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A genetic origin for acid-base imbalance triggers the mitochondrial damage that explains the autoimmune response and drives to gastric neuroendocrine tumours.

Abstract

BACKGROUND

Type I gastric neuroendocrine tumors (gNETs) arise from hypergastrinemia in patients with autoimmune chronic atrophic gastritis. According to the classical model, the gastric H+/K+ ATPase was the causative autoantigen recognized by CD4+ T cells in chronic autoimmune scenario that secretes IL-17 and correlates with parietal cell (PC) atrophy, which drives to gastric achlorhydria and increases the risk for gastric neoplasms. However, the mechanism by which the inflammatory response correlates with PC atrophy is not clearly defined.

METHODS

Recently, we found that the ATP4Ap.R703C mutation impaired PC function and gastric acidification, which drove familial gNET. Our group constructed a knock-in mouse model for the ATP4A mutation, which has served us to better understand the relation between impaired capability to export protons across the plasma membrane of PCs and tumor progression.

RESULTS

The ATP4Ap.R703C mutation drives gastric achlorhydria, but also deregulates the acid-base balance within PCs, affecting mitochondrial biogenesis. Mitochondrial malfunction activates ROS signaling, which triggers caspase-3-mediated apoptosis of parietal cells. In addition, when gastric euchlorhydria was restored, mitochondrial function is recovered. Infection by H. pylori promotes destabilization of the mitochondria of the PCs by a mechanism similar to that described for APT4Ap.R703C carriers.

CONCLUSIONS

A genetic origin that drives mitochondria alteration would initiate the gastric chronic inflammation instead of the classical IL-17 secretion-mediated mechanism explanation. Gastric euchlorhydria restoration is suggested to be indicated for mitochondrial recover. Our results open a new window to understand gastric neoplasms formation but also the inflammatory mechanisms and autoimmune disorders conducted by genetic origin that composes a premalignant scenario.

Authors+Show Affiliations

Human Genetics Group, Spanish National Cancer Research Center (CNIO), Melchor Fernández Almagro, 3, 28029, Madrid, Spain. Network of Research on Rare Diseases (CIBERER), 28029, Madrid, Spain.Human Genetics Group, Spanish National Cancer Research Center (CNIO), Melchor Fernández Almagro, 3, 28029, Madrid, Spain. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, CEINGE-Biotecnologie Avanzate, Napoli, Italia.Department of Gastroenterology, Hospital Comarcal de Inca, Balearic Islands Health Investigation Institute (IDISBA), 07300, Majorca, Spain.Human Genetics Group, Spanish National Cancer Research Center (CNIO), Melchor Fernández Almagro, 3, 28029, Madrid, Spain. ocalvete@cnio.es. Network of Research on Rare Diseases (CIBERER), 28029, Madrid, Spain. ocalvete@cnio.es.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31250150

Citation

Benítez, Javier, et al. "A Genetic Origin for Acid-base Imbalance Triggers the Mitochondrial Damage That Explains the Autoimmune Response and Drives to Gastric Neuroendocrine Tumours." Gastric Cancer : Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 2019.
Benítez J, Marra R, Reyes J, et al. A genetic origin for acid-base imbalance triggers the mitochondrial damage that explains the autoimmune response and drives to gastric neuroendocrine tumours. Gastric Cancer. 2019.
Benítez, J., Marra, R., Reyes, J., & Calvete, O. (2019). A genetic origin for acid-base imbalance triggers the mitochondrial damage that explains the autoimmune response and drives to gastric neuroendocrine tumours. Gastric Cancer : Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, doi:10.1007/s10120-019-00982-4.
Benítez J, et al. A Genetic Origin for Acid-base Imbalance Triggers the Mitochondrial Damage That Explains the Autoimmune Response and Drives to Gastric Neuroendocrine Tumours. Gastric Cancer. 2019 Jun 27; PubMed PMID: 31250150.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A genetic origin for acid-base imbalance triggers the mitochondrial damage that explains the autoimmune response and drives to gastric neuroendocrine tumours. AU - Benítez,Javier, AU - Marra,Roberta, AU - Reyes,José, AU - Calvete,Oriol, Y1 - 2019/06/27/ PY - 2019/04/08/received PY - 2019/06/20/accepted PY - 2019/6/29/entrez PY - 2019/6/30/pubmed PY - 2019/6/30/medline JF - Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association JO - Gastric Cancer N2 - BACKGROUND: Type I gastric neuroendocrine tumors (gNETs) arise from hypergastrinemia in patients with autoimmune chronic atrophic gastritis. According to the classical model, the gastric H+/K+ ATPase was the causative autoantigen recognized by CD4+ T cells in chronic autoimmune scenario that secretes IL-17 and correlates with parietal cell (PC) atrophy, which drives to gastric achlorhydria and increases the risk for gastric neoplasms. However, the mechanism by which the inflammatory response correlates with PC atrophy is not clearly defined. METHODS: Recently, we found that the ATP4Ap.R703C mutation impaired PC function and gastric acidification, which drove familial gNET. Our group constructed a knock-in mouse model for the ATP4A mutation, which has served us to better understand the relation between impaired capability to export protons across the plasma membrane of PCs and tumor progression. RESULTS: The ATP4Ap.R703C mutation drives gastric achlorhydria, but also deregulates the acid-base balance within PCs, affecting mitochondrial biogenesis. Mitochondrial malfunction activates ROS signaling, which triggers caspase-3-mediated apoptosis of parietal cells. In addition, when gastric euchlorhydria was restored, mitochondrial function is recovered. Infection by H. pylori promotes destabilization of the mitochondria of the PCs by a mechanism similar to that described for APT4Ap.R703C carriers. CONCLUSIONS: A genetic origin that drives mitochondria alteration would initiate the gastric chronic inflammation instead of the classical IL-17 secretion-mediated mechanism explanation. Gastric euchlorhydria restoration is suggested to be indicated for mitochondrial recover. Our results open a new window to understand gastric neoplasms formation but also the inflammatory mechanisms and autoimmune disorders conducted by genetic origin that composes a premalignant scenario. SN - 1436-3305 UR - https://www.unboundmedicine.com/medline/citation/31250150/A_genetic_origin_for_acid-base_imbalance_triggers_the_mitochondrial_damage_that_explains_the_autoimmune_response_and_drives_to_gastric_neuroendocrine_tumours L2 - http://dx.doi.org/10.1007/s10120-019-00982-4 DB - PRIME DP - Unbound Medicine ER -