Neuronal Redox-Imbalance in Rett Syndrome Affects Mitochondria as Well as Cytosol, and Is Accompanied by Intensified Mitochondrial O2 Consumption and ROS Release

Abstract

Rett syndrome (RTT), an X chromosome-linked neurodevelopmental disorder affecting almost exclusively females, is associated with various mitochondrial alterations. Mitochondria are swollen, show altered respiratory rates, and their inner membrane is leaking protons. To advance the understanding of these disturbances and clarify their link to redox impairment and oxidative stress, we assessed mitochondrial respiration in defined brain regions and cardiac tissue of male wildtype (WT) and MeCP2-deficient ( Mecp2 -/y ) mice. Also, we quantified for the first time neuronal redox-balance with subcellular resolution in cytosol and mitochondrial matrix. Quantitative roGFP1 redox imaging revealed more oxidized conditions in the cytosol of Mecp2 -/y hippocampal neurons than in WT neurons. Furthermore, cytosol and mitochondria of Mecp2 -/y neurons showed exaggerated redox-responses to hypoxia and cell-endogenous reactive oxygen species (ROS) formation. Biochemical analyzes exclude disease-related increases in mitochondrial mass in Mecp2 -/y hippocampus and cortex. Protein levels of complex I core constituents were slightly lower in Mecp2 -/y hippocampus and cortex than in WT; those of complex V were lower in Mecp2 -/y cortex. Respiratory supercomplex-formation did not differ among genotypes. Yet, supplied with the complex II substrate succinate, mitochondria of Mecp2 -/y cortex and hippocampus consumed more O 2 than WT. Furthermore, mitochondria from Mecp2 -/y hippocampus and cortex mediated an enhanced oxidative burden. In conclusion, we further advanced the molecular understanding of mitochondrial dysfunction in RTT. Intensified mitochondrial O 2 consumption, increased mitochondrial ROS generation and disturbed redox balance in mitochondria and cytosol may represent a causal chain, which provokes dysregulated proteins, oxidative tissue damage, and contributes to neuronal network dysfunction in RTT.

<p>Effects of Green Silver Nanoparticles on Apoptosis and Oxidative Stress in Normal and Cancerous Human Hepatic Cells in vitro</p>

“…However, mitochondria are the main source of ROS generation. 43 Some researchers reported that the increased ROS generation in Rett mice was accompanied by increased mitochondrial activity. 4,44 MMP contributes to the systemic oxidative burden and oxidative tissue damage in CHANG and HuH-7 cells.…”

Abnormalities of synaptic mitochondria in autism spectrum disorder and related neurodevelopmental disorders

“…A study performed in isolated mitochondria from the hippocampus and cortex of Mecp2 -KO mice indicated that hippocampal and cortical mitochondria are impaired as they release more ROS and consumed more O 2 compared to WT littermates [ 144 ]. Still, it is unclear if the mitochondrial defects found in these disease models can be solely attributed to increased respiration and if these alterations are the consequence of redox imbalances.…”

Reductive Stress-Induced Mitochondrial Dysfunction and Cardiomyopathy

“…They are summarized and graphically presented in Figure 1. RI increases mitochondrial ROS production by upregulating the activities of complexes I to IV [16] and impacts the NAD + /NADH balance leading to damage to lipids, proteins [17,18], and DNA [19]. Impaired oxidation of NADH to NAD + by the electron transport chain (ETC) is an adaptive mechanism of hypoxia, analogous to the "hypoxia-like" RI resulting from increased flux of glucose [20,21].…”

“…Reductive stress, first introduced in 1987 [10], is described as an excess of reducing equivalents, in the forms of NAD(P)H and/or glutathione, in the presence of intact oxidoreductive Figure 1: Interrelationship between RI and mitochondrial dysfunction. NAD + /NADH imbalance is the main cause leading to lipids, proteins, and DNA damage and triggering the increase in ROS production by the electron transport chain [16][17][18][19]. ROS are metabolic by-products generated by mitochondria that can damage macromolecules by structurally altering protein amino acids leading to formation of protein carbonyls, DNA mutation (e.g., single-and double-strand breaks, inter/intrastrand cross-links, and DNA-protein cross-links), and lipid peroxidation [29,30].…”