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Mitochondrial Metabolism in Major Neurological Diseases Zhengqiu Zhou University of Kentucky, [email protected]

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Mitochondrial Metabolism in Major Neurological Diseases Zhengqiu Zhou University of Kentucky, Zhengqiu.Zhou@Uky.Edu University of Kentucky UKnowledge Molecular and Cellular Biochemistry Faculty Molecular and Cellular Biochemistry Publications 11-23-2018 Mitochondrial Metabolism in Major Neurological Diseases Zhengqiu Zhou University of Kentucky, [email protected] Grant L. Austin University of Kentucky, [email protected] Lyndsay E. A. Young University of Kentucky, [email protected] Lance A. Johnson University of Kentucky, [email protected] Ramon Sun University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits oy u. Follow this and additional works at: https://uknowledge.uky.edu/biochem_facpub Part of the Biochemical Phenomena, Metabolism, and Nutrition Commons, Biochemistry, Biophysics, and Structural Biology Commons, and the Neuroscience and Neurobiology Commons Repository Citation Zhou, Zhengqiu; Austin, Grant L.; Young, Lyndsay E. A.; Johnson, Lance A.; and Sun, Ramon, "Mitochondrial Metabolism in Major Neurological Diseases" (2018). Molecular and Cellular Biochemistry Faculty Publications. 153. https://uknowledge.uky.edu/biochem_facpub/153 This Review is brought to you for free and open access by the Molecular and Cellular Biochemistry at UKnowledge. It has been accepted for inclusion in Molecular and Cellular Biochemistry Faculty Publications by an authorized administrator of UKnowledge. For more information, please contact [email protected]. Mitochondrial Metabolism in Major Neurological Diseases Notes/Citation Information Published in Cells, v. 7, issue 12, 229, p. 1-25. © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). Digital Object Identifier (DOI) https://doi.org/10.3390/cells7120229 This review is available at UKnowledge: https://uknowledge.uky.edu/biochem_facpub/153 cells Review Mitochondrial Metabolism in Major Neurological Diseases Zhengqiu Zhou 1,†, Grant L. Austin 1,†, Lyndsay E. A. Young 1, Lance A. Johnson 2 and Ramon Sun 1,* 1 Molecular & Cellular Biochemistry Department, University of Kentucky, Lexington, KY 40536, USA; [email protected] (Z.Z.); [email protected] (G.L.A.); [email protected] (L.E.A.Y.) 2 Department of Physiology, University of Kentucky, Lexington, KY 40536, USA; [email protected] * Correspondence: [email protected] † These authors contributed equally to this work. Received: 5 November 2018; Accepted: 21 November 2018; Published: 23 November 2018 Abstract: Mitochondria are bilayer sub-cellular organelles that are an integral part of normal cellular physiology. They are responsible for producing the majority of a cell’s ATP, thus supplying energy for a variety of key cellular processes, especially in the brain. Although energy production is a key aspect of mitochondrial metabolism, its role extends far beyond energy production to cell signaling and epigenetic regulation–functions that contribute to cellular proliferation, differentiation, apoptosis, migration, and autophagy. Recent research on neurological disorders suggest a major metabolic component in disease pathophysiology, and mitochondria have been shown to be in the center of metabolic dysregulation and possibly disease manifestation. This review will discuss the basic functions of mitochondria and how alterations in mitochondrial activity lead to neurological disease progression. Keywords: metabolism; mitochondria; Alzheimer’s disease; epilepsy; traumatic brain injury 1. General Mitochondrial Function 1.1. Mitochondria: Metabolic Hub of a Cell The mitochondrion is the result of evolution from a perfect marriage of an α-proteobacterium and a precursor of a modern eukaryotic cell, evidenced by it being the only non-nuclear sub-cellular organelle that has its own DNA [1]. In mammals, mitochondria are passed down maternally [2] and they are present in every cell in the body, except red blood cells [3]. Mitochondria are bilayer organelles with an outer and inner membrane that enclose the intermembrane space and a matrix compartment, respectively [4]. Mitochondrial DNA (mtDNA) are circular and reside within the matrix. Furthermore, mtDNA are intron-free which make them more susceptible to mutagenesis than nuclear DNA [5]. The mitochondrial proteome consists of over 3300 proteins and more are being identified daily [6]. mtDNA encode for 13 proteins that are part of the electron transport chain, which produces ATP via oxidative phosphorylation [7]. Transport of nuclear-encoded proteins to either the matrix or the intermembrane space requires separate signals. Matrix localization signals are located on the N-terminal of a protein and transport to the matrix