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Review
. 2020 Mar 6;12:52.
doi: 10.3389/fnagi.2020.00052. eCollection 2020.

Succination of Protein Thiols in Human Brain Aging

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Free PMC article
Review

Succination of Protein Thiols in Human Brain Aging

Mariona Jové et al. Front Aging Neurosci. .
Free PMC article

Abstract

Human brain evolution toward complexity has been achieved with increasing energy supply as the main adaptation in brain metabolism. Energy metabolism, like other biochemical reactions in aerobic cells, is under enzymatic control and strictly regulated. Nevertheless, physiologically uncontrolled and deleterious reactions take place. It has been proposed that these reactions constitute the basic molecular mechanisms that underlie the maintenance or loss-of-function of neurons and, by extension, cerebral functions during brain aging. In this review article, we focus attention on the role of the nonenzymatic and irreversible adduction of fumarate to the protein thiols, which leads to the formation of S-(2-succino)cysteine (2SC; protein succination) in the human brain. In particular, we first offer a brief approach to the succination reaction, features related to the specificity of protein succination, methods for their detection and quantification, the bases for considering 2SC as a biomarker of mitochondrial stress, the succinated proteome, the cross-regional differences in 2SC content, and changes during brain aging, as well as the potential regulatory significance of fumarate and 2SC. We propose that 2SC defines cross-regional differences of metabolic mitochondrial stress in the human brain and that mitochondrial stress is sustained throughout the healthy adult lifespan in order to preserve neuronal function and survival.

Keywords: 2-(S-succino)cysteine (2SC); cysteine; fumarate; loss-of-function; mitochondrial stress; posttranslational modification (PTM); thiol groups.

Figures

Figure 1
Figure 1
Mechanism of formation of 2SC. The figure shows the conversion of glucose to pyruvate in the glycolysis pathway. Then, pyruvate is converted to acetyl-CoA, which enters the tricarboxylic acid (TCA) cycle, and the reducing equivalents (NADH and FADH2) generated from glycolysis and the TCA cycle enter the mitochondrial electron transport chain (ETC). So, glycolysis, the TCA cycle, and the ETC are integrated pathways to catabolize energy substrates and drive ATP synthesis via the complex V (ATP synthase). Complexes I–IV of the ETC and ATP synthase are shown. Importantly, the nucleophilic addition of the TCA cycle metabolite fumarate to cysteine yields 2SC by a Michael addition reaction (R indicates peptide chain) in a non-enzymatic reaction called protein succination. Fumarate can also be exported outside mitochondria by carriers, potentially inducing 2SC formation in other cell proteins and even at the extracellular level.
Figure 2
Figure 2
Detection and quantification by GC/mass spectrometry (MS)/MS of 2SC in human brain samples. 2SC can be determined as trifluoroacetic acid methyl ester (TFAME) derivatives in acid hydrolyzed, delipidated, and reduced brain protein samples by GC/MS. (A) Structure, mass spectrum, and proposed fragmentation patterns of TFAME derivative of natural 2SC. (B) Detection of 2SC in human brain proteins. Selected ion chromatograms for brain proteins showing the m/z = 242 and m/z = 284 ions. (C) 2SC quantification in different regions of the human brain (adapted from Cabré et al., with permission). *p < 0.05. A significant difference with respect to the entorhinal cortex.
Figure 3
Figure 3
(A) Concentrations of fumarate (left) and 2SC (right) in different regions of the adult human cerebral cortex. Fumarate was detected and quantified with TQMS. The steady-state level of 2SC was measured with GC-MS. *p < 0.05; **p < 0.01. A significant difference with respect to the entorhinal cortex (adapted from Cabré et al., with permission). (B) Steady-state levels of 2SC in 12 regions of the adult healthy human central nervous system show a significant inverse correlation following a caudal-cranial axis (σ(rho) = −0.672, p < 0.001; adapted from Naudí et al., with permission). Values are mean ± SEM from 5–8 samples for each region. Abbreviations: SC, spinal cord; MO, medulla oblongata; CB, cerebellum; SN, substantia nigra; TH, thalamus; AM, amygdala; ST, striatum; EC, entorhinal cortex; HC, hippocampus; TC, temporal cortex; OC, occipital cortex; FC, frontal cortex. rho (σ), Spearman’s rank correlation coefficient. (C) Effects of aging and methionine restriction in old age on the concentration of 2SC in 13 different brain regions of rat. Values are mean ± SEM from 10 animals per group for each region. Abbreviations: SC, spinal cord (L, lumbar; T, thoracic; C, cervical); MO, medulla oblongata; P, pons; CB, cerebellum; TH, thalamus; HT, hypothalamus; ST, striatum; HC, hippocampus; TC, temporal cortex; OC, occipital cortex; FC, frontal cortex.
Figure 4
Figure 4
Protein succination may mediate neuroprotection by the activation of signaling pathways modulated by Nrf2. The transcription factor Nrf2 regulates the expression of genes encoding proteins with broad cytoprotective activities and mitochondrial functions. Nrf2 itself is regulated at the level of protein stability. Under baseline physiological conditions, Nrf2 is a short-lived protein that is exposed to incessant turnover via ubiquitination and proteasomal degradation. There are three known ubiquitin ligase systems that participate in the removal of Nrf2: (a) Keap1, a substrate adaptor protein for Cullin 3 (Cul3)/Rbx1 ubiquitin ligase; (b) glycogen synthase kinase (GSK)3/β-TrCP-dependent Cul1-based ubiquitin ligase; and (c) E3 ubiquitin ligase Hrd1. In addition to the ubiquitin ligase substrate adaptor protein activity, Keap1 is also the sensor for a wide array of small-molecule activators of Nrf2 (called inducers). Oxidants like reactive oxygen and nitrogen species, electrophiles like carbonyl compounds derived from lipid peroxidation or carbohydrates oxidation, and fumarate are all considered inducers. Inducers block the cycle of Keap1-mediated degradation of Nrf2 by chemically modifying (e.g., by protein succination) specific cysteine residues within Keap1 (Keap1 is a cysteine-rich protein; e.g., rat and mouse have 25 and human 27) or by directly disrupting the Keap1: Nrf2 binding interface. Consequently, Nrf2 is not degraded; it accumulates and translocates to the nucleus, forms a heterodimer with a small Maf protein, binds to antioxidant-response elements (AREs), and initiates transcription.

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