J Gastroenterol 2008; 43:780–788 DOI 10.1007/s00535-008-2231-4 Atrophic gastritis: deficient complex I of the respiratory chain in the mitochondria of corpus mucosal cells MARJU GRUNO 1,2 , NADEZHDA PEET 1 , ANDRES TEIN 2 , RIINA SALUPERE 3 , MEELI SIROTKINA 4 , JULIO VALLE 5 , ANTS PEETSALU 2 , and ENN K. SEPPET 1 1 Department of Pathophysiology, Centre of Molecular and Clinical Medicine, Faculty of Medicine, University of Tartu, 19 Ravila Street, 50411 Tartu, Estonia 2 Department of Surgery, Faculty of Medicine, University of Tartu, Tartu, Estonia 3 Department of Internal Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia 4 Department of Pathology, Tartu University Hospital, Tartu, Estonia 5 Department of Gastroenterology, Hospital Virgen de la Salud, Toledo, Spain Background. Mitochondrial dysfunction is one of the most characteristic properties of the cancer cell. However, it is not known whether oxidative energy metabolism has already become altered in conditions of atrophic gastritis, a precancerous state of gastric disease. The purpose of our study was to comparatively charac- terize oxidative phosphorylation (OXPHOS) in the atrophic and nonatrophic gastric corpus mucosa. Methods. Mucosal biopsies were taken from 12 patients with corpus dominant atrophic gastritis and from 12 patients with nonatrophic mucosa (controls). One part of the tissue samples was permeabilized with saponin for analysis of the function of the respiratory chain using high-resolution respirometry, and another part was used for histopathological examination. The serum level of pepsinogen I (S-PGI) was determined with a specific enzyme immunoassay (EIA). Results. Com- pared to the control group, the maximal capacity of OXPHOS in the atrophy group was almost twofold lower, the respiratory chain complex I-dependent res- piration, normalized to complex II-dependent respira- tion, was reduced, and respiratory control by ADP in the presence of succinate was increased in the atrophic corpus mucosa. In the whole cohort of the patients studied, serum S-PGI level correlated positively with complex I-dependent respiration or complex I- dependent to complex II-dependent respiration ratio. Conclusions. Corpus dominant atrophic gastritis is characterized by decreased respiratory capacity and relative deficiency of the respiratory complex I of mito- chondria in the mucosa, the latter defect probably limit- ing mitochondrial ATP production and energetic support of the secretory function of the zymogenic mucosal cells. Key words: respiratory chain, atrophy, gastritis, gastric mucosa, stomach Introduction Gastric corpus dominant atrophic gastritis, a consistent finding in pernicious anemia (PA), is a definitive risk factor for gastric cancer. 1,2 The prevalence of gastric carcinoma in PA patients is 1%–3%, and 2% of patients with gastric carcinoma have PA. 3 The mechanisms mediating the progression of atro- phic gastritis and its transition to carcinoma are unclear. It has been assumed that decreased acid secretion caused by a loss of parietal cells in the corpus mucosa predisposes to gastric cancer by several mechanisms, including impaired absorption of vitamin C and the con- stitution of the intragastric milieu allowing overgrowth of salivary and intestinal bacteria. 4 At the cellular level, increasing evidence points to the crucial role of distur- bances of energy metabolism. 5–8 Otto Warburg was the first to propose that development of cancer is asso- ciated with suppression of oxidative phosphorylation (OXPHOS) and activation of glycolysis. 9 More recent studies have related the pathophysiological role of mitochondria in cancer cell metabolism to their capabil- ity to produce reactive oxygen (ROS) and reactive nitrogen species. 10–12 Excess ROS in turn causes defects in the mitochondrial genome, thus leading to impaired OXPHOS, which not only limits ATP generation but also further promotes ROS production. 13 Recent data aim at mitochondria as key organelles in regulation of expression of the hypoxia-inducible factor-1α (HIF- 1α), which is responsible for shifting metabolism from OXPHOS to glycolysis, a characteristic change in the tumor cell. This shift is controlled by multiple means including the effects of ROS (see review 14 ) and mito- chondrial succinate metabolism. 15,16 Along with these Received: February 7, 2008 / Accepted: May 29, 2008 Reprint requests to: M. Gruno