Abstract
Introduction:
Mitochondrial dysfunction has been postulated to participate in the development of many neuropsychiatric disorders, but there is no consensus as to its role. The aim of this paper is to review recent studies and to outline the current understanding of the association between mitochondrial dysfunction and psychiatric disorders.
Methodology:
We reviewed articles that evaluated mitochondrial dysfunction and psychiatric disorders, with a particular focus on depression, bipolar disorder, anxiety disorders, obsessive-compulsive disorder, and autism spectrum disorder, and the association between mitochondrial dysfunction and development of these disorders.
Results:
Evidence suggests that alterations in mitochondrial morphology, brain energy metabolism, and mitochondrial enzyme activity may be involved in the pathophysiology of different neuropsychiatric disorders, given their key role in energy metabolism in the cell.
Conclusions:
Understanding the interactions between mitochondrial dysfunction and development of psychiatric disorders may help establish more effective therapeutic strategies for these disorders and thus lead to better outcomes for affected subjects.
Mitochondria; central nervous system; neuroplasticity; cell death
Introduction
Biological systems cannot be described as random molecules commanded by physical and chemical laws of diffusion and casual interactions.11. Lenaz G, Genova ML. Structure and organization of mitochondrial respiratory complexes: a new understanding of an old subject. Antioxid Redox Signal. 2010;12:961-1008. It is essential to understand biological phenomena as part of a large system; thus, the cell is now understood as an assembly of molecular machines made of proteins that interact to preserve their functions.22. Alberts B. The cell as a collection of protein machines: preparing the next generation of molecular biologists. Cell. 1998;92:291-4. The same occurs with the structure and function of mitochondria, and the traditional belief that mitochondria are autonomous organelles is changing. The current challenge is to understand the structural and functional cooperation of mitochondria with the rest of the cell, their relation to the endoplasmic reticulum,33. Pinton P, Giorgi C, Siviero R, Zecchini E, Rizzuto R. Calcium and apoptosis: ER-mitochondria Ca2+ transfer in the control of apoptosis. Oncogene. 2008;27:6407-18. and the cross-talk between nuclear and mitochondrial genetic machinery.44. Ryan MT, Hoogenraad NJ. Mitochondrial-nuclear communications. Annu Rev Biochem. 2007;76:701-22.
Mitochondria are essential for the life of the cell. They produce most of the adenosine triphosphate (ATP) by oxidative phosphorylation. Mitochondria have two membranes (outer and inner), an intermembrane space, and an internal matrix. The inner mitochondrial membrane contains the electron transport chain (ETC), the molecular machinery for energy production.55. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60:748-66. Five protein complexes form the ETC. Of these, three (I, III, and IV) pump protons (H+) through the inner membrane, generating a H+ gradient required for the synthesis of ATP at complex V (ATP synthase). The mitochondrial genome codes for 13 of the ETC proteins. The cell nucleus encodes other mitochondrial proteins (more than 1,000), which mediate processes such as the regulation of ion homeostasis, stress responses, cell survival, and signal transduction.55. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60:748-66.
Neuronal energy supplies are completely dependent on mitochondrial oxidative phosphorylation. Neurons have limited capacity to obtain energy through glycolysis when oxidative phosphorylation is compromised,66. Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolanos JP. The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol. 2009;11:747-52. which makes them particularly vulnerable to mitochondrial dysfunction.
The aim of this paper is to review recent findings and outline the current understanding of the association between mitochondrial dysfunction and psychiatric disorders, with a particular focus on depression, bipolar disorder (BD), anxiety disorders, obsessive-compulsive disorder, and autism spectrum disorders.
More than a power station
It is generally assumed that the mitochondrion is the energy-providing organelle of the cell, but it processes several other compounds as well.77. Briàre JJ, Chrétien D, Bénit P, Rustin P. Respiratory chain defects: what do we know for sure about their consequences in vivo? Biochim Biophys Acta. 2004;1659:172-7. Neurotransmitters and neurotrophic factors control mitochondrial dynamics through their influence upon neuronal energy metabolism, Ca2+ homeostasis, and dendritic and axonal motility.55. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60:748-66.
Many investigations have focused on the role of mitochondria in neurogenesis, especially during neuronal differentiation. The amount of this organelle per cell increases, while the velocity at which mitochondria move decreases, as neurite outgrowth slows and synaptogenesis takes place.88. Chang DT, Reynolds IJ. Differences in mitochondrial movement and morphology in young and mature primary cortical neurons in culture. Neuroscience. 2006;141:727-36. A study by Vayssiàre et al.99. Vayssiàre JL, Cordeau-Lossouarn L, Larcher JC, Basseville M, Gros F, Croizat B. Participation of the mitochondrial genome in the differentiation of neuroblastoma cells. In Vitro Cell Dev Biol. 1992;28A:763-72. showed that treatment with chloramphenicol (an inhibitor of mitochondrial protein synthesis) prevents cell differentiation, whereas oligomycin (an inhibitor of the mitochondrial ATP synthase) does not, suggesting that increased mitochondrial mass (but not ATP production) is required for neuronal differentiation. Additionally, the focal application of nerve growth factor (NGF) to growing axons results in an accumulation of mitochondria near the site of NGF stimulation by a mechanism that involves docking interactions with the actin cytoskeleton, suggesting a role for mitochondria in facilitating growth cone responses to neurotrophic factors.1010. Chada SR, Hollenbeck PJ. Nerve growth factor signaling regulates motility and docking of axonal mitochondria. Curr Biol. 2004;14:1272-6.
Presynaptic terminals characteristically contain multiple mitochondria, because the majority of the ATP produced is required to maintain synaptic ion homeostasis and phosphorylation reactions.55. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60:748-66. Looking beyond the obvious function of this organelle, recent findings from experimental models in which the motility and function of mitochondria were visualized suggest that mitochondria play active roles in synaptic plasticity.55. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60:748-66.
Interestingly, the movement of mitochondria into dendritic protrusions during synaptogenesis correlates with the development and morphological plasticity of spines; when dendritic mitochondrial content is increased, the number and plasticity of spines and synapses enhances greatly.1111. Li Z, Okamoto K, Hayashi Y, Sheng M. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell. 2004;119:873-87. It remains to be determined if and how recruitment of mitochondria within active synapses contributes to long-term changes in synaptic strength.55. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60:748-66. Besides, it is known that changes in mitochondrial functions, such as Ca2+ regulation, energy metabolism, and oxyradical production, play a role in synaptic plasticity as well.55. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60:748-66.
Mitochondria: the crucial signaling
Studies have showed emerging roles of mitochondria in neuroplasticity.1111. Li Z, Okamoto K, Hayashi Y, Sheng M. The importance of dendritic
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Several prominent signaling pathways that stimulate mitochondrial biogenesis and
energy metabolism, while simultaneously regulating neuroplasticity, have been
demonstrated.1313. Cheng A, Hou Y, Mattson MP. Mitochondria and neuroplasticity.
