Mitochondria in the Central Nervous System: Comparison
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Nearly half a century has passed since the discovery of cytoplasmic inheritance of human chloramphenicol resistance. The inheritance was then revealed to take place maternally by mitochondrial DNA (mtDNA) and mutations in mtDNA were identified as a cause of severe inheritable metabolic diseases with neurological manifestation. A growing number of preclinical studies have revealed that animal behaviors are influenced by the impairment of mitochondrial functions. Indeed, as high as 54% of patients with one of the most common primary mitochondrial diseases, mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, present psychiatric symptoms. Mitochondrial functions are observed to be compromised and to become less resilient under continuous stress. Furthermore, stress, inflammation, mitochondrial impairment have been linked to the activation of the tryptophan–kynurenine metabolic system, which observably contributes to the development of pathological conditions including neurological and psychiatric disorders.

  • mitochondria
  • stress resilience
  • plasticity
  • stress
  • kynurenine
  • neurodegenerative
  • psychiatry
  • Alzheimer's disease
  • depression
  • anxiety

1. Introduction

Mitochondria are double membrane-bound cell organelles abundant in the cytosol of eukaryotes. The most prominent role of mitochondria is the production of high-energy storage molecule adenosine triphosphate (ATP) [1][2][3]. For ultimate energy production, mitochondria employ a variety of metabolic activities, including the tricarboxylic (TCA) cycle, oxidative phosphorylation (OXPHOS), ketogenesis/ketolysis, fatty acid oxidation, and glutamate metabolism [4][5][6][7][8][9]. Each component forms a complex metabolic network and dynamically adapts to the cellular environment to ensure the optimal energy supply. Mitochondrial malfunction can occur due to the defects of proteins directly or indirectly responsible for the OXPHOS or to the dysfunction of cellular mechanisms outside of mitochondria [10][11][12][13]. However, the role of mitochondria is not limited to cellular energy production. Other functions of mitochondria include calcium storage, subcellular signaling such as gene expression, autophagy, and apoptosis, among others [14][15].
Meanwhile, the tryptophan (Trp)–kynurenine (KYN) metabolic system plays a major role in Trp metabolism, as over 95% of Trp catabolizes into nicotinamide adenine dinucleotide (NADH). Accumulating evidence is revealing that the enzymes and the metabolic products of the Trp-KYN system actively influence the metabolism of mitochondria and participates in normal aging in organisms as well as the pathogenesis of mitochondrial diseases, neurodegenerative diseases, and psychiatric disorders [16][17]. The enzymes of the Trp-KYN system are activated by inflammation, oxidative stress, antioxidant system, and downstream bioactive metabolites [18][19].
Normal functions of mitochondria are typically compensated in mitochondrial diseases, a heterogenous group of chronic, genetic, and often inherited metabolic disorders caused by mitochondrial dysfunction, resulting in the impairment of cellular energy production and other crucial mitochondrial functions [20]. The prevalence of inherited mitochondrial diseases is estimated to occur one in 5000 live births, and they are the most common inborn errors of metabolism [21]. Primary mitochondrial disease (PMD) is caused by the pathogenic mutation of mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) encoding either the proteins of OXPHOS or the proteins affecting the energy production of OXPHOS. Secondary mitochondrial diseases (SMDs) can be hereditary, caused by the genes for mtDNA transcription or expression, homeostasis, or metabolism [22]. Furthermore, mitochondrial dysfunction can be caused by acquired multifactorial diseases such as diabetes, cancer, heart or kidney disease, or neurodegenerative diseases [23][24].
Mitochondrial malfunction occurs in other conditions including normal aging in organisms, neurodegenerative diseases, and psychiatric disorders. Age-related physiological changes are strongly associated with mitochondrial malfunction with decreased mtDNA volume and mitochondrial integrity, which results from cumulative damage to mtDNAs by reactive chemical species [25]. Mitochondrial dysfunction also occurs in most neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s diseases (PD), Huntington’s disease (HD), Friedreich’s ataxia (FA), and amyotrophic lateral sclerosis (ALS) [26]. Psychiatric disorders include mood disorders such as major depressive disorder (MDD) and bipolar disorder (BD), schizophrenia (SCZ), autism spectrum disorder (ASD), and attention-deficit hyperactive disorder (ADHD) [27].

