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Abstract Wolfram syndrome is a rare genetic disease caused by mutations in the WFS1 or CISD2 gene. A primary defect in Wolfram syndrome involves poor ER Ca2+ handling, but how this disturbance leads to the disease is not known. The current study, performed in primary neurons, the most affected and disease-relevant cells, involving both Wolfram syndrome genes, explains how the disturbed ER Ca2+ handling compromises mitochondrial function and affects neuronal health. Loss of ER Ca2+ content and impaired ER-mitochondrial contact sites in the WFS1- or CISD2-deficient neurons is associated with lower IP3R-mediated Ca2+ transfer from ER to mitochondria and decreased mitochondrial Ca2+ uptake. In turn, reduced mitochondrial Ca2+ content inhibits mitochondrial ATP production leading to an increased NADH/NAD+ ratio. The resulting bioenergetic deficit and reductive stress compromise the health of the neurons. Our work also identifies pharmacological targets and compounds that restore Ca2+ homeostasis, enhance mitochondrial function and improve neuronal health.

Abstract Background Extracellular matrix (ECM) remodeling in skeletal muscle is a significant factor in the development of sarcopenia. This study aims to evaluate changes in ECM remodeling in the lumbar paravertebral muscles of sarcopenic rats using diffusion-tensor magnetic resonance imaging (DT-MRI) and compare them with histology. Methods Twenty 6-month-old female Sprague Dawley rats were randomly divided into the dexamethasone (DEX) group and the control (CON) group. Both groups underwent 3.0T MRI scanning, including Mensa, T2WI, and DT-MRI sequences. The changes in muscle fibers and extracellular matrix (ECM) of the erector spinal muscle were observed using hematoxylineosin and sirius red staining. The expressions of collagen I, III, and fibronectin in the erector spinae were detected by western blot. Pearson correlation analysis was employed to assess the correlation between MRI quantitative parameters and corresponding histopathology markers. Results The cross-sectional area and fractional anisotropy values of the erector spinae in the DEX group rats were significantly lower than those in the CON group (p

Background: Severe sarcopenia may result in severe disability. Early diagnosis is currently the key to enhancing the treatment of sarcopenia, and there is an urgent need for a highly sensitive and dependable tool to evaluate the course of early sarcopenia in clinical practice. This study aims to investigate longitudinally the early diagnosability of magnetic resonance imaging (MRI)-based fat infiltration and blood flow perfusion technology in sarcopenia progression. Methods: 48 Sprague-Dawley rats were randomly assigned into six groups that were based on different periods of dexamethasone (DEX) injection (0, 2, 4, 6, 8, 10 days). Multimodal MRI was scanned to assess muscle mass. Grip strength and swimming exhaustion time of rats were measured to assess muscle strength and function. Immunofluorescence staining for CD31 was employed to assess skeletal muscle capillary formation, and western blot was used to detect vascular endothelial growth factor-A (VEGF-A) and muscle ring finger-1 (MuRF-1) protein expression. Subsequently, we analyzed the correlation between imaging and histopathologic parameters. A receiver operating characteristic (ROC) analysis was conducted to assess the effectiveness of quantitative MRI parameters for discriminating diagnosis in both pre- and post-modeling of DEX-induced sarcopenic rats. Results: Significant differences were found in PDFF, R2* and T2 values on day 2 of DEX-induction compared to the control group, occurring prior to the MRI-CSA values and limb grip strength on day 6 of induction and swimming exhaustion time on day 8 of induction. There is a strong correlation between MRI-CSA with HE-CSA values (r = 0.67; p

Tumor necrosis factor (TNF)-α is a proinflammatory cytokine involved in the pathogenesis of sarcopenia, but its short half-life and inconsistent reproducibility limit the potential of TNF-α to be an ideal sarcopenia biomarker. Anti-TNF-α, a natural consequent autoantibody to TNF-α, is an indicator of relatively prolonged TNF-α exposure, has more stable concentrations than TNF-α and should be a better alternative as a biomarker of sarcopenia. Data from 484 participants from the I-Lan Longitudinal Aging Study were used for this study, and sarcopenia was defined by the Asian Working Group for Sarcopenia 2019 consensus. Plasma levels of anti-TNF-α were determined by a sandwich ELISA approach, and levels of TNF-α were determined by an immunoassay. Compared to nonsarcopenic participants, 43 sarcopenic participants had higher levels of anti-TNF-α (0.73 ± 0.19 vs. 0.79 ± 0.25 OD, p = 0.045). Plasma levels of anti-TNF-α were positively correlated with TNF-α (r = 0.24, p