ASN Neuro. 2010;2:e00045. Mitochondria are
distributed throughout the length of axons and presynaptic terminals. In addition,
they are found in dendrite shafts and associated with dendritic spines.1414. Cameron HA, Kaliszewski CK, Greer CA. Organization of
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Mitochondria also participate in the metabolism of reactive oxygen species (ROS),
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Among many specialized cell types in the body, neurons are particularly remarkable. They have tree-like shapes, are electrically excitable, and act in signal detection, integration, and storage, as well as in the generation of adaptive responses.1313. Cheng A, Hou Y, Mattson MP. Mitochondria and neuroplasticity. ASN Neuro. 2010;2:e00045. Through the use of imaging and molecular biology techniques for the study of mitochondria, several surprising properties and functions of mitochondria in neuroplasticity have been revealed. Mitochondria move rapidly within and between subcellular compartments1616. Zinsmaier KE, Babic M, Russo GJ. Mitochondrial transport dynamics in axons and dendrites. Results Probl Cell Differ. 2009;48:107-39.; undergo fission and fusion1717. Liesa M, Palacín M, Zorzano A. Mitochondrial dynamics in mammalian health and disease. Physiol Rev. 2009;89:799-845.; respond (e.g., move, change their energy output, take up or release calcium) to electrical activity and activation of neurotransmitters and growth factor receptors1818. MacAskill AF, Atkin TA, Kittler JT. Mitochondrial trafficking and the provision of energy and calcium buffering at excitatory synapses. Eur J Neurosci. 2010;32:231-40.; and function as signaling outposts that contain kinases, deacetylases, and other signal transduction enzymes.1919. Stowe DF, Camara AK. Mitochondrial reactive oxygen species production in excitable cells: modulators of mitochondrial and cell function. Antioxid Redox Signal. 2009;11:1373-414.
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brain-derived neurotrophic factor (BDNF) on synaptic plasticity. BDNF is known to
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Although changes in the location of mitochondria within axons and dendrites may play roles in synaptic plasticity, rapid functional changes in mitochondria are increasingly being implicated in synaptic plasticity. These changes may include mitochondrial Ca2+ uptake or release, production of superoxide and other ROS, and release of proteins and other factors.1313. Cheng A, Hou Y, Mattson MP. Mitochondria and neuroplasticity. ASN Neuro. 2010;2:e00045.
Apoptosis
Apoptosis is the prototypical form of programmed cell death (PCD) in neurons during development and adult cell turnover, and it may also occur in a range of neurodegenerative conditions. Under normal circumstances, apoptosis is suppressed, as a result of the rigorous compartmentalization of catabolic enzymes and their activators. Morphologically, it is characterized by cell shrinkage, membrane blebbing, and karyorrhexis.55. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60:748-66.
Mitochondria are also involved in cell death, being essential in many apoptotic responses. On a biochemical level, two apoptotic cascades that result in the activation of the executioner caspases 3 and 7 can be distinguished: an intrinsic pathway in which mitochondria play a pivotal role, and an extrinsic pathway that bypasses mitochondria.2626. Stefanis L. Caspase-dependent and -independent neuronal death: two distinct pathways to neuronal injury. Neuroscientist. 2005;11:50-62. In the extrinsic pathway, the engagement of a death receptor such as cluster of differentiation 95 (CD95) by its ligand recruits Fas-associated death domain protein (FADD), which in turn recruits caspase-8. The close proximity of the inactive caspase-8 monomers forces their dimerization, triggering catalytic activity and self-cleavage, which further stabilizes caspase-8 in its active form. Upon release into the cytosol, caspase-8 can either cleave and activate effector caspases, or cleave BH3 interacting-domain death agonist (BID), which induces mitochondrial outer membrane permeabilization. The subsequent activation of caspase-8 initiates the caspase cascade to activate downstream effector caspases, involving caspases -3, -6, and -7, leading to apoptosis of the cell.2727. Bender T, Martinou JC. Where killers meet-permeabilization of the outer mitochondrial membrane during apoptosis. Cold Spring Harb Perspect Biol. 2013;5:a011106. The intrinsic pathway, which predominates in neurons, is triggered by signals as trophic factor withdrawal, moderate overactivation of glutamate receptors, oxidative stress, and DNA damage.55. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60:748-66. These triggers activate kinases and transcription factors that induce mitochondrial translocation of Bax and Bak, which form pores in the outer mitochondrial membrane.55. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60:748-66.
Mitochondria also participate in death-regulating biochemical signals. For example, cytochrome c is restricted to the mitochondrial intermembrane space, which prevents its interaction with apoptotic-protease-activating factor 1 (Apaf-1), a cytosolic protein. When this membrane is compromised, cytochrome c binds to Apaf-1, leading to allosteric activation of pro-caspase-9, which in turn activates caspase-3.2828. Wang X. The expanding role of mitochondria in apoptosis. Genes Dev. 2001;15:2922-33. In the same way, Smac/DIABLO and Omi/HtrA2, two intermembrane proteins, are usually separated from cytosolic inhibitors of apoptosis proteins (IAPs). Once mitochondrial membrane permeabilization (MMP) occurs, Smac/DIABLO and Omi/HtrA2 inactivate IAP, preventing caspase -3 and -9 inhibition. Two DNAses, apoptosis inducer factor (AIF) and endonuclease G, are also normally confined to the mitochondrial intermembrane space, but following MMP they can move to the nucleus and mediate chromatinolysis.2929. Penninger JM, Kroemer G. Mitochondria, AIF and caspases: rivaling for cell death execution. Nat Cell Biol. 2003;5:97-9.
MMP is a key event in physiological as well as pathological cell death3030. Zamzami N, Kroemer G. Apoptosis: mitocondrial membrane permeabilization - the (w)hole story? Curr Biol. 2003;13:R71-3. and it is regulated at multiple levels. Many proapoptotic agents can induce MMP, including Ca2+, ROS, lipid messengers (e.g., ceramide and ganglioside GD3), and stress kinases. Briefly, MMP formation is facilitated by proapoptotic proteins from the Bcl-2 family, and is inhibited by antiapoptotic Bcl-2-like proteins.3030. Zamzami N, Kroemer G. Apoptosis: mitocondrial membrane permeabilization - the (w)hole story? Curr Biol. 2003;13:R71-3.
