Abnormal Iron and Lipid Metabolism Mediated Ferroptosis in Kidney Diseases and Its Therapeutic Potential

Ferroptosis is a newly identified form of regulated cell death driven by iron-dependent phospholipid peroxidation and oxidative stress. Ferroptosis has distinct biological and morphology characteristics, such as shrunken mitochondria when compared to other known regulated cell deaths. The regulation of ferroptosis includes different molecular mechanisms and multiple cellular metabolic pathways, including glutathione/glutathione peroxidase 4(GPX4) signaling pathways, which are involved in the amino acid metabolism and the activation of GPX4; iron metabolic signaling pathways, which are involved in the regulation of iron import/export and the storage/release of intracellular iron through iron-regulatory proteins (IRPs), and lipid metabolic signaling pathways, which are involved in the metabolism of unsaturated fatty acids in cell membranes. Ferroptosis plays an essential role in the pathology of various kidneys diseases, including acute kidney injury (AKI), chronic kidney disease (CKD), autosomal dominant polycystic kidney disease (ADPKD), and renal cell carcinoma (RCC). Targeting ferroptosis with its inducers/initiators and inhibitors can modulate the progression of kidney diseases in animal models. In this review, we discuss the characteristics of ferroptosis and the ferroptosis-based mechanisms, highlighting the potential role of the main ferroptosis-associated metabolic pathways in the treatment and prevention of various kidney diseases.

The Emergence of the Metabolic Signaling of the Nucleoredoxin-like Genes during Evolution

The nucleoredoxin-like genes NXNL1 and NXNL2 were identified through the biological activity of rod-derived cone viability factors (RdCVF and RdCVF2), the alternatively spliced variants produced by intron retention, that mediate signaling between rod and cone photoreceptors by stimulating glucose uptake. These therapeutic genes for inherited retinal degenerations also produce by splicing thioredoxin-like proteins that reduce oxidized cysteines in photoreceptor proteins. The first NXNL genes date from the first animal phyla. Intron retention produces an active RdCVF protein in the tentacles of Hydra vulgaris, a species without eyes. A Scallop RdCVF protein is produced by ciliated photoreceptors of the retina and binds its receptor, BSG1. In the lamprey, a descendent of early vertebrates, RdCVF metabolic signaling between rod and cones is fully established. In the mouse, the production of BSG1 by photoreceptors is regulated by cell-specific splicing inhibition. RdCVF signaling predates photoreceptors and evolved through two alternative splicing events.

Mitochondrial Heterogeneity in Metabolic Diseases

Mitochondria have distinct architectural features and biochemical functions consistent with cell-specific bioenergetic needs. However, as imaging and isolation techniques advance, heterogeneity amongst mitochondria has been observed to occur within the same cell. Moreover, mitochondrial heterogeneity is associated with functional differences in metabolic signaling, fuel utilization, and triglyceride synthesis. These phenotypic associations suggest that mitochondrial subpopulations and heterogeneity influence the risk of metabolic diseases. This review examines the current literature regarding mitochondrial heterogeneity in the pancreatic beta-cell and renal proximal tubules as they exist in the pathological and physiological states; specifically, pathological states of glucolipotoxicity, progression of type 2 diabetes, and kidney diseases. Emphasis will be placed on the benefits of balancing mitochondrial heterogeneity and how the disruption of balancing heterogeneity leads to impaired tissue function and disease onset.

Krebs Cycle Rewired: Driver of Atherosclerosis Progression?

: The tricarboxylic acid (TCA) cycle is the center of energy metabolism in eukaryotic cells and dynamically adjusted according to energy needs of cells. Macrophages are activated by inflammatory stimuli, and then two breakpoints in TCA cycle lead to the accumulation of intermediates. Atherosclerosis is a chronic inflammatory process. Here, the "non-metabolic" signaling functions of TCA cycle intermediates in the macrophage under inflammatory stimulation and the role of intermediates in the progression of atherosclerosis were discussed.

Cellular and Exosomal Regulations of Sepsis-Induced Metabolic Alterations

Sepsis is a sustained systemic inflammatory condition involving multiple organ failures caused by dysregulated immune response to infections. Sepsis induces substantial changes in energy demands at the cellular level leading to metabolic reprogramming in immune cells and stromal cells. Although sepsis-associated organ dysfunction and mortality have been partly attributed to the initial acute hyperinflammation and immunosuppression precipitated by a dysfunction in innate and adaptive immune responses, the late mortality due to metabolic dysfunction and immune paralysis currently represent the major problem in clinics. It is becoming increasingly recognized that intertissue and/or intercellular metabolic crosstalk via endocrine factors modulates maintenance of homeostasis, and pathological events in sepsis and other inflammatory diseases. Exosomes have emerged as a novel means of intercellular communication in the regulation of cellular metabolism, owing to their capacity to transfer bioactive payloads such as proteins, lipids, and nucleic acids to their target cells. Recent evidence demonstrates transfer of intact metabolic intermediates from cancer-associated fibroblasts via exosomes to modify metabolic signaling in recipient cells and promote cancer progression. Here, we review the metabolic regulation of endothelial cells and immune cells in sepsis and highlight the role of exosomes as mediators of cellular metabolic signaling in sepsis.