Regulation of Mitochondrial and Peroxisomal Metabolism in Female Obesity and Type 2 Diabetes.

Obesity and type 2 diabetes (T2D) are widespread metabolic disorders that significantly impact global health today, affecting approximately 17% of adults worldwide with obesity and 9.3% with T2D. Both conditions are closely linked to disruptions in lipid metabolism, where peroxisomes play a pivotal role.

Mitofusin-2 induced by exercise modifies lipid droplet-mitochondria communication, promoting fatty acid oxidation in male mice with NAFLD.

Background And Aim: The excessive accumulation of lipid droplets (LDs) is a defining characteristic of nonalcoholic fatty liver disease (NAFLD). The interaction between LDs and mitochondria is functionally important for lipid metabolism homeostasis. Exercise improves NAFLD, but it is not known if it has an effect on hepatic LD-mitochondria interactions.

Metabolic adaptations in severe obesity: Insights from circulating oxylipins before and after weight loss.

Background: The relationship between lipid mediators and severe obesity remains unclear. Our study investigates the impact of severe obesity on plasma concentrations of oxylipins and fatty acids and explores the consequences of weight loss.

Methods: In the clinical trial identifier NCT05554224 study, 116 patients with severe obesity and 63 overweight/obese healthy controls matched for age and sex (≈2:1) provided plasma.

Endoplasmic Reticulum Isolation: An Optimized Approach into Cells and Mouse Liver Fractionation.

The subfractionation of the endoplasmic reticulum (ER) is a widely used technique in cell biology. However, current protocols present limitations such as low yield, the use of large number of dishes, and contamination with other organelles. Here, we describe an improved method for ER subfractionation that solves other reported methods' main limitations of being time consuming and requiring less starting material.

Splice variants of mitofusin 2 shape the endoplasmic reticulum and tether it to mitochondria.

In eukaryotic cells, different organelles interact at membrane contact sites stabilized by tethers. Mitochondrial mitofusin 2 (MFN2) acts as a membrane tether that interacts with an unknown partner on the endoplasmic reticulum (ER). In this work, we identified the splice variant ERMIT2 as the ER tethering partner of MFN2.

Decreased expression of mitochondrial aminoacyl-tRNA synthetases causes downregulation of OXPHOS subunits in type 2 diabetic muscle.

Type 2 diabetes mellitus (T2D) affects millions of people worldwide and is one of the leading causes of morbidity and mortality. The skeletal muscle (SKM) is one of the most important tissues involved in maintaining glucose homeostasis and substrate oxidation, and it undergoes insulin resistance in T2D. In this study, we identify the existence of alterations in the expression of mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs) in skeletal muscle from two different forms of T2D: early-onset type 2 diabetes (YT2) (onset of the disease before 30 years of age) and the classical form of the disease (OT2).

Phospholipid Membrane Transport and Associated Diseases.

Phospholipids are the basic structure block of eukaryotic membranes, in both the outer and inner membranes, which delimit cell organelles. Phospholipids can also be damaged by oxidative stress produced by mitochondria, for instance, becoming oxidized phospholipids. These damaged phospholipids have been related to prevalent diseases such as atherosclerosis or non-alcoholic steatohepatitis (NASH) because they alter gene expression and induce cellular stress and apoptosis.

Neuregulin 4 Downregulation Induces Insulin Resistance in 3T3-L1 Adipocytes through Inflammation and Autophagic Degradation of GLUT4 Vesicles.

The adipokine Neuregulin 4 (Nrg4) protects against obesity-induced insulin resistance. Here, we analyze how the downregulation of Nrg4 influences insulin action and the underlying mechanisms in adipocytes. Validated shRNA lentiviral vectors were used to generate scramble (Scr) and Nrg4 knockdown (KD) 3T3-L1 adipocytes.

Epithelial-Mesenchymal Transition (EMT) Induced by TGF-β in Hepatocellular Carcinoma Cells Reprograms Lipid Metabolism.

(1) Background: The transforming growth factor (TGF)-β plays a dual role in liver carcinogenesis. At early stages, it inhibits cell growth and induces apoptosis. However, TGF-β expression is high in advanced stages of hepatocellular carcinoma (HCC) and cells become resistant to TGF-β induced suppressor effects, responding to this cytokine undergoing epithelial-mesenchymal transition (EMT), which contributes to cell migration and invasion.

Mitochondrial Dynamics and Liver Cancer.

Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer. Due to its rising incidence and limited therapeutic options, HCC has become a leading cause of cancer-related death worldwide, accounting for 85% of all deaths due to primary liver cancers. Standard therapy for advanced-stage HCC is based on anti-angiogenic drugs such as sorafenib and, more recently, lenvatinib and regorafenib as a second line of treatment.

Deregulation of Lipid Homeostasis: A Fa(c)t in the Development of Metabolic Diseases.

Lipids are important molecules for human health. The quantity and quality of fats consumed in the diet have important effects on the modulation of both the natural biosynthesis and degradation of lipids. There is an important number of lipid-failed associated metabolic diseases and an increasing number of studies suggesting that certain types of lipids might be beneficial to the treatment of many metabolic diseases.