In this regard, several studies have sought to understand the role of each of the proteins involved in the process. While caspase inhibition can prevent cell death, it does not prevent cytochrome c release, compromising mitochondrial ATP generation and increasing superoxide production. These alterations can make neurons vulnerable to necrosis.55. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60:748-66. This is similar to AIF and HtrA2, which could impair mitochondrial function when released into the cytosol.3131. Cheung EC, Joza N, Steenaart NA, McClellan KA, Neuspiel M, McNamara S, et al. Dissociating the dual roles of apoptosis-inducing factor in maintaining mitochondrial structure and apoptosis. EMBO J. 2006;25:4061-73.,3232. Martins LM, Morrison A, Klupsch K, Fedele V, Moisoi N, Teismann P, et al. Neuroprotective role of the Reaper-related serine protease HtrA2/Omi revealed by targeted deletion in mice. Mol Cell Biol. 2004;24:9848-62. In addition, studies have shown that mitochondria can themselves release controlled amounts of cytochrome c, Smac, HtrA2, and AIF, by a still-unclear mechanism.3333. Huang X, Zhai D, Huang Y. Dependence of permeability transition pore opening and cytochrome C release from mitochondria on mitochondria energetic status. Mol Cell Biochem. 2001;224:1-7.,3434. Wang H, Yu SW, Koh DW, Lew J, Coombs C, Bowers W, et al. Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death. J Neurosci. 2004;24:10963-73. Inhibitors of caspase -1 and -3 modify LTP of synaptic transmission in hippocampal synapses,3535. Lu C, Wang Y, Furukawa K, Fu W, Ouyang X, Mattson MP. Evidence that caspase-1 is a negative regulator of AMPA receptor-mediated long-term potentiation at hippocampal synapses. J Neurochem. 2006;97:1104-10.,3636. Gulyaeva NV, Kudryashov IE, Kudryashova IV. Caspase activity is essential for long-term potentiation. J Neurosci Res. 2003;73:853-64. indicating functions for apoptotic cascades in synaptic plasticity.
Reactive oxygen species
Mitochondria are the main intracellular source of ROS55. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60:748-66.,3737. Massaad CA, Klann E. Reactive oxygen species in the regulation of synaptic plasticity and memory. Antioxid Redox Signal. 2011;14:2013-54.; ROS production contributes to mitochondrial damage in a range of pathologies and is also important in redox signaling from the organelle to the cell.3838. Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, and aging. Cell. 2005;120:483-95.,3939. Droge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002;82:47-95.
Each complex of the mitochondrial respiratory chain has a singular function and works
in association with the others. A fault at any part of the chain can disturb energy
supply. In the absence of ADP, the movement of H+ through ATP
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respiratory chain (State IV respiration), and
O2
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On the other hand, the mitochondrion possesses various antioxidant defenses that detoxify O2 −• and H2O2. Superoxide is enzymatically converted to H2O2 by a family of metalloenzymes called superoxide dismutases (SOD).4747. Fridovich I. Superoxide radical and superoxide dismutases. Annu Rev Biochem. 1995;64:97-112. H2O2 can diffuse to the cytosol and then be converted to H2O by glutathione peroxidase and catalase. Moreover, mitochondria use several antioxidant molecules, such as coenzyme Q10 (ubiquinone), creatine, nicotinamide, and glutathione, to interrupt or minimize oxidative processes.55. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60:748-66.
Despite their potential to cause damage, ROS act on signaling functions in physiological processes, including synaptic plasticity and learning and memory.4848. Kishida KT, Klann E. Sources and targets of reactive oxygen species in synaptic plasticity and memory. Antioxid Redox Signal. 2007;9:233-44.
Ca2+ signaling
Mitochondria also play a role in calcium homeostasis.1818. MacAskill AF, Atkin TA, Kittler JT. Mitochondrial trafficking
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(Ca2+) is the principal second messenger that contributes to the
regulation of both neurotransmission and short- and long-term neuronal plasticity in
the brain. The role of Ca2+ signals in apoptosis has been further
reinforced by the demonstration that antiapoptotic proteins (such as Bcl-2) decrease
Ca2+ levels in the endoplasmic reticulum (ER) and reduce
cytosolic and mitochondrial Ca2+ responses to extracellular stimuli
by increasing the leak of Ca2+ from the ER.5050. Pinton P, Ferrari D, Magalhães P, Schulze-Osthoff K, Di
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52. Palmer AE, Jin C, Reed JC, Tsien RY. Bcl-2-mediated alterations
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proteins, on the other hand, exert the opposite effect.5454. Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD,
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The fine spatial and temporal organization of intracellular calcium signals is essential to central nervous system (CNS) function.5555. Duchen MR. Mitochondria, calcium-dependent neuronal death and neurodegenerative disease. Pflugers Arch. 2012;464:111-21. Signals are conveyed throughout the CNS by local changes in calcium concentration ([Ca2+]c).5555. Duchen MR. Mitochondria, calcium-dependent neuronal death and neurodegenerative disease. Pflugers Arch. 2012;464:111-21. Thus, the Ca2+ signals that are essential for synaptic transmission and therefore for transmission of information throughout the CNS are transmitted to the mitochondria, where it is assumed that Ca2+ modulates mitochondrial metabolism as described elsewhere - with upregulation of the TCA cycle, ATP synthase, and the aspartate carrier,5656. Pardo B, Contreras L, Serrano A, Ramos M, Kobayashi K, Iijima M, et al. Essential role of aralar in the transduction of small Ca2+ signals to neuronal mitochondria. J Biol Chem. 2006;281:1039-47. and presumably with a consequent increase in the supply of ATP.
Alternatively, local changes in intracellular Ca2+ concentration ([Ca2+]c) can diffuse across the cell, leading to an effect at a distant site. Indeed, mitochondrial Ca2+ overload has long been associated with necrosis in heart ischemia-reperfusion injury and excitotoxicity.5757. Orrenius S, Zhivotovsky B, Nicotera P. Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol. 2003;4:552-65.
An important element of the neuronal signaling machinery is the expression of glutamate receptors. Among them, two are Ca2+ permeable: the N-methyl-D-aspartate (NMDA) receptor and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. These receptors play a crucial role in regulation of Ca2+ influx associated with synaptic activity and modulation.5555. Duchen MR. Mitochondria, calcium-dependent neuronal death and neurodegenerative disease. Pflugers Arch. 2012;464:111-21. Choi5858. Choi DW. Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci Lett. 1985;58:293-7. showed that prolonged exposure to high concentrations of glutamate leads to Ca2+-dependent cell death in neuronal culture.
