Targeting calcium-mediated inter-organellar crosstalk in cardiac diseases.

Introduction: Abnormal calcium signaling between organelles such as the sarcoplasmic reticulum (SR), mitochondria and lysosomes is a key feature of heart diseases. Calcium serves as a secondary messenger mediating inter-organellar crosstalk, essential for maintaining the cardiomyocyte function.

Areas Covered: This article examines the available literature related to calcium channels and transporters involved in inter-organellar calcium signaling.

The Role of Palmitoleic Acid in Regulating Hepatic Gluconeogenesis through SIRT3 in Obese Mice.

Hepatic gluconeogenesis is a crucial process to maintain glucose level during starvation. However, unabated glucose production in diabetic patients is a major contributor to hyperglycemia. Palmitoleic acid is a monounsaturated fatty acid (16:1n7) that is available from dietary sources.

Temporal and spatially controlled APP transgene expression using Cre-dependent alleles.

Although a large number of mouse models have been made to study Alzheimer's disease, only a handful allow experimental control over the location or timing of the protein being used to drive pathology. Other fields have used the Cre and the tamoxifen-inducible CreER driver lines to achieve precise spatial and temporal control over gene deletion and transgene expression, yet these tools have not been widely used in studies of neurodegeneration. Here, we describe two strategies for harnessing the wide range of Cre and CreER driver lines to control expression of disease-associated amyloid precursor protein (APP) in modeling Alzheimer's amyloid pathology.

Localized glucose import, glycolytic processing, and mitochondria generate a focused ATP burst to power basement-membrane invasion.

Invasive cells use transient, energy-consuming protrusions to breach basement membrane (BM) barriers. Using the ATP sensor PercevalHR during anchor cell (AC) invasion in Caenorhabditis elegans, we show that BM invasion is accompanied by an ATP burst from mitochondria at the invasive front. RNAi screening and visualization of a glucose biosensor identified two glucose transporters, FGT-1 and FGT-2, which bathe invasive front mitochondria with glucose and facilitate the ATP burst to form protrusions.

Fly Cell Atlas: A single-nucleus transcriptomic atlas of the adult fruit fly.

For more than 100 years, the fruit fly has been one of the most studied model organisms. Here, we present a single-cell atlas of the adult fly, Tabula , that includes 580,000 nuclei from 15 individually dissected sexed tissues as well as the entire head and body, annotated to >250 distinct cell types. We provide an in-depth analysis of cell type-related gene signatures and transcription factor markers, as well as sexual dimorphism, across the whole animal.

Imaging-Based Screening of Deubiquitinating Proteases Identifies Otubain-1 as a Stabilizer of c-MYC.

The ubiquitin-proteasome pathway precisely controls the turnover of transcription factors in the nucleus, playing an important role in maintaining appropriate quantities of these regulatory proteins. The transcription factor c-MYC is essential for normal development and is a critical cancer driver. Despite being highly expressed in several tissues and malignancies, the c-MYC protein is also continuously targeted by the ubiquitin-proteasome pathway, which can either facilitate or inhibit c-MYC degradation.

Atomic structure of the Leishmania spp. Hsp100 N-domain.

Hsp100 is an ATP-dependent unfoldase that promotes protein disaggregation or facilitates the unfolding of aggregation-prone polypeptides marked for degradation. Recently, new Hsp100 functions are emerging. In Plasmodium, an Hsp100 drives malaria protein export, presenting a novel drug target.

Inhibition of the Anti-Apoptotic Bcl-2 Family by BH3 Mimetics Sensitize the Mitochondrial Permeability Transition Pore Through Bax and Bak.

Mitochondrial permeability transition pore (MPTP)-dependent necrosis contributes to numerous pathologies in the heart, brain, and skeletal muscle. The MPTP is a non-selective pore in the inner mitochondrial membrane that is triggered by high levels of matrix Ca, and sustained opening leads to mitochondrial dysfunction. Although the MPTP is defined by an increase in inner mitochondrial membrane permeability, the expression of pro-apoptotic Bcl-2 family members, Bax and Bak localization to the outer mitochondrial membrane is required for MPTP-dependent mitochondrial dysfunction and subsequent necrotic cell death.