2. Mitochondria in the Central Nervous System

The brain accounts for only 2% of the body weight; however, it consumes as much as 20% of body’s total oxygen supply. An estimated number of one to two million mitochondria is present per single neuron in the human substantia nigra [28]. Mitochondria take responsibility for the production of cellular energy and the proper conduction of neural circuits in the nervous system [29][30][31][32][33]. Mitochondria are multifunctional organelles maintaining calcium homeostasis and signaling to other organelles in the cell as well as with other mitochondria at distance [34][35]. Furthermore, mitochondria are highly plastic in morphology, functions, and cell cycle, depending on the tissue type and the need of cells [36]. Mitochondria can be even transferred from cell to cell [37].

2.1. Mitochondrial Bioenergetics

Glucose, other sugars, and some amino acids are broken down in the cytosol to three-carbon molecule pyruvate which transfers into the mitochondria. Pyruvate is degraded to two carbon molecule acetyl coenzyme A (acetyl-CoA) which enters the second stage of cellular respiration, the TCA cycle that takes place in the matrix of mitochondria. Initially, Szent-Györgyi reported a cyclic chemical reaction between a four-carbon molecule (oxaloacetate) and two four-carbon molecules (fumarate and L-(-)-malate (the Szent-Györgyi cycle)). Later, Krebs revealed larger cyclic biochemical reactions in which a two-carbon molecule “triose” bonds with oxaloacetate to form a six-carbon molecule citrate, which is then oxidized to a five-carbon molecule (alpha-ketoglutarate) and four-carbon molecules (succinyl-CoA, succinate, fumarate, and malate), thus forming the TCA cycle (the Krebs cycle) [38]. “Triose” was eventually identified as a product of pyruvate and coenzyme A, acetyl-CoA [39][40]. The TCA cycle employs eight different enzymes, reproducing one molecule of oxaloacetate, two molecules of carbon dioxide, water, three molecules of NADH, and one molecule of flavin adenine dinucleotide (FADH2) and guanosine triphosphate (GTP). GTP is readily converted to ATP. In the TCA cycle, most of the high-energy storage molecule ATP is consumed by NAD+ and FAD to form NADH and FADH2 [29] (Figure 1a). The NAD+ excess has been reported to improve mitochondrial function and thus prolong the life span of mice [30].
Figure 1. The tricarboxylic acid cycle (TCA) and its interface with the tryptophan (Trp)–kynurenine (KYN) metabolic system. (a) The TCAcycle is initiated with acetyl coenzyme A (acetyl-CoA) reacting with oxaloacetate to form citrate. Citrate is oxidized to alpha (α)-ketoglutarate (2-oxoglutarate) with the formation of nicotinamide adenine dinucleotide (NADH). α-ketoglutarate is oxidized to succinyl coenzyme A (succinyl-CoA) with the formation of NADH. Succinyl-CoA is converted to succinate with the formation of adenosine triphosphate (ATP). Succinate is oxidized to fumarate with the formation of flavin adenine dinucleotide (FADH2). Fumarate is hydrated to malate which is oxidized to oxaloacetate to end the cycle. (b) Cytosolic kynurenine aminotransferase (KAT) I catalyzes the reaction of an S-substituted L-Cys to pyruvate. KAT I also catalyzes the reaction of L-glutamine to α-ketoglutarate (2-oxoglutarate). (c) Mitochondrial KAT II, KAT III, and KAT IV catalyze the reaction of α-ketoglutarate catalyzes the reaction of L-glutamine to α-ketoglutarate (2-oxoglutarate) to L-glutamate. (d) KAT II catalyzes the reaction of α-ketoglutarate (2-oxoglutarate) to 2-oxoadipate which is eventually degraded to acetyl-CoA. (e) Mitochondrial KAT III catalyzes the reaction of an S-substituted L-Cys to pyruvate. (f) Mitochondrial KAT IV catalyzes the reaction of α-ketoglutarate (2-oxoglutarate) and L-aspartate to α-ketoglutarate (2-oxaloacetate) and L-glutamate.
Of note, 16–18 carbon chain fatty acids transported by plasma albumin diffuse into the cytosol using a protein transporter. Consuming ATP, fatty acid is transformed to acyl coenzyme A (acyl-CoA) that crosses the inner membrane of mitochondria by carnitine-acyl-CoA transferase. The beta-oxidation takes place in the mitochondrial matrix in which acetyl-CoA, water, and five ATP molecules are produced by shortening two carbon chains until an acyl-CoA molecule is reduced to an acetyl-CoA molecule [31]. Amino acids are recycled to produce new proteins, but when they are in excess, or cells are under starvation, amino acids are catabolized to supply energy. All essential amino acids except histidine, alanine, and cysteine (Cys) are involved in mitochondrial metabolic pathways. All essential amino acids are converted to pyruvate in the cytosol, which enters to mitochondria to fuel in the TCA cycle [36]. NADH and FADH2 transfer their energy to the third stage of cellular respiration OXPHOS consisting of the electron transport, chemiosmosis, and ATP synthesis. The electron transport chain (ETC) generates a proton (H+) gradient across the inner membrane and the subsequent return of the H+ to the matrix produces ATP from ADP by ATP synthetase. The ETC is a group of protein complexes composed of the NADH coenzyme Q reductase (Complex I), coenzyme Q, succinate dehydrogenase (Complex II), cytochrome bc1 complex (Complex III), and cytochrome c oxidase (Complex IV). NADH donates an electron to Complex I, generating three protons, while FADH2 donates an electron to Complex II, generating two protons. ATP synthetase (Complex V) utilizes a proton gradient across the inner membrane to synthesize ATP from ADP and inorganic phosphate (Pi) [32]. In general, three to four protons are required to produce one ATP with 42% efficiency of energy conservation [33]. However, the cellular energy production can be altered under stressful condition or pathological processes according to the availability of substrates, enzyme activity, mitochondrial and cellular conditions, and adjacent biosystems including Trp-KYN metabolic system.