Activation of NMDA receptors by glutamate results in an increase in [Ca2+]c.5959. Nicholls DG. Mitochondrial calcium function and dysfunction in the central nervous system. Biochim Biophys Acta. 2009;1787:1416-24.,6060. Pivovarova NB, Andrews SB. Calcium-dependent mitochondrial function and dysfunction in neurons. FEBS J. 2010;277:3622-36. In addition, depolarization induces opening of voltage-gated Ca2+ channels, while the activity of the plasma membrane Na+/Ca2+ exchangers is reversed. During this increase in [Ca2+]c, mitochondria accumulate and retain Ca2+ to buffer the cytosolic loading. However, this increase in [Ca2+]c caused by glutamate promotes extensive accumulation of Ca2+ for several hours. In this context, it has been shown that necrosis is initiated by this delayed Ca2+ influx, which is independent of Ca2+ release from mitochondria, but dependent on declining activity of cytoplasmic Ca2+ clearing mechanisms (for example, calpain-mediated cleavage of Na+/Ca2+ exchanger). Following the initiation of necrosis, mitochondria are overloaded with Ca2+, the electrochemical proton gradient collapses, and necrotic cell death is induced.6161. Bano D, Young KW, Guerin CJ, Lefeuvre R, Rothwell NJ, Naldini L, et al. Cleavage of the plasma membrane Na+/Ca2+ exchanger in excitotoxicity. Cell. 2005;120:275-85. Thus, it seems that alteration of this cellular response (for example, by a tumor or viral proteins)5151. Pinton P, Ferrari D, Rapizzi E, Di Virgilio F, Pozzan T, Rizzuto R. The Ca2+ concentration of the endoplasmic reticulum is a key determinant of ceramide-induced apoptosis: significance for the molecular mechanism of Bcl-2 action. EMBO J. 2001;20:2690-701.,5454. Scorrano L, Oakes SA, Opferman JT, Cheng EH, Sorcinelli MD, Pozzan T, et al. BAX and BAK regulation of endoplasmic reticulum Ca2+: a control point for apoptosis. Science. 2003;300:135-9.,6262. Campanella M, de Jong AS, Lanke KW, Melchers WJ, Willems PH, Pinton P, et al. The coxsackievirus 2B protein suppresses apoptotic host cell responses by manipulating intracellular Ca2+ homeostasis. J Biol Chem. 2004;279:18440-50.,6363. Chami M, Ferrari D, Nicotera P, Paterlini-Brechot P, Rizzuto R. Caspase-dependent alterations of Ca2+ signaling in the induction of apoptosis by hepatitis B virus X protein. J Biol Chem. 2003;278:31745-55. plays a role in the pathogenesis of human disorders. Prolonged permeability transition pore opening leads to a complete collapse of the membrane potential and Ca2+ release, which results in the complete loss of mitochondrial function and necrotic cell death.
Mitochondrial impairment and psychiatric disorders
Mitochondrial dysfunction has been studied in patients with brain diseases, including neurodegenerative diseases and psychiatric disorders.6464. Jhons DR. The other human genome: mitochondrial DNA and disease. Nat Med. 1996;2:1065-8.,6565. Schon EA, Manfredi G. Neuronal degeneration and mitochondrial dysfunction. J Clin Invest. 2003;111:303-12. Evidence that patients with psychiatric disorders (depression, BD, and schizophrenia) exhibit mitochondrial abnormalities at the structural, molecular, and functional levels has been reviewed6666. Shao L, Martin MV, Watson SJ, Schatzberg A, Akil H, Myers RM, et al. Mitochondrial involvement in psychiatric disorders. Ann Med. 2008;40:281-95. (Figure 1).
Several events can compromise mitochondrial function and integrity. These include abnormal elevation of Ca2+, glutamate excitotoxicity, glutathione depletion, and altered gene expression of electron transport chain complexes. Additionally, the mitochondria are the main intracellular source of ROS, and ROS production contributes to mitochondrial dysfunction. Furthermore, mitochondrial dysfunction decreases ATP levels, causes apoptosis and oxidative stress, and inhibits ion pumps, and these changes are associated with psychiatric disorders. Akt = protein kinase B; AMPK = monophosphate-activated protein kinase; CtBP1 = C-terminal-binding protein 1; CO = carbon monoxide; mTOR = mammalian target of rapamycin; NF-kB = nuclear factor - kappa B; NO = citric oxide; PKA = protein kinase A; PKC = protein kinase C; PI3K = phosphoinositide 3-kinase; ROS = reactive oxygen species.
These findings suggest that a mitochondrial deficit is sufficient to trigger one or more psychiatric disorders. Mitochondrial deficits in psychiatric disorders are suggested by positron emission tomography (PET) analysis of brain energy metabolism.55. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60:748-66. In addition, data suggesting a role for mitochondrial alterations in psychiatric disorders are only correlations; therefore, it remains to be determined whether these alterations contribute to the disease process or are just epiphenomena.55. Mattson MP, Gleichmann M, Cheng A. Mitochondria in neuroplasticity and neurological disorders. Neuron. 2008;60:748-66.
Interestingly, psychiatric symptoms have been observed in subjects with mitochondrial diseases. Fattal et al.6767. Fattal O, Budur K, Vaughan AJ, Franco K. Review of the literature on major mental disorders in adult patients with mitochondrial diseases. Psychosomatics. 2006;47:1-7. identified 19 confirmed cases of mitochondrial disease with psychiatric complications, including BD, major depressive disorder, psychosis, anxiety disorders, and personality changes. Indeed, symptoms of mental illness have been previously documented in subjects affected by mitochondrial cytopathies.6868. Scaglia F. The role of mitochondrial dysfunction in psychiatric disease. Dev Disabil Res Rev. 2010;16:136-43. In addition, a case report of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), a typical mitochondrial encephalopathy, which had presented as mania prior to diagnosis, supports the role of mtDNA mutations in the etiology of psychiatric disorders.6969. Grover S, Padhy SK, DAS CP, Vasishta RK, Sharan P, Chakrabarti S. Mania as a first presentation in mitochondrial myopathy. Psychiatry Clin Neurosci. 2006;60:774-85.
Taken together, the reviewed lines of evidence, including ultrastructural, neuroradiological, biochemical, and genetic data, seem to point to a possible role of mitochondrial dysfunction in the pathological mechanism of some psychiatric disorders. However, the exact mechanisms by which deficits of energy metabolism occur in the brain of subjects affected with psychiatric disorders are not completely understood.6868. Scaglia F. The role of mitochondrial dysfunction in psychiatric disease. Dev Disabil Res Rev. 2010;16:136-43.
Mitochondrial dysfunctions (leading to decreased ATP production, oxidative stress, and apoptosis) occur in the early stages of different neurodegenerative diseases associated with mood disorders. Findings from genetic, postmortem brain, brain-imaging, and biomarker studies in humans with psychiatric disorders and rodent models of such disorders have confirmed this hypothesis.
