Yuki Kambe* and Atsuro Miyata
Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8544, Japan
Received: 31 August, 2015; Accepted: 10 October, 2015; Published: 14 October, 2015
Yuki Kambe, Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima 890-8544, Japan, Tel.: +81-99-275-5256; Fax: +81-99-265-8567; E-mail:
Kambe Y, Miyata A (2015) Potential Involvement of Mitochondrial Dysfunction in Major Depressive Disorder: Recent Evidence. Arch Depress Anxiety 1(1): 019-028.DOI: 10.17352/2455-5460.000004
© 2015 Kambe Y, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Major depressive disorder; Mitochondria; Reactive oxygen species; Human postmortem brain; Human peripheral tissue; Rodent model for major depressive disorder
Major depressive disorder (MDD) is a leading cause of morbidity and mortality, and it is a common psychological disorder in the world. Present antidepressants modulate monoamine systems directly or indirectly, because MDD is classically considered as a neurochemical disease, in which monoamine systems are perturbed including serotonin, noradrenaline or dopamine systems. However, recent evidences suggest that MDD is associated with the impairments of synaptic plasticity or cellular resilience to stress. Cellular resilience is maintained by mitochondria with the supplying cellular fuel or ATP. In addition, it is suggested that mitochondrial functions in neurons influence synaptic plasticity. Therefore, impairment of mitochondrial function can be the cause of the MDD. The present review article summarizes the recent evidences about the association between mitochondrial impairment and MDD, and it suggests that improvement of mitochondrial function become a potential drug target for MDD.
CMS: Chronic Mild Stress; ETC: Electron Transporting Chain; GSH: Glutathione; MDA: Malondialdehyde; MDD: Major depressive disorder; mtDNA: Mitochondrial DNA; OXPHOS: Oxidative phosphorylation; ROS: Reactive oxygen species; SOD: Superoxide dismutase; TCA: Tricarboxylic acid
Major depressive disorder (MDD), a common psychological disorder, is a leading cause of morbidity and mortality worldwide; however, its pathophysiology remains largely unknown. An epidemiological study showed that 4.3% of the world's population has had MDD at least once in their lifetime . Although the number of patients is still increasing, existing medicine is not adequately effective in most cases. Almost all medicines for MDD are based on the “monoamine theory”. This theory was originally established based on knowledge of the mechanism of action of imipramine, which inhibits the reuptake of monoamines, including serotonin and noradrenaline into the presynaptic terminal, leading to an increase of monoamines in the synaptic cleft, and resulting in an antidepressant effect . Therefore, most medicines used in MDD treatment affect the monoamine system . However, it is also known that one-third of MDD patients are resistant to existing antidepressants . Thus, new drug targets, which are not based on the monoamine theory, are required.
Mitochondria have now emerged as the apparent pathological basis or drug target for MDD . There is a recent report by the CONVERGE consortium showing the mitochondrial relationship with MDD, which suggested that two loci on chromosome 10 contribute to risk of MDD: one near the SIRT1 gene, and the other in an intron of the LHPP gene . LHPP is an enzyme whose function is not fully understood, and SIRT1 is important for energy-producing cell structures called mitochondria . This study was the first to show robust genetic links to MDD. In addition, co-morbidity of mitochondrial disorders and psychiatric disorders was previously reported in a study focused on patients with mitochondrial disorders . Co-morbidity of MDD was assessed by Fattel et al. in 36 adults who suffered from mitochondrial disorders. Fifty four percent of these patients fulfilled the criteria for lifetime MDD, and this prevalence is much higher than the 15% lifetime prevalence rate of depression in the general population . In addition, 18 patients, from a cohort of 68 children confirmed with mitochondrial disease, were more likely to be affected by MDD (50%) than normal children (10%) which is the norm scores of an American population. Moreover, child behavior checklist T-scores for withdrawn/ depressive behavior is significantly different between the groups of mitochondrial disease and norm of American population . Thus, in the present review article, we discuss the recent advances in knowledge on mitochondrial dysfunction in MDD, and suggest mitochondrial deficit as a new drug target for MDD.
The cellular energy horse, mitochondria
Classically, mitochondria have been considered a source of production of ATP or its metabolites to fulfill cellular energy demands. Multiple carbon substrates are used for the production of ATP, such as pyruvate from glycolysis, glutamine or other amino acids and fatty acids. These carbon substrates are introduced into the tricarboxylic acid (TCA) cycle in the mitochondrial matrix and used for generation of NADH and FADH2. NADH and FADH2 work as electron donors, and deliver electrons to the electron transporting chain (ETC). The transportation of electrons is coupled with the pumping out of protons from the mitochondrial matrix to the inter membrane space by complexes I, III and IV, located in the mitochondrial inner membrane. This pumping of protons creates proton gradients across the inner mitochondrial membrane, and generates a proton motive force, composed of a small chemical component and a large electrical membrane potential. This proton motive force is used by Complex V to generate ATP from ADP and phosphate, in a process called oxidative phosphorylation (OXPHOS) [11,12]. Specifically, the brain uses 20% of the total oxygen consumed by the body at rest, but represents only 2% of body mass . In addition, neurons are critically and almost exclusively dependent on mitochondrial OXPHOS as a major source of ATP, and have a limited capacity to upregulate energy supply through glycolysis when OXPHOS is compromised [14,15].
