Regulation of respiratory complex I assembly by FMN cofactor targeting.

Respiratory complex I plays a crucial role in the mitochondrial electron transport chain and shows promise as a therapeutic target for various human diseases. While most studies focus on inhibiting complex I at the Q-site, little is known about inhibitors targeting other sites within the complex. In this study, we demonstrate that diphenyleneiodonium (DPI), a N-site inhibitor, uniquely affects the stability of complex I by reacting with its flavin cofactor FMN. Treatment with DPI blocks the final stage of complex I assembly, leading to the complete and reversible degradation of complex I in different cellular models. Growing cells in medium lacking the FMN precursor riboflavin or knocking out the mitochondrial flavin carrier gene SLC25A32 results in a similar complex I degradation. Overall, our findings establish a direct connection between mitochondrial flavin homeostasis and complex I stability and assembly, paving the way for novel pharmacological strategies to regulate respiratory complex I.

Primary Sjögren's syndrome as independent risk factor for subclinical atherosclerosis.

OBJECTIVE: To assess the prevalence of subclinical atherosclerosis in patients with primary Sjögren's syndrome (pSS) and its possible association with clinical and analytical parameters of the disease. METHODS: In this cross-sectional study, 38 consecutive patients with pSS were compared with 38 age and sex healthy controls. Demographic variables and classic cardiovascular risk factors (CVRFs): Hypertension, dyslipidemia, diabetes mellitus, obesity, and smoking habit were assessed in both groups, and also disease-related features were collected in pSS group. The presence of subclinical atherosclerosis was assessed by carotid ultrasound, with carotid intima-media thickness (CIMT) measurement and determination of the presence of atheromatous plaques. RESULTS: Subclinical atherosclerosis presence was remarkably greater in patients with pSS than in healthy controls (OR = 4.17, 95%CI [1.27-16.54]), as well as CIMT values (0.79 ± 0.43mm vs. 0.66 ± 0.27mm; P = .02). No differences for classic CVRFs were found between both groups. An association of subclinical atherosclerosis with erythrocyte sedimentation rate (ESR) and rheumatoid factor (RF) was observed in patients with pSS. CONCLUSION: This cohort showed a greater prevalence of subclinical atherosclerosis in patients with pSS, indicating this disease as an independent risk factor for presence of early vascular damage.

Variant pathogenic prediction by locus variability: the importance of the current picture of evolution.

Accurate detection of pathogenic single nucleotide variants (SNVs) is a key challenge in whole exome and whole genome sequencing studies. To date, several in silico tools have been developed to predict deleterious variants from this type of data. However, these tools have limited power to detect new pathogenic variants, especially in non-coding regions. In this study, we evaluate the use of a new metric, the Shannon Entropy of Locus Variability (SELV), calculated as the Shannon entropy of the variant frequencies reported in genome-wide population studies at a given locus, as a new predictor of potentially pathogenic variants in non-coding nuclear and mitochondrial DNA and also in coding regions with a selective pressure other than that imposed by the genetic code, e.g splice-sites. For benchmarking, SELV was compared to predictors of pathogenicity in different genomic contexts. In nuclear non-coding DNA, SELV outperformed CDTS (AUCSELV = 0.97 in ROC curve and PR-AUCSELV = 0.96 in Precision-recall curve). For non-coding mitochondrial variants (AUCSELV = 0.98 in ROC curve and PR-AUCSELV = 1.00 in Precision-recall curve) SELV outperformed HmtVar. Moreover, SELV was compared against two state-of-the-art ensemble predictors of pathogenicity in splice-sites, ada-score, and rf-score, matching their overall performance both in ROC (AUCSELV = 0.95) and Precision-recall curves (PR-AUC = 0.97), with the advantage that SELV can be easily calculated for every position in the genome, as opposite to ada-score and rf-score. Therefore, we suggest that the information about the observed genetic variability in a locus reported from large scale population studies could improve the prioritization of SNVs in splice-sites and in non-coding regions.

Regulation and functional role of the electron transport chain supercomplexes.

