The Central Role of Biometals Maintains Oxidative Balance in the Context of Metabolic and Neurodegenerative Disorders

Abstract

Traditionally, oxidative stress as a biological aspect is defined as an imbalance between the free radical generation and antioxidant capacity of living systems. The intracellular imbalance of ions, disturbance in membrane dynamics, hypoxic conditions, and dysregulation of gene expression are all molecular pathogenic mechanisms closely associated with oxidative stress and underpin systemic changes in the body. These also include aspects such as chronic immune system activation, the impairment of cellular structure renewal, and alterations in the character of the endocrine secretion of diverse tissues. All of these mentioned features are crucial for the correct function of the various tissue types in the body. In the present review, we summarize current knowledge about the common roots of metabolic and neurodegenerative disorders induced by oxidative stress. We discuss these common roots with regard to the way that (1) the respective metal ions are involved in the maintenance of oxidative balance and (2) the metabolic and signaling disturbances of the most important biometals, such as Mg²⁺, Zn²⁺, Se²⁺, Fe²⁺, or Cu²⁺, can be considered as the central connection point between the pathogenesis of both types of disorders and oxidative stress.

Figure 1

The progression of pathological changes in adipose tissue after initial fat accumulation with a focus on participation of hypoxic condition. Lowered oxygen saturation in enlarged adipose tissue leads to hypoxic conditions. Mitochondrial dysfunction in hypoxic tissue causes alterations in the electron transport chain and thus an increase in generated ROS, which are critical for the further activation of immune cells and the development of chronic inflammation. The activation of relevant genes leads to the pathogenesis of metabolic disorders and creates the vicious cycles further empowering the pathological changes. The interconnections between the pathological processes leading to the final metabolic disorders are marked in boxes. Red arrows indicate the flow of changes and the vicious cycles between each pathological stage, together with the causative effect and the ablation of gene expression between specific grades of pathogenesis.

Figure 2

Schematic illustration demonstrating the relationship between adipocytes and immune cells in white adipose tissue with an accent on magnesium regulatory functions. (a) Normal magnesium levels preserve the standard physiological activity of the ATP-dependent Ca²⁺ pump. A low intracellular concentration of calcium keeps immune cells in an inactive state. (b) A decrease in the magnesium concentration reduces the excretion rate of calcium ions from cells via the Mg²⁺-dependent Ca²⁺ pump. Activated immune cells in adipose tissue secrete proinflammatory cytokines with inhibitory effects on adipocyte metabolism. Genes responsible for mitochondrial biogenesis (PPARγ, PGC1-α, NRF1–2, and UCP) are attenuated under proinflammatory conditions, leading to the attenuation of mitochondrial functions. Higher expression of leptin is connected to an increase in fat tissue mass caused by metabolic stagnation. Upregulation of resistin is complementary to the stimulated expression of proinflammatory cytokines. Adiponectin secretion is attenuated by proinflammatory cytokines resulting in the aggravation of glucose tolerance and the development of insulin resistance.

Figure 3

The causative mechanisms of the pathological elevation of nitrosative/oxidative species and their abilities to modify relevant proteins associated with the pathogenesis of neurodegenerative diseases. The activation of iNOS by inflammatory processes and of nNOS by Ca²⁺ influx through NMDAR leads to an increase in intracellular levels of RNS. On the other hand, ROS is generated upon mitochondrial dysfunction, and endoplasmic reticulum (ER) stress is a result of dopamine metabolism by monoamine oxidase (MAO). Hypoxic conditions and toxic compounds, such as rotenone and MPTP, are also considered as carriers of harmful effects to the physiology of the mentioned organelles. However, rotenone and MPTP also exert stimulatory effects on iNOS. Damaged and aggregated proteins create a solid base on which to create a vicious cycle by the strengthening of iNOS activity and by the deepening of mitochondrial and ER dysfunctioning.