Mitochondria as an intracellular calcium store
Mitochondria have been shown to be responsible for the clearance of cytosolic Ca2+ in cells and are able to accumulate a large amount of Ca2+ . Mitochondrial Ca2+ uptake is regulated in a sophisticated manner, and consequently affects multiple cellular processes. The mitochondrial Ca2+ uptake from cytosol to the mitochondrial matrix controls the rate of energy production through the modulation of Ca2+-sensitive metabolic enzymes. TCA cycle enzymes are highly sensitive to changes in concentration of Ca2+, which presumably binds directly to isocitrate dehydrogenase and α-ketoglutarate dehydrogenase, whereas pyruvate dehydrogenase is activated by the Ca2+-sensitive pyruvate dehydrogenase phosphatase. Complex IV and complex III may also be regulated by intramitochondrial Ca2+. Matrix Ca2+ may also regulate OXPHOS through an effect on the adenine nucleotide trans locator and on F1Fo-ATP synthase [15,17,18]. This modulation of energy production occurs with a spatial and temporal profile similar to intracellular Ca2+ signaling, and regulates mitochondrial motility and morphology .
Reactive oxygen species (ROS) as a byproduct of ETC
Mitochondria are a very important source of reactive oxygen species (ROS) in most mammalian cells. The production of ROS is important because it underlies oxidative damage in many diseases and contributes to retrograde redox signaling from organelles to the cytosol and nucleus. Superoxide (O2-) is the proximal mitochondrial ROS, and predominantly produced in Complex I. The generation of O2- within the mitochondrial matrix depends critically on proton motive force, the NADH/NAD+ and CoQH2/CoQ ratios and the local O2 concentration . Because mitochondria are the major producers of ROS in mammalian cells, mitochondrial DNA (mtDNA) is prone to oxidative damage. Many studies have consistently shown that 8-oxo-dG, one of the common products of DNA oxidation, is detected at higher levels in mtDNA than in nuclear DNA, suggesting that mtDNA is more susceptible to oxidative damage. As mtDNA encodes essential components of oxidative phosphorylation and protein synthesis machinery, oxidative damage-induced mtDNA mutations that impair either the assembly or the function of the respiratory chain will in turn trigger further accumulation of ROS .
Mitochondrial dysfunction in MDD
Altered ETC or OXPHOS: Alteration of the expressions and activity of complexes in ETC, or mitochondrial oxygen consumption have been studied in postmortem brain, skeletal muscle or platelet biopsies from MDD patients in comparison to normal healthy controls.
Postmortem brain: Postmortem brain Decreased expression of complexes of the ETC was reported in patients with MDD compared to healthy controls. The functional Complex I assembly requires 3 catalytic subunits, such as the 24, 51 and 75-kDa subunits. The expression of the 24 kDa subunit was significantly decreased in the prefrontal cortex of MDD patients in comparison with that of normal healthy controls . In addition, the expression of the 24, 51 and 75-kDa subunits were significantly decreased in the cerebellar lateral hemispheres, and 24-kDa subunit was significantly decreased in the prefrontal cortex of MDD patients . Not only decreased expressions but also decreased activity were reported in MDD patients, as Complex I activity was significantly reduced in the prefrontal cortex of MDD patients . Additionally, altered mitochondrial function and amino acid metabolism are associated with MDD. Abdellah et al. found a signiﬁcant reduction in the rate of the neuronal TCA cycle in glutamatergic neurons by carbon-13 MRS, implicating the glutamatergic system and mitochondrial energy metabolism in the pathology of MDD .
Peripheral tissue: It is known that mitochondrial activity in peripheral tissue is related to brain function to some extent. In intact platelets, physiological respiration, the maximal capacity of the electron transport system and respiratory rate after Complex I inhibition are decreased in MDD patients who have reached partial remission, compared to normal healthy controls . In addition, in muscle biopsies, the mitochondrial ATP production rate and the enzymatic activity ratio between NADH-cytochrome c reductase and cytochrome c oxidase, or between succinate-cytochrome c reductase and cytochrome c oxidase, was lower in MDD patients in comparison with normal healthy controls . However, in another study, Complex I activity was measured by assessing NADH ferricyanide reductase activity, and no diﬀerence in enzymatic activity was observed between mitochondrial preparations from platelets of MDD patients with recurrent MDD and those of healthy controls .
Animal studies: In a mouse model of MDD developed more than 20 years ago, the chronic mild (or unpredictable or variable) stress (CMS) model was developed as an animal model of depression. The foundation of this model was that following long-term exposure to a series of mild, but unpredictable stressors, animals would develop a state of impaired reward salience that is akin to anhedonia. In this state, the hypothalamic–pituitary–adrenal axis (HPA) is activated, which results in the release of corticosteroid hormones from the adrenal glands [29,30]. Rezin et al., showed that the activity of Complexes I, III and IV was reduced without affecting Complex II and creatine kinase activity in both the cerebral cortex and the cerebellum. This reduction was associated with reduced sweet food ingestion and increased adrenal gland weight after 40 days of CMS . In addition, a single infusion of ketamine at low dose robustly decreases depressive symptoms in humans . Acute administration of ketamine reversed the reduction of Complex I, III and IV activity in cerebral cortex and cerebellum with associated reversal of the reduction of sweet food ingestion and increased adrenal gland weight mediated by CMS . A different study carried out by another group also suggested that CMS reduced Complex I, II and V activity, and led to anhedonia, reduced sucrose intake, and depressed behavior including increased immobility in a forced swim test .
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