Assessing dementia conversion in patients with mild cognitive impairment (MCI) remains challenging owing to pathological heterogeneity. While many MCI patients ultimately proceed to Alzheimer’s disease (AD), a subset of patients remain stable for various times. Our aim was to characterize the plasma metabolites of nineteen MCI patients proceeding to AD (P-MCI) and twenty-nine stable MCI (S-MCI) patients by untargeted metabolomics profiling. Alterations in the plasma metabolites between the P-MCI and S-MCI groups, as well as between the P-MCI and AD groups, were compared over the observation period. With the help of machine learning-based stratification, a 20-metabolite signature panel was identified that was associated with the presence and progression of AD. Furthermore, when the metabolic signature panel was used for classification of the three patient groups, this gave an accuracy of 73.5% using the panel. Moreover, when specifically classifying the P-MCI and S-MCI subjects, a fivefold cross-validation accuracy of 80.3% was obtained using the random forest model. Importantly, indole-3-propionic acid, a bacteria-generated metabolite from tryptophan, was identified as a predictor of AD progression, suggesting a role for gut microbiota in AD pathophysiology. Our study establishes a metabolite panel to assist in the stratification of MCI patients and to predict conversion to AD.

Cisd2 (CDGSH iron sulfur domain 2) is a pro-longevity gene that extends the lifespan and health span of mice, ameliorates age-associated structural damage and limits functional decline in multiple tissues. Non-alcoholic fatty liver disease (NAFLD), which plays an important role in age-related liver disorders, is the most common liver disease worldwide. However, no medicines that can be used to specifically and effectively treat NAFLD are currently approved for this disease. Our aim was to provide pathological and molecular evidence to show that Cisd2 protects the liver from age-related dysregulation of lipid metabolism and protein homeostasis. This study makes four major discoveries. Firstly, a persistently high level of Cisd2 protects the liver from age-related fat accumulation. Secondly, proteomics analysis revealed that Cisd2 ameliorates age-related dysregulation of lipid metabolism, including lipid biosynthesis and β-oxidation, in mitochondria and peroxisomes. Thirdly, Cisd2 attenuates aging-associated oxidative modifications of proteins. Finally, Cisd2 regulates intracellular protein homeostasis by maintaining the functionality of molecular chaperones and protein synthesis machinery. Our proteomics findings highlight Cisd2 as a novel molecular target for the development of therapies targeting fatty liver diseases, and these new therapies are likely to help prevent subsequent malignant progression to cirrhosis and hepatocellular carcinoma.

CISD2 is located within the chromosome 4q region frequently deleted in hepatocellular carcinoma (HCC). Mice with Cisd2 heterozygous deficiency develop a phenotype similar to the clinical manifestation of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Cisd2 haploinsufficiency causes a low incidence (20%) of spontaneous HCC and promotes HBV-associated and DEN-induced HCC; conversely, 2-fold overexpression of Cisd2 suppresses HCC in these models. Mechanistically, Cisd2 interacts with Serca2b and mediates its Ca2+ pump activity via modulation of Serca2b oxidative modification, which regulates ER Ca2+ uptake and maintains intracellular Ca2+ homeostasis in the hepatocyte. CISD2 haploinsufficiency disrupts calcium homeostasis, causing ER stress and subsequent NAFLD and NASH. Hemizygous deletion and decreased expression of CISD2 are detectable in a substantial fraction of human HCC specimens. These findings substantiate CISD2 as a haploinsufficient tumor suppressor and highlights Cisd2 as a drug target when developing therapies to treat NAFLD/NASH and prevent HCC.

Nonalcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), are the most common chronic liver diseases worldwide. However, drugs to treat NAFLD and NASH are an unmet clinical need. This study sought to provide evidence that Cisd2 is a molecular target for the development of treatments targeting NAFLD and NASH. Several discoveries are pinpointed. The first is that Cisd2 dosage modulates the severity of Western diet-induced (WD-induced) NAFLD. Specifically, Cisd2 haploinsufficiency accelerates NAFLD development and exacerbates progression toward NASH. Conversely, an enhanced Cisd2 copy number attenuates liver pathogenesis. Secondly, when a WD is fed to mice, transcriptomic analysis reveals that the major alterations affecting biological processes are related to inflammation, lipid metabolism, and DNA replication/repair. Thirdly, among these differentially expressed genes, the most significant changes involve Nrf2-mediated oxidative stress, cholesterol biosynthesis, and fatty acid metabolism. Finally, increased Cisd2 expression protects the liver from oxidative stress and reduces the occurrence of mitochondrial DNA deletions. Taken together, our mouse model reveals that Cisd2 plays a crucial role in protecting the liver from WD-induced damages. The development of therapeutic agents that effectively enhance Cisd2 expression is one potential approach to the treatment of WD-induced fatty liver diseases.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and is the major risk factor leading to hepatocellular carcinoma (HCC). Cisd2 haploinsufficiency in mice causes NAFLD by disrupting Ca2+ homeostasis, indicating that CISD2 is a molecular target for the treatment of NAFLD and the prevention of HCC.