Depression
Several lines of evidence suggest that mitochondrial dysfunction is an important component of the neurobiology of depression. Patients with depression have reduced glucose utilization in the prefrontal cortex, anterior cingulate gyrus, and caudate nucleus.7070. Videbech P. PET measurements of brain glucose metabolism and blood flow in major depressive disorder: a critical review. Acta Psychiatr Scand. 2000;101:11-20. The energy metabolism deficits observed in patients with depression may be widespread, as suggested by data that demonstrates reduced mitochondrial ATP production and increased mitochondrial DNA deletions as compared with control subjects.7171. Gardner A, Johansson A, Wibom R, Nennesmo I, von Döbeln U, Hagenfeldt L, et al. Alterations of mitochondrial function and correlations with personality traits in selected major depressive disorder patients. J Affect Disord. 2003;76:55-68.
Magarinos et al.7272. Magarinos AM, Deslandes A, Mcewen B. Effects of antide pressants and benzodiazepine treatments on the dendritic structure CA3 pyramidal neurons after chronic stress. Eur J Pharmacol. 1999;371:113-22. found that stress did not affect the number of neuronal mitochondria; however, the total mitochondrial area increased after a stress paradigm, suggesting that longer duration of stress could compromise ATP synthesis. Gardner et al.7373. Gardner A, Salmaso D, Nardo D, Micucci F, Nobili F, Sanchez-Crespo A, et al. Mitochondrial function is related to alterations at brain SPECT in depressed patients. CNS Spectr. 2008;13:805-14. showed a significant decrease of mitochondrial ATP production and mitochondrial enzyme content in muscle of patients with major depressive disorder. Madrigal et al.7474. Madrigal JL, Olivenza R, Moro MA, Lizasoain I, Lorenzo P, Rodrigo J, et al. Glutathione depletion, lipid peroxidation and mitochondrial dysfunction are induced by chronic stress in rat brain. Neuropsychopharmacology. 2001;24:420-9. reported that complexes I-III and II-III of the mitochondrial respiratory chain were inhibited in the rat brain after chronic stress, as was brain Na+, K+-ATPase.7575. Gamaro GD, Streck EL, Matté C, Prediger ME, Wyse AT, Dalmaz C. Reduction of hippocampal Na+, K+-ATPase activity in rats subjected to an experimental model of depression. Neurochem Res. 2003;28:1339-44. Rezin et al.7676. Rezin GT, Cardoso MR, Gonçalves CL, Scaini G, Fraga DB, Riegel RE, et al. Inhibition of mitochondrial respiratory chain in brain of rats subjected to an experimental model of depression. Neurochem Int. 2008;53:395-400. reported that mitochondrial respiratory chain complexes I, III and IV were inhibited in the cerebral cortex and cerebellum of rats after 40 days of chronic mild stress (CMS), and this was reversed by administration of ketamine.7777. Rezin GT, Gonçalves CL, Daufenbach JF, Fraga DB, Santos PM, Ferreira GK, et al. Acute administration of ketamine reverses the inhibition of mitochondrial respiratory chain induced by chronic mild stress. Brain Res Bull. 2009;79:418-21. Gong et al.7878. Gong Y, Chai Y, Ding JH, Sun XL, Hu G. Chronic mild stress damages mitochondrial ultrastructure and function in mouse brain. Neurosci Lett. 2011;488:76-80. showed that exposure to CMS inhibited mitochondrial respiration and dissipated mitochondrial membrane potential. In addition, the mitochondrial ultrastructure was altered in brains of mice exposed to CMS.7878. Gong Y, Chai Y, Ding JH, Sun XL, Hu G. Chronic mild stress damages mitochondrial ultrastructure and function in mouse brain. Neurosci Lett. 2011;488:76-80.
Genetic evidence points to a role for mitochondrial impairment in depression. Postmortem brain tissue from a patient with severe depression was found to have more mtDNA deletions than postmortem muscle tissues from the same patient, suggesting that the accumulation of mtDNA deletions in the brain might play a role in the pathophysiology of depression.7979. Suomalainen A, Majander A, Haltia M, Somer H, Lönnqvist J, Savontaus ML, et al. Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and familial progressive external ophthalmoplegia. J Clin Invest. 1992;90:61-6.
Bipolar disorder
Several investigators have proposed that mitochondrial dysfunction is related to the
pathophysiology of BD. Brain magnetic resonance spectroscopy has demonstrated
decreased levels of N-acetyl-aspartate (a marker of mitochondrial energy production)
in the prefrontal cortex of patients with BD as compared with healthy controls,
indicating neurodevelopmental alterations in the former.8080. Caetano SC, Olvera RL, Hatch JP, Sanches M, Chen HH, Nicoletti
M, et al. Lower N-acetyl-aspartate levels in prefrontal cortices in pediatric
bipolar disorder: a 1H magnetic resonance spectroscopy study. J Am
Acad Child Adolesc Psychiatry. 2011;50:85-94. Stork & Renshaw8181. Stork C, Renshaw PF. Mitochondrial dysfunction in bipolar
disorder: evidence from magnetic resonance spectroscopy research. Mol
Psychiatry. 2005;10:900-19. proposed a hypothesis of mitochondrial dysfunction in BD that
involves impaired oxidative phosphorylation, a shift toward glycolytic energy
production, a decrease in total energy production and/or substrate availability, and
altered phospholipid metabolism. Postmortem studies have reported changes in
mitochondrial-related gene expression in BD as well.8282. Iwamoto K, Bundo M, Kato T. Altered expression of
mitochondria-related genes in postmortem brains of patients with bipolar
disorder or schizophrenia, as revealed by large-scale DNA microarray analysis.
Hum Mol Genet. 2005;14:241-53.,8383. Munakata K, Iwamoto K, Bundo M, Kato T. Mitochondrial DNA
3243A>G mutation and increased expression of LARS2 gene in the brains of
patients with bipolar disorder and schizophrenia. Biol Psychiatry.
2005;57:525-32. In addition, manic-like
hyperactivity induced by d-amphetamine, which is considered an animal model of
mania, is associated with oxidative stress in the rat brain.8484. Frey BN, Martins MR, Petronilho FC, Dal-Pizzol F, Quevedo J,
Kapczinski F. Increased oxidative stress after repeated amphetamine exposure:
possible relevance as a model of mania. Bipolar Disord.
2006;8:275-80.
85. Frey BN, Valvassori SS, Gomes KM, Martins MR, Dal-Pizzol F,
Kapczinski F, et al. Increased oxidative stress in submitochondrial particles
after chronic amphetamine exposure. Brain Res. 2006;1097:224-9.-8686. Frey BN, Valvassori SS, Réus GZ, Martins MR, Petronilho FC,
Bardini K, et al. Effects of lithium and valproate on amphetamine-induced
oxidative stress generation in an animal model of mania. J Psychiatry Neurosci.
