‐cholesterol or methionine‐choline deficient diet. The molecular mechanisms underlying GCN5L1‐regulated NASH were further explored and verified in mice. Results and conclusions GCN5L1 expression was increased in NASH patients. Upregulated GCN5L1 level was also illustrated in NASH mice. Mice with hepatocyte‐specific GCN5L1 conditional knockout improved the inflammatory response compared to GCN5L1flox/flox mice. However, overexpression of mitochondrial GCN5L1 augmented the inflammatory response. Mechanically, GCN5L1 acetylated CypD and enhanced its binding with ATP5B, which induced the opening of mitochondrial permeability transition pores and the release of mitochondrial ROS into the cytoplasm. The increased ROS promoted ferroptosis of hepatocytes and induced accumulation of high mobility group box 1 in the microenvironment, which recruited neutrophils and induced the generation of neutrophil extracellular traps (NETs). NETs block impaired GCN5L1‐induced NASH progression. Furthermore, the upregulation of GCN5L1 in NASH was contributed by lipid overload‐induced endoplasmic reticulum stress. Together, mitochondrial GCN5L1 has a vital function in promoting NASH progression by regulating oxidative metabolism and the hepatic inflammatory microenvironment. Thus, GCN5L1 might be a potential intervention target in NASH treatment.

The Interplay between Ferroptosis and Neuroinflammation in Central Neurological Disorders

“…Furthermore, both inflammatory cells and ferroptotic cells can release hypermigratory histone box 1 (HMGB1), a protein that plays a crucial role in neutrophil recruitment [234]. Based on the aforementioned discoveries, we propose several hypotheses: In certain central nervous system disorders, such as degenerative diseases and acute-phase conditions like trauma, there may exist a detrimental cycle involving intracerebral nerve cells, peripheral neutrophils, and intracerebral nerve cells.…”

Targeting epigenetic and posttranslational modifications regulating ferroptosis for the treatment of diseases

“…GCN5L1 acetylated CypD and enhanced its binding with ATP5B, resulting in mitochondrial ROS into the cytoplasm, which promotes ferroptosis of hepatocytes and induces accumulation of high mobility group box 1 in the microenvironment, thereby inducing the generation of NETs. 462 Liver IRI Ubiquitination GPX4 TMEM16A interacts with GPX4 to induce its ubiquitination and degradation, thereby enhancing ferroptosis. TMEM16A deficiency alleviates hepatic IRI via suppressing GPX4-mediated ferroptosis.…”

“…GCN5L1 acetylates CypD to enhance its binding to ATP5B, resulting in the release of mitochondrial ROS (mtROS) into the cytoplasm, which promotes ferroptosis in hepatocytes and induces the accumulation of high mobility group box 1 in the microenvironment, thereby inducing the formation of neutrophil extracellular traps (NETs). 462 …”