Hematopoiesis under telomere attrition at the single-cell resolution.

The molecular mechanisms that drive hematopoietic stem cell functional decline under conditions of telomere shortening are not completely understood. In light of recent advances in single-cell technologies, we sought to redefine the transcriptional and epigenetic landscape of mouse and human hematopoietic stem cells under telomere attrition, as induced by pathogenic germline variants in telomerase complex genes. Here, we show that telomere attrition maintains hematopoietic stem cells under persistent metabolic activation and differentiation towards the megakaryocytic lineage through the cell-intrinsic upregulation of the innate immune signaling response, which directly compromises hematopoietic stem cells' self-renewal capabilities and eventually leads to their exhaustion.

Altered Chromatin States Drive Cryptic Transcription in Aging Mammalian Stem Cells.

A repressive chromatin state featuring trimethylated lysine 36 on histone H3 (H3K36me3) and DNA methylation suppresses cryptic transcription in embryonic stem cells. Cryptic transcription is elevated with age in yeast and nematodes, and reducing it extends yeast lifespan, though whether this occurs in mammals is unknown. We show that cryptic transcription is elevated in aged mammalian stem cells, including murine hematopoietic stem cells (mHSCs) and neural stem cells (NSCs) and human mesenchymal stem cells (hMSCs).

Retinal patterns and the cellular repertoire of neuropsin (Opn5) retinal ganglion cells.

Obtaining a parts list of the sensory components of the retina is vital to understand the effects of light in behavior, health, and disease. Rods, cones, and intrinsically photosensitive retinal ganglion cells (ipRGCs) are the best described photoreceptors in the mammalian retina, but recent functional roles have been proposed for retinal neuropsin (Opn5)-an atypical opsin. However, little is known about the pattern of Opn5 expression in the retina.

Role of FoxO transcription factors in aging and age-related metabolic and neurodegenerative diseases.

Aging happens to all of us as we live. Thanks to the improved living standard and discovery of life-saving medicines, our life expectancy has increased substantially across the world in the past century. However, the rise in lifespan leads to unprecedented increases in both the number and the percentage of individuals 65 years and older, accompanied by the increased incidences of age-related diseases such as type 2 diabetes mellitus and Alzheimer's disease.

Pathogenic tau accelerates aging-associated activation of transposable elements in the mouse central nervous system.

Transposable elements comprise almost half of the mammalian genome. A growing body of evidence suggests that transposable element dysregulation accompanies brain aging and neurodegenerative disorders, and that transposable element activation is neurotoxic. Recent studies have identified links between pathogenic forms of tau, a protein that accumulates in Alzheimer's disease and related "tauopathies," and transposable element-induced neurotoxicity.

Host and microbiota metabolic signals in aging and longevity.

Aging is an inevitable biochemical process that adversely affects personal health and poses ever-increasing challenges to society. Recent research has revealed the crucial role of metabolism in regulating aging and longevity. During diverse metabolic processes, the host organism and their symbiotic partners-the microbiota-produce thousands of chemical products (metabolites).

Fluorescent Probes and Mass Spectrometry-Based Methods to Quantify Thiols in Biological Systems.

Fluorescent probes and mass spectrometry are the two most popular and complementary methods to quantify thiols in biological systems. In this review, we focus on the widely used and commercially available methods to detect and quantify thiols in living cells and the general approaches applied in mass spectrometry-based thiol quantification. We hope that this review can serve as a general guide for redox biologists who are interested in thiol species.

Alpha-single chains of collagen type VI inhibit the fibrogenic effects of triple helical collagen VI in hepatic stellate cells.

