A noncanonical cGAS-STING pathway drives cellular and organismal aging.

Accumulation of cytosolic DNA has emerged as a hallmark of aging, inducing sterile inflammation. Stimulator of interferon genes (STING) protein translates the sensing of cytosolic DNA by cyclic-GMP-AMP synthase (cGAS) into an inflammatory response. However, the molecular mechanisms whereby cytosolic DNA-induced cGAS-STING pathway leads to aging remain poorly understood.

At last: the mitochondrial pyruvate carrier structure revealed!

Mitochondrial pyruvate carrier (MPC) inhibitors have shown promise as therapeutics for treating several chronic diseases. However, the structure of MPC and the molecular mechanisms by which it interacts with inhibitors have remained unclear, impeding rational drug design. Multiple groups have now independently resolved the structure of the MPC heterodimer.

A non-canonical cGAS-STING pathway drives cellular and organismal aging.

Unlabelled: Accumulation of cytosolic DNA has emerged as a hallmark of aging, inducing sterile inflammation. STING (Stimulator of Interferon Genes) protein translates the sensing of cytosolic DNA by cGAS (cyclic-GMP-AMP synthase) into an inflammatory response. However, the molecular mechanisms whereby cytosolic DNA-induced cGAS-STING pathway leads to aging remain poorly understood.

2-Chloro- and 2-Bromopalmitic acids inhibit mitochondrial function in airway epithelial cells.

2-Chloropalmitic acid (2-ClPA) and 2-bromopalmitic acid (2-BrPa) increase in inflammatory lung disease associated with formation of hypochlorous or hypobromous acid, and exposure to halogen gases. Moreover, these lipids may elicit cell responses that contribute to lung injury, but the mechanisms remain unclear. Here, we tested the hypothesis that 2-ClPA and 2-BrPA induce metabolic defects in airway epithelial cells by targeting mitochondria.

Metabolic dysfunction and insulin sensitizers in acute and chronic disease.

Introduction: The concept of insulin resistance has been a major topic for more than 5 decades. While there are several treatments that may impact insulin resistance, this pathology is uniquely addressed by mitochondrially directed thiazolidinedione (TZD) insulin sensitizers. Understanding of this mechanism of action and consideration of 'insulin resistance' as a consequence of metabolic inflammation allows a new paradigm for approaching chronic diseases.

Advancing mitochondrial therapeutics: Synthesis and pharmacological evaluation of pyrazole-based inhibitors targeting the mitochondrial pyruvate carrier.

Inhibition of mitochondrial pyruvate transport via the mitochondrial pyruvate carrier (MPC) has shown beneficial effects in treating metabolic diseases, certain cancers, various forms of neurodegeneration, and hair loss. These benefits arise either from the direct inhibition of mitochondrial pyruvate metabolism or from the metabolic rewiring when pyruvate entry is inhibited. However, current MPC inhibitors are either nonspecific or possess poor pharmacokinetic properties.

Momordicine-I suppresses head and neck cancer growth by modulating key metabolic pathways.

One of the hallmarks of cancer is metabolic reprogramming which controls cellular homeostasis and therapy resistance. Here, we investigated the effect of momordicine-I (M-I), a key bioactive compound from Momordica charantia (bitter melon), on metabolic pathways in human head and neck cancer (HNC) cells and a mouse HNC tumorigenicity model. We found that M-I treatment on HNC cells significantly reduced the expression of key glycolytic molecules, SLC2A1 (GLUT-1), HK1, PFKP, PDK3, PKM, and LDHA at the mRNA and protein levels.

Membrane lipid nanodomains modulate HCN pacemaker channels in nociceptor DRG neurons.

Cell membranes consist of heterogeneous lipid nanodomains that influence key cellular processes. Using FRET-based fluorescent assays and fluorescence lifetime imaging microscopy (FLIM), we find that the dimension of cholesterol-enriched ordered membrane domains (OMD) varies considerably, depending on specific cell types. Particularly, nociceptor dorsal root ganglion (DRG) neurons exhibit large OMDs.

Ketone Body Metabolism is Not Required for Improvement of Heart Failure by Ketogenic Diet in Mice.

Failing hearts increasingly metabolize ketone bodies, and enhancing ketosis improves heart failure (HF) remodeling. Circulating ketones are elevated by fasting/starvation, which is mimicked with a high-fat, low-carbohydrate "ketogenic diet" (KD). While speculated that KD improves HF through increased ketone oxidation, some evidence suggests KD paradoxically downregulates cardiac ketone oxidation despite increased ketone delivery.

Computational structural prediction and chemical inhibition of the human mitochondrial pyruvate carrier protein heterodimer complex.

The mitochondrial pyruvate carrier (MPC) plays a role in numerous diseases including neurodegeneration, metabolically dependent cancers, and the development of insulin resistance. Several previous studies in genetic mouse models or with existing inhibitors suggest that inhibition of the MPC could be used as a viable therapeutic strategy in these diseases. However, the MPC's structure is unknown, making it difficult to screen for and develop therapeutically viable inhibitors.

Loss of mitochondrial pyruvate transport initiates cardiac glycogen accumulation and heart failure.

Heart failure involves metabolic alterations including increased glycolysis despite unchanged or decreased glucose oxidation. The mitochondrial pyruvate carrier (MPC) regulates pyruvate entry into the mitochondrial matrix, and cardiac deletion of the MPC in mice causes heart failure. How MPC deletion results in heart failure is unknown.

Double Cyclization Tandem Mass for Identification and Quantification of Phosphatidylcholines Using Isobaric Six-Plex Capillary nLC-MS/MS.

