Higd1a Protects Cells from Lipotoxicity under High-Fat Exposure

Li, Tong; Xian, Wenjing; Gao, Yang; Jiang, Shuai; Yu, Qihong; Zheng, Qichang; Zhang, Yong

doi:10.1155/2019/6051262

Cited by 11 publications

(9 citation statements)

References 32 publications

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“…Moreover, Myr upregulated the p53-inducible protein 1 ( TP53INP1 ) gene, which also promotes autophagy by interacting with autophagy-related protein family (ATG) [ 48 ]. The expression of SNX14, involved in the regulation of autophagy and lipid metabolism, was significantly increased by Myr [ 49 , 50 ], as well as that of hypoxia inducible gene 1 ( HIGD1A ), involved in oxidative stress and lipotoxicity protection [ 51 ]. At the same time, Myr downregulated ACACA, the rate-limiting enzyme regulating de novo fatty acid synthesis, whose increased activity has been associated with inflammation and CFTR deficiency [ 52 , 53 ].…”

Section: Resultsmentioning

confidence: 99%

“…Its gene product was recently reported to protect cells from hypoxia and from lipotoxicity related to fat oxidation impairment. Indeed, HIGD1a decreases oxygen radical production, helping to maintain a normal mitochondrial function [ 51 ]. A reduced autophagy paired with lipid accumulation because of decreased oxidation rate was already observed in CF cells and rescued by Myr [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

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Cystic Fibrosis Defective Response to Infection Involves Autophagy and Lipid Metabolism

Mingione

Ottaviano

Barcella

et al. 2020

Cells

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Cystic fibrosis (CF) is a hereditary disease, with 70% of patients developing a proteinopathy related to the deletion of phenylalanine 508. CF is associated with multiple organ dysfunction, chronic inflammation, and recurrent lung infections. CF is characterized by defective autophagy, lipid metabolism, and immune response. Intracellular lipid accumulation favors microbial infection, and autophagy deficiency impairs internalized pathogen clearance. Myriocin, an inhibitor of sphingolipid synthesis, significantly reduces inflammation, promotes microbial clearance in the lungs, and induces autophagy and lipid oxidation. RNA-seq was performed in Aspergillusfumigatus-infected and myriocin-treated CF patients’ derived monocytes and in a CF bronchial epithelial cell line. Fungal clearance was also evaluated in CF monocytes. Myriocin enhanced CF patients’ monocytes killing of A. fumigatus. CF patients’ monocytes and cell line responded to infection with a profound transcriptional change; myriocin regulates genes that are involved in inflammation, autophagy, lipid storage, and metabolism, including histones and heat shock proteins whose activity is related to the response to infection. We conclude that the regulation of sphingolipid synthesis induces a metabolism drift by promoting autophagy and lipid consumption. This process is driven by a transcriptional program that corrects part of the differences between CF and control samples, therefore ameliorating the infection response and pathogen clearance in the CF cell line and in CF peripheral blood monocytes.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cystic Fibrosis Defective Response to Infection Involves Autophagy and Lipid Metabolism

Mingione

Ottaviano

Barcella

et al. 2020

Cells

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“…HIGD-1A is induced by hypoxia in a HIF-1-dependent manner. Similarly, ROS accumulation in HepG2 cells promotes HIGD-1A expression levels by upregulating HIF-1α and PGC-1α expression levels under high-fat exposure (39). HIGD-1A inhibits the pERK/p27KIP1/retinoblastoma protein signaling pathway, which leads to cell cycle arrest (40).…”

Section: Discussionmentioning

confidence: 96%

HIGD‑1B inhibits hypoxia‑induced mitochondrial fragmentation by regulating OPA1 cleavage in cardiomyocytes

et al. 2021

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The dynamic regulation of mitochondrial morphology is key for eukaryotic cells to manage physiological challenges. Therefore, it is important to understand the molecular basis of mitochondrial dynamic regulation. The aim of the present study was to explore the role of HIG1 hypoxia inducible domain family member 1B (HIGD-1B) in hypoxia-induced mitochondrial fragmentation. Protein expression was determined via western blotting. Immunofluorescence assays were performed to detect the subcellular location of HIGD-1B. Cell Counting Kit-8 assays and flow cytometry were carried out to measure cell viability and apoptosis, respectively. Protein interactions were evaluated by co-immunoprecipitation. In the present study, it was found that HIGD-1B serves a role in cell survival by maintaining the integrity of the mitochondria under hypoxic conditions. Knockdown of HIGD-1B promoted mitochondrial fragmentation, while overexpression of HIGD-1B increased survival by preventing activation of caspase-3 and -9. HIGD-1B expression was associated with cell viability and apoptosis in cardiomyocytes. Furthermore, HIGD-1B delayed the cleavage process of optic atrophy 1 (OPA1) and stabilized mitochondrial morphology by interacting with OPA1. Collectively, the results from the present study identified a role for HIGD-1B as an inhibitor of the mitochondrial fission in cardiomyocytes.

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“…The HIGD1A protein of mammals is related to Rcf1 and Rcf2 of yeast (7). Using fluorescence microscopy, Li et al (40) have shown that knockdown of human HIGD1A in cultured cells lowers mitochondrial membrane potential, whereas overexpression of HIGD1A protects.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible gene domain 1 proteins in yeast mitochondria protect against proton leak through complex IV

Hoang

Strogolova

Mosley

et al. 2019

Journal of Biological Chemistry

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Hypoxia-inducible gene domain 1 (HIGD1) proteins are small integral membrane proteins, conserved from bacteria to humans, that associate with oxidative phosphorylation supercomplexes. Using yeast as a model organism, we have shown previously that its two HIGD1 proteins, Rcf1 and Rcf2, are required for the generation and maintenance of a normal membrane potential (ΔΨ) across the inner mitochondrial membrane (IMM). We postulated that the lower ΔΨ observed in the absence of the HIGD1 proteins may be due to decreased proton pumping by complex IV (CIV) or enhanced leak of protons across the IMM. Here we measured the ΔΨ generated by complex III (CIII) to discriminate between these possibilities. First, we found that the decreased ΔΨ observed in the absence of the HIGD1 proteins cannot be due to decreased proton pumping by CIV because CIII, operating alone, also exhibited a decreased ΔΨ when HIGD1 proteins were absent. Because CIII can neither lower its pumping stoichiometry nor transfer protons completely across the IMM, this result indicates that HIGD1 protein ablation enhances proton leak across the IMM. Second, we demonstrate that this proton leak occurs through CIV because ΔΨ generation by CIII is restored when CIV is removed from the cell. Third, the proton leak appeared to take place through an inactive population of CIV that accumulates when HIGD1 proteins are absent. We conclude that HIGD1 proteins in yeast prevent CIV inactivation, likely by preventing the loss of lipids bound within the Cox3 protein of CIV.

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Higd1a Protects Cells from Lipotoxicity under High-Fat Exposure

Cited by 11 publications

References 32 publications

Cystic Fibrosis Defective Response to Infection Involves Autophagy and Lipid Metabolism

Cystic Fibrosis Defective Response to Infection Involves Autophagy and Lipid Metabolism

HIGD‑1B inhibits hypoxia‑induced mitochondrial fragmentation by regulating OPA1 cleavage in cardiomyocytes

Hypoxia-inducible gene domain 1 proteins in yeast mitochondria protect against proton leak through complex IV

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