2006;31:326-32. Corrêa et
al.8787. Corrêa C, Amboni G, Assis LC, Martins MR, Kapczinski F,
Streck EL, et al. Effects of lithium and valproate on hippocampus citrate
synthase activity in an animal model of mania. Prog Neuropsychopharmacol Biol
Psychiatry. 2007;31:887-91. showed that citrate synthase
activity was inhibited in the rat hippocampus after mania induced by amphetamine,
and this was reversed by valproate (VPA) and lithium (Li) administration. In
contrast, Streck et al.8888. Streck EL, Amboni G, Scaini G, Di-Pietro PB, Rezin GT,
Valvassori SS, et al. Brain creatine kinase activity in an animal model of
mania. Life Sci. 2008;82:424-9. demonstrated that
amphetamine inhibited creatine kinase activity in rat brains, but VPA and Li were
not able to prevent this. Zugno et al.8989. Zugno AI, Valvassori SS, Scherer EB, Mattos C, Matté C,
Ferreira CL, et al. Na+,K+-ATPase activity in an animal model of
mania. J Neural Transm. 2009;116:431-6.
showed that amphetamine increased Na+, K+-ATPase
activity in rat brains, and that VPA or Li reversed this effect. Moreover, VPA and
Li did not alter Na+, K+-ATPase activity. Valvassori
et al.9090. Valvassori SS, Rezin GT, Ferreira CL, Moretti M, Gonçalves
CL, Cardoso MR, et al. Effects of mood stabilizers on mitochondrial respiratory
chain activity in brain of rats treated with d-amphetamine. J Psychiatr Res.
2010;44:903-9. showed that AMPH inhibited
mitochondrial respiratory chain activity in rat brains, and VPA, but not Li,
reversed this. Feier et al.9191. Feier G, Valvassori SS, Varela RB, Resende WR, Bavaresco DV,
Morais MO, et al. Lithium and valproate modulate energy metabolism in an animal
model of mania induced by methamphetamine. Pharmacol Biochem Behav.
2013;103:589-96. showed that
methamphetamine inhibited the activities of Krebs cycle enzymes and complexes of the
mitochondrial respiratory chain, and Li and VPA reversed methamphetamine-induced
energy metabolism dysfunction.
Bachmann et al.9292. Bachmann RF, Wang Y, Yuan P, Zhou R, Li X, Alesci S, et al. Common effects of lithium and valproate on mitochondrial functions: protection against methamphetamineinduced mitochondrial damage. Int J Neuropsychopharmacol. 2009;12:805-22. have demonstrated that long-term treatment with Li and VPA enhanced cell respiration rate, mitochondrial membrane potential, and mitochondrial oxidation in SH-SY5Y cells. Additionally, methamphetamine reduces mitochondrial cytochrome c, mitochondrial antiapoptotic Bcl-2/Bax ratio, and mitochondrial cytochrome oxidase (COX) activity, and treatment with Li or VPA prevents these alterations. Treatment with Li or VPA prevented Bcl-2 attenuation of apoptosis by sequestering pro-caspases; preventing the release of mitochondrial apoptogenic factors, such as calcium, cytochrome c, and apoptosis-inducing factor, into the cytoplasm; and enhancing mitochondrial calcium uptake.9393. Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science. 1998;281:1322-6.,9494. Bruckheimer EM, Cho SH, Sarkiss M, Hermann J, McDonnell TJ. The Bcl-2 gene family and apoptosis. Adv Biochem Eng Biotechnol. 1998;62:75-105. Studies showed that upregulation of Bcl-2 is a result of the activation of extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K) pathways by mood stabilizers.9595. Chen G, Henter ID, Manji HK. Translational research in bipolar disorder: emerging insights from genetically based models. Mol Psychiatry. 2010;15:883-95.
Patients with BD exhibit impaired brain energy metabolism, reduced levels of mitochondrial proteins involved in energy metabolism, and increased mtDNA mutations.9696. Kato T. Mitochondrial dysfunction as the molecular basis of bipolar disorder: therapeutic implications. CNS Drugs. 2007;21:1-11. A study using Southern blot analysis did not demonstrate mtDNA deletions in postmortem cerebral cortex samples of patients with mood disorders. When a highly sensitive quantitative PCR method was used, more mtDNA deletions were found in the brains of patients with BD than in control brains.9797. Kato T, Stine OC, McMahon FJ, Crowe RR. Increased levels of a mitochondrial DNA deletion in the brain of patients with bipolar disorder. Biol Psychiatry. 1997;42:871-5. Konradi et al.9898. Konradi C, Eaton M, MacDonald ML, Walsh J, Benes FM, Heckers S. Molecular evidence for mitochondrial dysfunction in bipolar disorder. Arch Gen Psychiatry. 2004;61:300-8. reported decreased expression of nuclear genes coding for the enzyme complexes responsible for oxidative phosphorylation and reduced expression of nuclear genes related to proteasome degradation in the hippocampus of nine subjects with BD. MacDonald et al.9999. MacDonald ML, Naydenov A, Chu M, Matzilevich D, Konradi C. Decrease in creatine kinase messenger RNA expression in the hippocampus and dorsolateral prefrontal cortex in bipolar disorder. Bipolar Disord. 2006;8:255-64. showed that creatine kinase mtRNA was decreased in patients with BD, mainly in the hippocampus. The inhibition of creatine kinase activity by amphetamine reinforces the hypothesis that metabolism impairment is involved in the pathophysiology of BD.
Anxiety disorders
Recent evidence demonstrates that impairment of cellular plasticity and resilience may underlie the pathophysiology of anxiety disorders, and that antidepressants have major effects on the signaling pathways that regulate neuroplasticity and cell survival.100100. Coyle JT, Duman RS. Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron. 2003;38:157-60.,101101. Duman RS. Pathophysiology of depression: the concept of synaptic plasticity. Eur Psychiatry. 2002;17:306-10.
It has been suggested that mitochondrial Ca2+ sequestration plays a key role in modulating the tone of synaptic plasticity in a variety of neuroanatomical regions, including those implicated in the pathophysiology of anxiety disorders.102102. Schweitzer N. Pegging pathology on mitochondrial dysfunction. Scientist. 2004;18:28. A study about the relative roles of mitochondrial and ER Ca2+ buffering showed that dendritic mitochondria rapidly accumulate Ca2+, while the ER displays a more delayed increase in Ca2+ during high-frequency stimulation.103103. Pivovarova NB, Pozzo-Miller LD, Hongpaisan J, Andrews SB. Correlated calcium uptake and release by mitochondria and endoplasmic reticulum of CA3 hippocampal dendrites after afferent synaptic stimulation. J Neurosci. 2002;22:10653-61. Thus, is possible that the regulation of mitochondrial function plays an important role in regulating the synaptic strength of the neuronal circuitry mediating complex behaviors.