Pulmonary glycogen deficiency as a new potential cause of respiratory distress syndrome.

The glycogenin knockout mouse is a model of Glycogen Storage Disease type XV. These animals show high perinatal mortality (90%) due to respiratory failure. The lungs of glycogenin-deficient embryos and P0 mice have a lower glycogen content than that of wild-type counterparts.

Macrophage mitochondrial MFN2 (mitofusin 2) links immune stress and immune response through reactive oxygen species (ROS) production.

MFN2 (mitofusin 2) is required for mitochondrial fusion and for mitochondria-endoplasmic reticulum interaction. Using myeloid-conditional KO mice models, we found that MFN2 but not MFN1 is a prerequisite for the adaptation of mitochondrial respiration to stress conditions as well as for the production of reactive oxygen species (ROS). The deficient ROS production in the absence of MFN2 impairs the induction of cytokines and nitric oxide, and is associated with dysfunctional autophagy, apoptosis, phagocytosis, and antigen processing.

Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease.

Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH).

Regulation of death receptor signaling by the autophagy protein TP53INP2.

TP53INP2 positively regulates autophagy by binding to Atg8 proteins. Here, we uncover a novel role of TP53INP2 in death-receptor signaling. TP53INP2 sensitizes cells to apoptosis induced by death receptor ligands.

SUCNR1 controls an anti-inflammatory program in macrophages to regulate the metabolic response to obesity.

Succinate is a signaling metabolite sensed extracellularly by succinate receptor 1 (SUNCR1). The accumulation of succinate in macrophages is known to activate a pro-inflammatory program; however, the contribution of SUCNR1 to macrophage phenotype and function has remained unclear. Here we found that activation of SUCNR1 had a critical role in the anti-inflammatory responses in macrophages.

The mitochondrial negative regulator MCJ is a therapeutic target for acetaminophen-induced liver injury.

Acetaminophen (APAP) is the active component of many medications used to treat pain and fever worldwide. Its overuse provokes liver injury and it is the second most common cause of liver failure. Mitochondrial dysfunction contributes to APAP-induced liver injury but the mechanism by which APAP causes hepatocyte toxicity is not completely understood.

Early-onset and classical forms of type 2 diabetes show impaired expression of genes involved in muscle branched-chain amino acids metabolism.

The molecular mechanisms responsible for the pathophysiological traits of type 2 diabetes are incompletely understood. Here we have performed transcriptomic analysis in skeletal muscle, and plasma metabolomics from subjects with classical and early-onset forms of type 2 diabetes (T2D). Focused studies were also performed in tissues from ob/ob and db/db mice.

Role of the Transforming Growth Factor-β in regulating hepatocellular carcinoma oxidative metabolism.

Transforming Growth Factor beta (TGF-β) induces tumor cell migration and invasion. However, its role in inducing metabolic reprogramming is poorly understood. Here we analyzed the metabolic profile of hepatocellular carcinoma (HCC) cells that show differences in TGF-β expression.

Critical reappraisal confirms that Mitofusin 2 is an endoplasmic reticulum-mitochondria tether.

The discovery of the multiple roles of mitochondria-endoplasmic reticulum (ER) juxtaposition in cell biology often relied upon the exploitation of Mitofusin (Mfn) 2 as an ER-mitochondria tether. However, this established Mfn2 function was recently questioned, calling for a critical re-evaluation of Mfn2's role in ER-mitochondria cross-talk. Electron microscopy and fluorescence-based probes of organelle proximity confirmed that ER-mitochondria juxtaposition was reduced by constitutive or acute Mfn2 deletion.

Mfn1 Deficiency in the Liver Protects Against Diet-Induced Insulin Resistance and Enhances the Hypoglycemic Effect of Metformin.

Mitochondrial function can be influenced by mitochondrial shape and connectivity with other cellular organelles through fusion and fission processes. Disturbances in mitochondrial architecture and mitochondrial fusion-related genes are observed in situations of type 2 diabetes and obesity, leading to a highly fissioned mitochondrial network. To directly test the effect of reduced mitochondrial fusion on hepatic metabolism, we generated mice with a liver-specific deletion of the Mfn1 gene (Mfn1LKO) and monitored their energy homeostasis, mitochondrial function, and susceptibility to diet-induced insulin resistance.

Mfn2 deficiency links age-related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway.

Mitochondrial dysfunction and accumulation of damaged mitochondria are considered major contributors to aging. However, the molecular mechanisms responsible for these mitochondrial alterations remain unknown. Here, we demonstrate that mitofusin 2 (Mfn2) plays a key role in the control of muscle mitochondrial damage.

A new quinoxaline-containing peptide induces apoptosis in cancer cells by autophagy modulation.

The synthesis of a new small library of quinoxaline-containing peptides is described. After cytotoxic evaluation in four human cancer cell lines, as well as detailed biological studies, it was found that the most active compound, RZ2, promotes the formation of acidic compartments, where it accumulates, blocking the progression of autophagy. Further disruption of the mitochondrial membrane potential and an increase in mitochondrial ROS was observed, causing cells to undergo apoptosis.