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Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion
BACKGROUND: Mitochondria are involved in cancer energy metabolism, although the mechanisms underlying the involvement of mitoribosomal dysfunction in hepatocellular carcinoma (HCC) remain poorly understood. Here, we investigated the effects of mitoribosomal impairment-mediated alterations on the imm...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9114962/ https://www.ncbi.nlm.nih.gov/pubmed/35580931 http://dx.doi.org/10.1136/jitc-2021-004337 |
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author | Song, Byong-Sop Moon, Ji Sun Tian, Jingwen Lee, Ho Yeop Sim, Byeong Chang Kim, Seok-Hwan Kang, Seul Gi Kim, Jung Tae Nga, Ha Thi Benfeitas, Rui Kim, Yeongmin Park, Sanghee Wolfe, Robert R. Eun, Hyuk Soo Shong, Minho Lee, Sunjae Kim, Il-Young Yi, Hyon-Seung |
author_facet | Song, Byong-Sop Moon, Ji Sun Tian, Jingwen Lee, Ho Yeop Sim, Byeong Chang Kim, Seok-Hwan Kang, Seul Gi Kim, Jung Tae Nga, Ha Thi Benfeitas, Rui Kim, Yeongmin Park, Sanghee Wolfe, Robert R. Eun, Hyuk Soo Shong, Minho Lee, Sunjae Kim, Il-Young Yi, Hyon-Seung |
author_sort | Song, Byong-Sop |
collection | PubMed |
description | BACKGROUND: Mitochondria are involved in cancer energy metabolism, although the mechanisms underlying the involvement of mitoribosomal dysfunction in hepatocellular carcinoma (HCC) remain poorly understood. Here, we investigated the effects of mitoribosomal impairment-mediated alterations on the immunometabolic characteristics of liver cancer. METHODS: We used a mouse model of HCC, liver tissues from patients with HCC, and datasets from The Cancer Genome Atlas (TCGA) to elucidate the relationship between mitoribosomal proteins (MRPs) and HCC. In a mouse model, we selectively disrupted expression of the mitochondrial ribosomal protein CR6-interacting factor 1 (CRIF1) in hepatocytes to determine the impact of hepatocyte-specific impairment of mitoribosomal function on liver cancer progression. The metabolism and immunophenotype of liver cancer was assessed by glucose flux assays and flow cytometry, respectively. RESULTS: Single-cell RNA-seq analysis of tumor tissue and TCGA HCC transcriptome analysis identified mitochondrial defects associated with high-MRP expression and poor survival outcomes. In the mouse model, hepatocyte-specific disruption of the mitochondrial ribosomal protein CRIF1 revealed the impact of mitoribosomal dysfunction on liver cancer progression. Crif1 deficiency promoted programmed cell death protein 1 expression by immune cells in the hepatic tumor microenvironment. A [U-(13)C(6)]-glucose tracer demonstrated enhanced glucose entry into the tricarboxylic acid cycle and lactate production in mice with mitoribosomal defects during cancer progression. Mice with hepatic mitoribosomal defects also exhibited enhanced progression of liver cancer accompanied by highly exhausted tumor-infiltrating T cells. Crif1 deficiency induced an environment unfavorable to T cells, leading to exhaustion of T cells via elevation of reactive oxygen species and lactate production. CONCLUSIONS: Hepatic mitoribosomal defects promote glucose partitioning toward glycolytic flux and lactate synthesis, leading to T cell exhaustion and cancer progression. Overall, the results suggest a distinct role for mitoribosomes in regulating the immunometabolic microenvironment during HCC progression. |
format | Online Article Text |
id | pubmed-9114962 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-91149622022-06-04 Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion Song, Byong-Sop Moon, Ji Sun Tian, Jingwen Lee, Ho Yeop Sim, Byeong Chang Kim, Seok-Hwan Kang, Seul Gi Kim, Jung Tae Nga, Ha Thi Benfeitas, Rui Kim, Yeongmin Park, Sanghee Wolfe, Robert R. Eun, Hyuk Soo Shong, Minho Lee, Sunjae Kim, Il-Young Yi, Hyon-Seung J Immunother Cancer Basic Tumor Immunology BACKGROUND: Mitochondria are involved in cancer energy metabolism, although the mechanisms underlying the involvement of mitoribosomal dysfunction in hepatocellular carcinoma (HCC) remain poorly understood. Here, we investigated the effects of mitoribosomal impairment-mediated alterations on the immunometabolic characteristics of liver cancer. METHODS: We used a mouse model of HCC, liver tissues from patients with HCC, and datasets from The Cancer Genome Atlas (TCGA) to elucidate the relationship between mitoribosomal proteins (MRPs) and HCC. In a mouse model, we selectively disrupted expression of the mitochondrial ribosomal protein CR6-interacting factor 1 (CRIF1) in hepatocytes to determine the impact of hepatocyte-specific impairment of mitoribosomal function on liver cancer progression. The metabolism and immunophenotype of liver cancer was assessed by glucose flux assays and flow cytometry, respectively. RESULTS: Single-cell RNA-seq analysis of tumor tissue and TCGA HCC transcriptome analysis identified mitochondrial defects associated with high-MRP expression and poor survival outcomes. In the mouse model, hepatocyte-specific disruption of the mitochondrial ribosomal protein CRIF1 revealed the impact of mitoribosomal dysfunction on liver cancer progression. Crif1 deficiency promoted programmed cell death protein 1 expression by immune cells in the hepatic tumor microenvironment. A [U-(13)C(6)]-glucose tracer demonstrated enhanced glucose entry into the tricarboxylic acid cycle and lactate production in mice with mitoribosomal defects during cancer progression. Mice with hepatic mitoribosomal defects also exhibited enhanced progression of liver cancer accompanied by highly exhausted tumor-infiltrating T cells. Crif1 deficiency induced an environment unfavorable to T cells, leading to exhaustion of T cells via elevation of reactive oxygen species and lactate production. CONCLUSIONS: Hepatic mitoribosomal defects promote glucose partitioning toward glycolytic flux and lactate synthesis, leading to T cell exhaustion and cancer progression. Overall, the results suggest a distinct role for mitoribosomes in regulating the immunometabolic microenvironment during HCC progression. BMJ Publishing Group 2022-05-16 /pmc/articles/PMC9114962/ /pubmed/35580931 http://dx.doi.org/10.1136/jitc-2021-004337 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Basic Tumor Immunology Song, Byong-Sop Moon, Ji Sun Tian, Jingwen Lee, Ho Yeop Sim, Byeong Chang Kim, Seok-Hwan Kang, Seul Gi Kim, Jung Tae Nga, Ha Thi Benfeitas, Rui Kim, Yeongmin Park, Sanghee Wolfe, Robert R. Eun, Hyuk Soo Shong, Minho Lee, Sunjae Kim, Il-Young Yi, Hyon-Seung Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion |
title | Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion |
title_full | Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion |
title_fullStr | Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion |
title_full_unstemmed | Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion |
title_short | Mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and T cell exhaustion |
title_sort | mitoribosomal defects aggravate liver cancer via aberrant glycolytic flux and t cell exhaustion |
topic | Basic Tumor Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9114962/ https://www.ncbi.nlm.nih.gov/pubmed/35580931 http://dx.doi.org/10.1136/jitc-2021-004337 |
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