Moreover, monoamine oxidase inhibitors (MAOIs), known for their anxiolytic and
antidepressant properties, improve mitochondrial function.104104. Thiffault C, Quirion R, Poirier J. The effect of L-deprenyl,
D-deprenyl and MDL72974 on mitochondrial respiration: a possible mechanism
leading to an adaptive increase in superoxide dismutase activity. Brain Res Mol
Brain Res. 1997;49:127-36. The activation of mitochondrial benzodiazepine receptors
reduced stress and anxiety in rats, and neurosteroids that had been widely
recognized as having anxiolytic properties have specific binding sites on
mitochondria and have been confirmed to modulate mitochondrial Ca2+
efflux and increase mitochondrial resilience.105105. Aikey JL, Nyby JG, Anmuth DM, James PJ. Testosterone rapidly
reduces anxiety in male house mice (Mus musculus). Horm Behav.
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peripheral mitochondrial benzodiazepine receptors in the hippocampus stimulates
allopregnanolone synthesis and produces anxiolytic-like effects in the rat.
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Binding of estradiol to synaptosomal mitochondria: physiological significance.
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108. Kaasik A, Safiulina D, Kalda A, Zharkovsky A.
Dehydroepiandrosterone with other neurosteroids preserve neuronal mitochondria
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and alpha-estradiol limit the functional alterations of rat brain mitochondria
submitted to different experimental stresses. Neuroscience.
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neurosteroids in the mirrored chamber behavior test in mice. Brain Res.
1997;752:61-71.-111111. Reddy DS, Kulkarni SK. Role of GABA-A and mitochondrial
diazepam binding inhibitor receptors in the anti-stress activity of
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Murphy et al.112112. Murphy AN, Bredesen DE, Cortopassi G, Wang E, Fiskum G. Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. Proc Natl Acad Sci USA. 1996;93:9893-8. have shown in isolated mitochondria that Bcl-2 overexpression increases mitochondrial Ca2+ uptake capacity, increasing the resistance of mitochondria to Ca2+-induced inhibition of respiration. Einat et al.,113113. Einat H, Yuan P, Manji HK. Increased anxiety-like behaviors and mitochondrial dysfunction in mice with targeted mutation of the Bcl-2 gene: further support for the involvement of mitochondrial function in anxiety disorders. Behav Brain Res. 2005;165:172-80. using BCL2-heterozygous mice, demonstrated an increase in anxiety-like behavior with reduced mitochondrial Bcl-2 levels, suggesting that mitochondrial function, modulated by Bcl-2, may be related to the regulation of anxiety behaviors, thus playing a critical role in the etiology of anxiety disorders.
Obsessive-compulsive disorder
Obsessive-compulsive disorder (OCD) is a common psychiatric disorder defined by the
presence of obsessive thoughts and repetitive compulsive actions, and it often
includes anxiety and depressive symptoms.114114. Torres AR, Lima MC. [Epidemiology of obsessive-compulsive
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Although the etiology of OCD remains unknown, the results of twin studies, familial
studies, and segregation analysis have provided evidence that OCD has a strong
genetic component.115115. Inouye E. Similar and dissimilar manifestations of
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117. Hanna GL, Himle JA, Curtis GC, Gillespie BW. A family study of
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118. van Grootheest DS, Cath DC, Beekman AT, Boomsma DI. Twin
studies on obsessive-compulsive disorder: a review. Twin Res Hum Genet.
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Some investigators have also found markers of oxidative stress in the brain tissues
of patients with OCD.120120. Kuloglu M, Atmaca M, Tezcan E, Gecici O, Tunckol H, Ustundag B.
Antioxidant enzyme activities and malondialdehyde levels in patients with
obsessive-compulsive disorder. Neuropsychobiology.
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121. Selek S, Herken H, Bulut M, Ceylan MF, Celik H, Savas HA, et
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evaluation of oxidant-antioxidant status. Prog Neuropsychopharmacol Biol
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N. Study of oxidative stress in obsessive compulsive disorder in response to
treatment with Fluoxetine. Indian J Clin Biochem.
2009;24:194-7. Moreover, Kuloglu et al.120120. Kuloglu M, Atmaca M, Tezcan E, Gecici O, Tunckol H, Ustundag B.
Antioxidant enzyme activities and malondialdehyde levels in patients with
obsessive-compulsive disorder. Neuropsychobiology.
2002;46:27-32. showed significantly lower levels of
vitamin E and C, and higher levels of malondialdehyde (MDA) in patients with OCD
compared to controls, suggesting that OCD is linked to oxidative stress. Free
radicals in the brain are mainly produced by catecholamine metabolism, and this
increase in catecholaminergic metabolism seems to be associated with increased
tissue damage.123123. Jesberger JA, Richardson JS. Oxygen free radicals and brain
dysfunction. Int J Neurosci. 1991;57:1-17.,124124. Weber GF. The pathophysiology of reactive oxygen intermediates
in the central nervous system. Med Hypothesis. 1994;43:223-30. Depleted levels of glutathione (GSH) have also been found
in postmortem prefrontal cortex samples of patients with psychiatric disorders.125125. Gawryluk JW, Wang JF, Andreazza AC, Shao L, Young LT. Decreased
levels of glutathione, the major brain antioxidant, in post-mortem prefrontal
cortex from patients with psychiatric disorders. Int J Neuropsychopharmacol.
2011;14:123-30. Diminished GSH levels affect mitochondrial
function and inhibit the activity of the mitochondrial complexes, especially complex
I.126126. Bharath S, Hsu M, Kaur D, Rajagopalan S, Andersen JK.
Glutathione, iron and Parkinson's disease. Biochem Pharmacol.
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Although no molecules that induce OCD symptoms have been identified, several neurotransmitters, including serotonin, dopamine, glutamate and gamma-aminobutyric acid (GABA), have been suggested to play regulatory roles in OCD. Neurotransmitters are highly redox-reactive molecules, and produce ROS during normal neurotransmission. Alterations in these neurotransmitter pathways may increase the oxidative burden in the brain.127127. Dean OM, van den Buuse M, Bush AI, Copolov DL, Ng F, Dodd S, et al. A role for glutathione in the pathophysiology of bipolar disorder and schizophrenia? Animal models and relevance to clinical practice. Curr Med Chem. 2009;16:2965-76. On the other hand, some investigators have suggested that dopamine also plays an important role in the pathogenesis of OCD.128128. Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci. 1990;13:266-71.,129129. Brambilla F, Bellodi L, Perna G, Arancio C, Bertani A. Dopamine function in obsessive compulsive disorder: growth hormone response to apomorphine stimulation. Biol Psychiatry. 1997;42:889-97.
In addition, a multivariate logistic regression analysis demonstrated that MnSOD,
UCP2 I/D genotypes, and GSH had significant impacts on OCD.
Prevalence differences between the genders of OCD patients have been previously
reported.130130. Lochner C, Hemmings SM, Kinnear CJ, Moolman-Smook JC, Corfield
VA, Knowles JA, et al. Gender in obsessive-compulsive disorder: clinical and
genetic findings. Eur Neuropsychopharmacol. 2004;14:105-13.