2.2. Other Mitochondrial Functions

Mitochondria play an important role in cellular calcium homeostasis. The concentration of calcium ions in the intermembrane space is the same as that in the cytosol due to the high permeability of the outer mitochondria membrane. A higher concentration of mitochondrial calcium ions enhances ATP production; however, severe calcium overloads are associated with pathological conditions [34][35][41]. Mitochondria constantly communicate with other cellular organelles such the nucleus, the ER, lysozymes, and peroxisomes. The coordinated interaction of mitochondrial and nuclear factors is required for mitochondrial gene expression offered by mitochondrial ribonuclease P, ribosomal RNAs, transfer RNAs, introns, and a protein [42]. The nucleus sends signals to the mitochondria via anterograde regulation to modulate mitochondrial biogenesis upon stressful events. On the other hand, mitochondria constantly transmit information on mitochondrial status and cellular stress to the nucleus by retrograde signaling [43]. Mitochondria and the ER are at a close contact through the mitochondria-associated membrane to exchange information on energy production, calcium homeostasis, lipid transport, and apoptosis [44]. Lysosomes interact with mitochondria to transport amino acids, lipids, and calcium ions [45]. Mitochondria and peroxisomes function in concert in fatty acid metabolism. Mitochondria degrade long-chain fatty acids to supply acetyl-CoA and produce ATP, while peroxisome performs beta-oxidation to generate hydrogen peroxide and anabolic metabolic metabolism such as plasmalogen and bile acid synthesis [46]. Mitochondria undergo division during mitosis, dividing equally between the cell soma to daughter cells in interaction with the ER and cytoskeleton [47]. The morphology, functions, and dynamics of mitochondria change upon tissue differentiation [48]. Mitochondria constantly divide and fuse, controlling their morphology and functions. The fusion takes place by initially merging the outer membrane and subsequently the inner membrane of two mitochondria. The continuous events of fusion and division generate mitochondrial networks [49]. Mitophagy refers to mitochondrial autophagy in which double-membraned vesicle autophagosomes deliver mitochondria to lysosomes for destruction. Mitophagy is induced by prolonged fission, promoting the repair process, but may lead to mitochondrial degradation. MicroRNAs play an important role in regulation of protein expression responsible for autophagy [50]. Mitochondria also induce an immune response via the activation of the mitochondrial antiviral signaling protein which leads to the secretion of cytokines via the virally infected cells [51]. Furthermore, mitochondria induce mitochondrial apoptosis through mitochondrial outer membrane permeabilization which leads to the disruption of mitochondrial outer membrane and the release of intermembrane space proteins such as cytochrome c [52]. Therefore, mitochondria impairment may lead to multifarious consequences from ion homeostasis to entire organismal levels.

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