The interaction of extracellular matrix (ECM) components with hepatic stellate cells (HSCs) is thought to perpetuate fibrosis by stimulating signaling pathways that drive HSC activation, survival and proliferation. Consequently, disrupting the interaction between ECM and HSCs is considered a therapeutical avenue although respective targets and underlying mechanisms remain to be established. Here we have interrogated the interaction between type VI collagen (CVI) and HSCs based on the observation that CVI is 10-fold upregulated during fibrosis, closely associates with HSCs in vivo and promotes cell proliferation and cell survival in cancer cell lines.

The exploration of N6-deoxyadenosine methylation in mammalian genomes.

N-methyladenine (N-mA, mdA, or 6mA), a prevalent DNA modification in prokaryotes, has recently been identified in higher eukaryotes, including mammals. Although 6mA has been well-studied in prokaryotes, the function and regulatory mechanism of 6mA in eukaryotes are still poorly understood. Recent studies indicate that 6mA can serve as an epigenetic mark and play critical roles in various biological processes, from transposable-element suppression to environmental stress response.

Gut cytokines modulate olfaction through metabolic reprogramming of glia.

Infection-induced aversion against enteropathogens is a conserved sickness behaviour that can promote host survival. The aetiology of this behaviour remains poorly understood, but studies in Drosophila have linked olfactory and gustatory perception to avoidance behaviours against toxic microorganisms. Whether and how enteric infections directly influence sensory perception to induce or modulate such behaviours remains unknown.

Glial-Specific Deletion of Med12 Results in Rapid Hearing Loss via Degradation of the Stria Vascularis.

Mediator protein complex subunit 12 (Med12) is a core component of the basal transcriptional apparatus and plays a critical role in the development of many tissues. Mutations in Med12 are associated with X-linked intellectual disability syndromes and hearing loss; however, its role in nervous system function remains undefined. Here, we show that temporal conditional deletion of Med12 in astrocytes in the adult CNS results in region-specific alterations in astrocyte morphology.

FoxO3 deficiency in cortical astrocytes leads to impaired lipid metabolism and aggravated amyloid pathology.

The rise of life expectancy of the human population is accompanied by the drastic increases of age-associated diseases, in particular Alzheimer's disease (AD), and underscores the need to understand how aging influences AD development. The Forkhead box O transcription factor 3 (FoxO3) is known to mediate aging and longevity downstream of insulin/insulin-like growth factor signaling across species. However, its function in the adult brain under physiological and pathological conditions is less understood.

A quantitative yeast aging proteomics analysis reveals novel aging regulators.

Calorie restriction (CR) is the most robust longevity intervention, extending lifespan from yeast to mammals. Numerous conserved pathways regulating aging and mediating CR have been identified; however, the overall proteomic changes during these conditions remain largely unexplored. We compared proteomes between young and replicatively aged yeast cells under normal and CR conditions using the Stable-Isotope Labeling by Amino acids in Cell culture (SILAC) quantitative proteomics and discovered distinct signatures in the aging proteome.

Fructose Causes Liver Damage, Polyploidy, and Dysplasia in the Setting of Short Telomeres and p53 Loss.

Studies in humans and model systems have established an important role of short telomeres in predisposing to liver fibrosis through pathways that are incompletely understood. Recent studies have shown that telomere dysfunction impairs cellular metabolism, but whether and how these metabolic alterations contribute to liver fibrosis is not well understood. Here, we investigated whether short telomeres change the hepatic response to metabolic stress induced by fructose, a sugar that is highly implicated in non-alcoholic fatty liver disease.

Phosphorylation-Dependent Interactome of Ryanodine Receptor Type 2 in the Heart.

Hyperphosphorylation of the calcium release channel/ryanodine receptor type 2 (RyR2) at serine 2814 (S2814) is associated with multiple cardiac diseases including atrial fibrillation and heart failure. Despite recent advances, the molecular mechanisms driving pathological changes associated with RyR2 S2814 phosphorylation are still not well understood. Using affinity-purification coupled to mass spectrometry (AP-MS), we investigated the RyR2 interactome in ventricles from wild-type (WT) mice and two S2814 knock-in mutants: the unphosphorylated alanine mutant (S2814A) and hyperphosphorylated mimic aspartic acid mutant (S2814D).