131. Labad J, Menchon JM, Alonso P, Segalas C, Jimenez S, Jaurrieta
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showed that mitochondrial uncoupling protein 2 (UCP-2) regulates neurotransmission
and that overexpression of UCP2 prevents dopamine transmission in
the CNS. Knockdown of the UCP2 gene increases mitochondrial
membrane potential and ROS production in murine endothelial cells.134134. Duval C, Nàgre-Salvayre A, Dogilo A, Salvayre R,
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(UCP2-UCP3) and energy metabolism/obesity in Pima indians. Hum Mol Genet.
1998;7:1431-5. have suggested that a 45 bp insertion in
UCP2 affects the amount and activity of UCP-2 protein by
influencing mRNA stability, translation, and posttranslational modification. De
Bilbao et al.136136. de Bilbao F, Arsenijevic D, Vallet P, Hjelle OP, Ottersen OP,
Bouras C, et al. Resistance to cerebral ischemic injury in UCP2 knockout mice:
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J Neurochem. 2004;89:1283-92. suggested that resistance
to cerebral ischemic injury in UCP2 knockout mice is regulated by
mitochondrial GSH levels in microglia.
Although the pathology of mitochondrial disorders in OCD has not yet been identified,
it is well known that mitochondrial dysfunction related to mutations of
mitochondrial DNA or of nuclear-encoded genes linked to mitochondrially based
oxidative phosphorylation leads to impaired energy metabolism, perturbs calcium
homeostasis, and increases ROS and apoptosis,137137. Calabrese V, Lodi R, Tonon C, D'Agata V, Sapienza M,
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influence on neurotransmitter release, leading to OCD, since synaptic transmission
requires high levels of ATP.
Autism spectrum disorder
Clinical, genetic, and biochemical evidence suggests that mitochondrial dysfunction in autism spectrum disorder (ASD) is more common than expected. Some patients with ASD phenotypes clearly have genetic-based primary mitochondrial disease.140140. Haas RH. Autism and mitochondrial disease. Dev Disabil Res Rev. 2010;16:144-53.
ASD encompass severe developmental disorders characterized by variable degrees of impairment in language, communication, and social skills, as well as by repetitive and stereotypic patterns of behavior. Substantial percentages of autistic patients display peripheral markers of mitochondrial energy metabolism dysfunction, such as elevated lactate, pyruvate, and alanine levels in blood, urine, and/or cerebrospinal fluid, serum carnitine deficiency, and/or enhanced oxidative stress. These biochemical abnormalities are accompanied by highly heterogeneous clinical presentations, which generally encompass neurological and systemic symptoms that are relatively unusual in idiopathic autistic disorder. In some patients, these abnormalities have been successfully explained by the presence of specific mutations or rearrangements in their mitochondrial or nuclear DNA. However, in most cases, abnormal energy metabolism cannot be immediately linked to specific genetic or genomic defects. Recent evidence from postmortem studies of autistic brains points to abnormalities in the mitochondrial function as possible downstream consequences of dysreactive immunity and altered Ca2+ signaling.141141. Palmieri L, Persico AM. Mitochondrial dysfunction in autism spectrum disorders: cause or effect? Biochim Biophys Acta. 2010;1797:1130-7.
The neurobiological basis for autism remains poorly understood. However, research
suggests that environmental factors and neuroinflammation, in addition to genetic
factors, are contributors.142142. El-Ansary A, Al-Ayadhi L. Neuroinflammation in autism spectrum
disorders. J Neuroinflammation. 2012;9:265. Recent
evidence points to inflammatory mechanisms contributing to autism. Vargas et
al.143143. Vargas DL, Nascimbene C, Krishnan C, Zimmerman AW, Pardo CA.
Neuroglial activation and neuroinflammation in the brain of patients with
autism. Ann Neurol. 2005;57:67-81. suggested that neuroinflammatory
processes are present in the autistic brain by showing that transforming growth
factor (TGF-β1), interleukin (IL)-6 and IL-10 are increased in the brain of
autistic patients. A number of studies have also shown that inflammatory cytokines,
including tumor necrosis factor (TNF)-α, interferon (IFN)-γ, IL-1, IL-6,
IL-8, and IL-12, are elevated in blood mononuclear cells, serum, plasma, and
cerebrospinal fluid (CSF) of autistic subjects.144144. Singh VK. Plasma increase of interleukin-12 and
interferon-gamma: pathological significance in autism. J Neuroimmunol.
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145. Croonenberghs J, Bosmans E, Deboutte D, Kenis G, Maes M.
Activation of the inflammatory response system in autism. Neuropsychobiology.
2002;45:1-6.
146. Molloy CA, Morrow AL, Meinzen-Derr J, Schleifer K, Dienger K,
ManningCourtney P, et al. Elevated cytokine levels in children with autism
spectrum disorder. J Neuroimmunol. 2006;172:198-205.
147. Ashwood P, Wakefield AJ. Immune activation of peripheral blood
and mucosal CD3α lymphocyte cytokine profiles in children with autism and
gastrointestinal symptoms. J Neuroimmunol. 2006;173:126-34.
148. Chez MG, Burton Q, Dowling T, Chang M, Khanna P, Kramer C.
Memantine as adjunctive therapy in children diagnosed with autistic spectrum
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Conclusions
Mitochondria play a pivotal role in cellular energy metabolism. The final product of this process is ATP, used as a source of chemical energy. Besides this major role, mitochondria have been shown to be involved in other functions, such as signaling, calcium homeostasis, cellular differentiation, and cell death, as well as control of the cell cycle and of cell growth (Figure 2). Thus, understanding the interactions between mitochondrial dysfunction and development of psychiatric disorders, such as depression, BD, anxiety disorders, OCD, and ASDs, may help establish more effective therapeutic strategies for these psychiatric conditions and, consequently, enable better outcomes for affected subjects. Moreover, this evidence highlights the role of mitochondrial dysfunction in the pathophysiology of psychiatric disorders, which represents an interesting research prospect.
Mitochondria are commonly known for their important role in ATP synthesis through the electron transport chain. However, mitochondria also operate in different control systems, such as ROS metabolism and Ca+2 levels, to ensure cellular homeostasis. Such systems modulate the activity of key signaling pathways, which, in turn, regulate the expression and function of multiple nuclear co-regulators and transcription factors, triggering different responses and thus acting on synaptic plasticity and neurogenesis. ATP = adenosine triphosphate; ROS = reactive oxygen species.
Acknowledgements
This study was supported by grants from the Graduate Program in Health Sciences at Universidade do Extremo Sul Catarinense (UNESC), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
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Publication Dates
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Publication in this collection
15 Apr 2014 -
Date of issue
13 May 2014
History
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Received
1 Aug 2013 -
Accepted
3 Oct 2013