Mitochondria are one of the most exhaustively investigated organelles in the cell and most attention has been paid to the components of the mitochondrial electron transport chain (ETC) in the last 100 years. The ETC collects electrons from NADH or FADH2 and transfers them through a series of electron carriers within multiprotein respiratory complexes (complex I to IV) to oxygen, therefore generating an electrochemical gradient that can be used by the F1-F0-ATP synthase (also named complex V) in the mitochondrial inner membrane to synthesize ATP. The organization and function of the ETC is a continuous source of surprises. One of the latest is the discovery that the respiratory complexes can assemble to form a variety of larger structures called super-complexes (SCs). This opened an unexpected level of complexity in this well-known and fundamental biological process. This review will focus on the current evidence for the formation of different SCs and will explore how they modulate the ETC organization according to the metabolic state. Since the field is rapidly growing, we also comment on the experimental techniques used to describe these SC and hope that this overview may inspire new technologies that will help to advance the field.

Endothelial dysfunction and subclinical atheromatosis in patients with systemic sclerosis.

OBJECTIVES: To assess subclinical vascular features in patients with systemic sclerosis (SSc) via carotid ultrasound, and flow-mediated vasodilation (FMD), as measures of cardiovascular risk (CVR). METHODS: This was a cross-sectional study of 70 patients diagnosed with SSc (diffuse or limited forms), on whom a vascular study protocol was performed to assess angiodynamic parameters measured by FMD in brachial artery and carotid ultrasound lesions: carotid intima-media thickness (CIMT) and carotid atheroma plaques (AP). Classical CVR factors were also assessed, as well as main features of SSc regarding skin and organic involvement, laboratory parameters, presence of autoantibodies and specific treatments. RESULTS: 94% of patients were women with a mean age of 50.2±12.5 years. 84% had endothelial dysfunction (ED), being severe in 49%, statistically associated with glucocorticoid (GC) treatment (OR=8.78; CI=1.52-50.78; p=0.015). CIMT was pathological in 39%, 23% had AP (none had significative haemo-dymanic stenosis). Serum vitamin D concentration (25(OH)D3) showed a protective effect on CIMT (OR=0.94; CI=0.89-0.99; p=0.025). No differences between types of SSc were obtained; neither association between SSc features and classical CVR factors. CONCLUSIONS: GC treatment has implications in CVR, despite in SSc GC doses administered are lower than in other autoimmune diseases (in our cohort even prednisone ≤10 mg daily was associated with ED). GC may be associated with an early vascular damage in these patients, which could lead to changes in FMD, ED and finally AP. On the other hand, optimum levels of 25(OH)D3 seemed to be beneficial against vascular damage.

A treat-to-target approach for gout confers renoprotective effect in patients with chronic kidney disease stage 3.

The aim of this study was to assess changes in the estimated glomerular filtration rate (eGFR) in gouty patients with chronic kidney disease (CKD) using a "treat-to-target" (T2T) approach in gout. This multicenter observational retrospective study included patients diagnosed with gout and CKD stage 3 taking xanthine oxidase inhibitors (XOIs) (allopurinol or febuxostat) for at least 12 months. All patients were treated using a T2T strategy according to national gout guidelines to achieve the target levels of serum uric acid (sUA; < 5-6 mg/dl) within 6 months of the first visit. The primary outcome was to assess changes in eGFR. The effects of independent variables were analyzed over eGFR in a linear mixed-effects (LME) model. Fifty patients with gout and CKD stage 3 treated with XOIs with a T2T strategy for 12 months were included. Eighty-two percent of the patients achieved the sUA target during the study period. The improvement seen in eGFR was higher during the first 6 months, showing a median increase of 7.54 ml/min/m2 (SE = 1.25) and trending towards stability over 12 months. For every 1 mg/dl of decrease in sUA, an improvement of 1.5 ml/min/m2 in eGFR was observed (coefficient ± SE: - 1.58 ± 0.26) (p < 0.001) with no differences between type and dosage of XOIs treatment, colchicine administration, age, sex, and smoking status. A reduction in sUA levels using a T2T approach with XOIs at an optimal dose is possible and could help conserve and improve renal function in gouty patients with CKD stage 3.