Multiplexing of phosphatidylcholine analysis is hindered by a lack of appropriate derivatization. Presented here is a tagging scheme that uses a quaternary amine tag and targets the hydroxy group of the phosphate, which switches the net charge from neutral to +2. Quantitative yields were achieved from >99% reaction completion derived by dimethoxymethyl morpholinium (DMTMM) activation.

Obesity-related T cell dysfunction impairs immunosurveillance and increases cancer risk.

Obesity is a well-established risk factor for human cancer, yet the underlying mechanisms remain elusive. Immune dysfunction is commonly associated with obesity but whether compromised immune surveillance contributes to cancer susceptibility in individuals with obesity is unclear. Here we use a mouse model of diet-induced obesity to investigate tumor-infiltrating CD8  T cell responses in lean, obese, and previously obese hosts that lost weight through either dietary restriction or treatment with semaglutide.

Metabolic Drivers and Rescuers of Heart Failure.

Cardiac hypertrophy and heart failure involve a number of metabolic alterations. Human genetic mutations and murine genetic deficiency models of metabolic enzymes or transporters largely suggest that these alterations in metabolism are maladaptive and contribute to the cardiac remodeling and dysfunction. Here, we discuss insights into metabolic alterations identified in cardiac hypertrophy and failure, as well as dietary and pharmacologic therapies that counteract these metabolic alterations and have been shown to significantly improve heart failure.

Membrane Lipid Nanodomains Modulate HCN Pacemaker Channels in Nociceptor DRG Neurons.

Cell membranes consist of heterogeneous lipid nanodomains that influence key cellular processes. Using FRET-based fluorescent assays and fluorescence lifetime imaging microscopy (FLIM), we found that the dimension of cholesterol-enriched ordered membrane domains (OMD) varies considerably, depending on specific cell types. Particularly, nociceptor dorsal root ganglion (DRG) neurons exhibit large OMDs.

Hepatic pyruvate and alanine metabolism are critical and complementary for maintenance of antioxidant capacity and resistance to oxidative insult.

Objective: Mitochondrial pyruvate is a critical intermediary metabolite in gluconeogenesis, lipogenesis, and NADH production. As a result, the mitochondrial pyruvate carrier (MPC) complex has emerged as a promising therapeutic target in metabolic diseases. Clinical trials are currently underway.

Ube4A maintains metabolic homeostasis and facilitates insulin signaling in vivo.

Objective: Defining the regulators of cell metabolism and signaling is essential to design new therapeutic strategies in obesity and NAFLD/NASH. E3 ubiquitin ligases control diverse cellular functions by ubiquitination-mediated regulation of protein targets, and thus their functional aberration is associated with many diseases. The E3 ligase Ube4A has been implicated in human obesity, inflammation, and cancer.

Enhancing Hepatic MBOAT7 Expression in Mice With Nonalcoholic Steatohepatitis.

Background And Aims: Polymorphisms near the membrane bound O-acyltransferase domain containing 7 (MBOAT7) genes are associated with worsened nonalcoholic fatty liver (NASH), and nonalcoholic fatty liver disease (NAFLD)/NASH may decrease MBOAT7 expression independent of these polymorphisms. We hypothesized that enhancing MBOAT7 function would improve NASH.

Methods: Genomic and lipidomic databases were mined for MBOAT7 expression and hepatic phosphatidylinositol (PI) abundance in human NAFLD/NASH.

The Hepatic Mitochondrial Pyruvate Carrier as a Regulator of Systemic Metabolism and a Therapeutic Target for Treating Metabolic Disease.

Pyruvate sits at an important metabolic crossroads of intermediary metabolism. As a product of glycolysis in the cytosol, it must be transported into the mitochondrial matrix for the energy stored in this nutrient to be fully harnessed to generate ATP or to become the building block of new biomolecules. Given the requirement for mitochondrial import, it is not surprising that the mitochondrial pyruvate carrier (MPC) has emerged as a target for therapeutic intervention in a variety of diseases characterized by altered mitochondrial and intermediary metabolism.

Mitochondrial pyruvate carrier inhibition initiates metabolic crosstalk to stimulate branched chain amino acid catabolism.

Objective: The mitochondrial pyruvate carrier (MPC) has emerged as a therapeutic target for treating insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis (NASH). We evaluated whether MPC inhibitors (MPCi) might correct impairments in branched chain amino acid (BCAA) catabolism, which are predictive of developing diabetes and NASH.

Methods: Circulating BCAA concentrations were measured in people with NASH and type 2 diabetes, who participated in a recent randomized, placebo-controlled Phase IIB clinical trial to test the efficacy and safety of the MPCi MSDC-0602K (EMMINENCE; NCT02784444).

A DUAL MTOR/NAD+ ACTING GEROTHERAPY.

The geroscience hypothesis states that a therapy that prevents the underlying aging process should prevent multiple aging related diseases. The mTOR (mechanistic target of rapamycin)/insulin and NAD+ (nicotinamide adenine dinucleotide) pathways are two of the most validated aging pathways. Yet, it's largely unclear how they might talk to each other in aging.

STAT1 Drives the Interferon-Like Response and Aging Hallmarks in Progeria.

Hutchinson-Gilford progeria syndrome (HGPS), a devastating premature aging disease caused by the mutant lamin-A protein "progerin," features robust sterile inflammation/interferon (IFN)-like response. Targeting inflammation delays cellular and organismal HGPS phenotypes. However, specific mechanisms driving the sterile inflammation/IFN-like response and how this response causes tissue degeneration/loss in HGPS are unknown.