Ailesel akdeniz ateşi (FMF) tanılı hastalarda mitokondriyal stres ile ilişkili mitokondriyal derive peptidlerin rolü

Abstract

The MEFV gene responsible for familial Mediterranean fever (FMF) disease encodes the Pirin protein. Pyrin, along with proteins such as NLRP3 (NOD like receptor protein 3) and ASC (Apoptosis-associated speck-like protein) is involved in the regulation of inflammasomes, multiprotein complexes that intensify inflammatory responses. Inflammasomes provide activation of caspase-1, which causes IL-􀀔􀈕􀀃􀁄􀁑􀁇􀀃IL-18 maturation and release. It is still controversial that mitochondria contribute to the NLRP3 inflammasome and the formation of cytokines. The discovery of a number of mitochondrial derived peptides (MDP) encoded in mitochondrial DNA and associated with mitochondrial stress suggests a more complex interaction between these relationships. Humanin, one of the MDPs, has been shown to have cytoprotective effects and an inhibitory effect on NLRP3 inflammasome, IL-􀀔􀈕􀀃􀁄􀁑􀁇􀀃􀀬􀀯-18. Another MDP, MOTS-C, has been shown to have anti-inflammatory properties, decrease TNF-􀄮􀀃􀁄􀁑􀁇􀀃􀀬􀀯-6 levels and increase IL10 levels. This study, which aims to determine how Humanin and MOTS-C change in different clinical conditions (attack, non-attack, subclinical inflammation) of FMF patients, is the first study in the literature. Children with a diagnosis of FMF who applied to the pediatric rheumatology and pediatric emergency clinic were included in the study. While the patient group in the study was formed into four subgroups (remission FMF, newly diagnosed FMF, Attack FMF, FMF with subclinical inflammation), a control group was also formed for comparison. Assuming that the effect size of the difference between the groups to be examined by power analysis would be at a medium level (f = 0.3), it was calculated that 80% power could be obtained at a 95% confidence level, when at least 148 people (at least 37 people for each patient subgroup) were included in the study. Hemogram and acute phase indicators were studied from venous blood taken at admission. At the same time, serum MOTS-C, humanin, IL-􀀔􀈕􀀏􀀃􀀬􀀯-18 and IL-10 levels were analyzed from an additional 10 cc of venous blood stored at -80 degrees until the end of the study. Comparisons were made between subgroups within the patient group as well as the patient and healthy groups. In our study, we found that MOTS-c levels were significantly higher in the patient group than in the healthy group (p=0.0001). Humanin levels were found to be statistically significantly higher in the healthy group than in the patient group (p=0.024) (Table 1). Humanin was significantly lower in the attack FMF group compared to newly diagnosed FMF, FMF with subclinical inflammation, and healthy controls (p=0.0001) (Table 2). In our study, it was found that there was a statistically significant and positive moderate-strong correlation between humanin, IL-􀀔􀈕􀀏􀀃􀀬􀀯-10 and IL-18 in almost all groups (p=0.001). This study showed that Humanin from MDPs was significantly lower in FMF patients than healthy controls, and MOTS-C was significantly higher in patients compared to healthy controls. These results are a clear example of the need for further investigation of mitochondrial stress in FMF patients. Further studies revealing the relationship of FMF with mitochondrial stress and mitochondrial derived peptides may contribute to a better understanding of the pathogenesis of autoinflammatory diseases.