requires membrane potential and ATP hydrolysis [8]. The intermembrane translocation signal is a hydrophilic region internal to the cell membrane that directs protein localization independent of membrane potential or ATP hydrolysis [9,10]. The intermembrane space is home to proteins important for mitochondrial structural integrity and multiple proteins in the BCL-2 family that control programmed cell death or apoptosis [11,12]. The intermembrane space and mitochondrial matrix contain proteins for the Cells 2018, 7, 229; doi:10.3390/cells7120229 www.mdpi.com/journal/cells Cells 2018, 7, 229 2 of 25 tricarboxylic acid (TCA) cycle—the major metabolic hub for cellular homeostasis and the electron transport chain that generates ATP from the redox gradient [13–15]. During ATP production, mitochondria generate a large number of reactive oxygen species (ROS) that are contained within the matrix [16]. Controlled release of ROS supports signaling events [17–19]; however, ectopic release of ROS from the mitochondria can result in DNA, RNA, and protein damage that ultimately leads to cell death [20,21]. Recent advances in techniques such as real-time oxygen consumption monitoring [22] and stable isotope enriched metabolomics have revealed an enormous amount of information on mitochondrial metabolism and its connection to cellular physiology [23,24]. These studies confirm that mitochondrion is an extremely complex and dynamic organelle and is at the crossroads of cellular metabolism and signaling. 1.2. Mitochondria and Energy Production The major biochemical pathway in the matrix of a mitochondrion is the TCA cycle, shown in Figure1. Dr. Hans Adolf Krebs won the Nobel Prize in Physiology or Medicine in 1953 for its discovery; hence, it is also referred to as the Krebs cycle [25]. Dr. Krebs discovered that all of the enzymes in the TCA cycle are bi-directional in cell-free assays [25] which led to the illustration of the circular pathway seen in biochemical textbooks. The primary role of the TCA cycle is to extract electrons from carbon sources in the form of NADH and FADH2 and supply them to the electron transport chain (ETC) for the production of ATP [26,27]. Cytoplasmic metabolites supply the TCA cycle to facilitate its continuous operation and are divided into two categories: (1) the canonical oxidative pathway and (2) anaplerotic pathways. The canonical oxidation pathway is a continuation from glycolysis, where pyruvate enters the TCA cycle as acetyl-CoA, carried out by the enzyme pyruvate dehydrogenase (PDH), which is then converted to citrate [27,28]. This is viewed as the major pathway to supply oxidative phosphorylation or ATP production. The anaplerotic pathways involve metabolic enzymes such as pyruvate carboxylase (PCB) [29], phosphoenolpyruvate carboxykinase (PEPCK) [30], malic enzyme (ME) [31], glutaminase (GLS) [32] and glutamate dehydrogenase (GDH) [33]. While PCB, PEPCK and ME connect the TCA cycle with glycolysis; GLS/GDH supply carbon from glutamine. Anaplerotic pathways are bi-directional and most commonly believed to primarily maintain compartmentalized metabolite pools between the cytosol and mitochondria but not contribute to ATP production directly [34,35]. However, alternative studies have suggested that glutamine supports NADH production from the GLS/GDH anaplerotic pathway equally, if not more, when compared to the canonical pathway [36,37]. Figure 1. Major pathways and metabolite exchange that take place in the mitochondria. 1: Glycolysis Cells 2018, 7, 229 3 of 25 and gluconeogenesis connects to the mitochondria by phosphoenolpyruvate (PEP), pyruvate and lactate. 2: Fatty acid biosynthesis and oxidation utilize citrate and acetyl-CoA as metabolic intermediates. 3: Glutathione (GSH) is produced in the mitochondria from glutamate, which maintains cellular redox balance. 4: Protein biosynthesis uses de novo synthesized amino acids from the mitochondria. 5 Neurotransmitter biosynthesis (proline and GABA) partially takes place in the mitochondria then continues in the cytosol. 6: Electron Transport Chain subunits I-V make up the Oxidative Phosphorylation pathway and are located on the inner mitochondrial membrane and use reducing equivalents, NADH and FADH2, as electron sources. Electrons move through the subunits from I or II to IV, which creates a proton gradient in the process. The proton gradient is used by subunit V to generate ATP. 7: Fumarate and succinate are exported to the cytosol as enzyme co-factors. 8: 1-carbon metabolism supplies carbon for purine nucleotide biosynthesis and methylation of proteins and DNA. 9: Aspartate (Asp) supports pyrimidine ring biosynthesis. !: Canonical oxidative pathway. !: Anaplerotic pathway. Pyruvate dehydrogenase (PDH); pyruvate carboxylase (PCB); phosphoenolpyruvate
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