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Cardon, I.; Grobecker, S.; Kücükoktay, S.; Bader, S.; Jahner, T.; Nothdurfter, C.; Koschitzki, K.; Berneburg, M.; Weber, B.H.F.; Stöhr, H.; et al. Major Depression as a Mitochondria-Associated Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/53869 (accessed on 01 July 2024).
Cardon I, Grobecker S, Kücükoktay S, Bader S, Jahner T, Nothdurfter C, et al. Major Depression as a Mitochondria-Associated Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/53869. Accessed July 01, 2024.
Cardon, Iseline, Sonja Grobecker, Selin Kücükoktay, Stefanie Bader, Tatjana Jahner, Caroline Nothdurfter, Kevin Koschitzki, Mark Berneburg, Bernhard H. F. Weber, Heidi Stöhr, et al. "Major Depression as a Mitochondria-Associated Disease" Encyclopedia, https://encyclopedia.pub/entry/53869 (accessed July 01, 2024).
Cardon, I., Grobecker, S., Kücükoktay, S., Bader, S., Jahner, T., Nothdurfter, C., Koschitzki, K., Berneburg, M., Weber, B.H.F., Stöhr, H., Höring, M., Liebisch, G., Braun, F., Rothammer-Hampl, T., Riemenschneider, M.J., Rupprecht, R., Milenkovic, V.M., & Wetzel, C.H. (2024, January 16). Major Depression as a Mitochondria-Associated Disease. In Encyclopedia. https://encyclopedia.pub/entry/53869
Cardon, Iseline, et al. "Major Depression as a Mitochondria-Associated Disease." Encyclopedia. Web. 16 January, 2024.
Major Depression as a Mitochondria-Associated Disease
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This entry is adapted from the peer-reviewed paper 10.3390/ijms25020963

The link between mitochondria and major depressive disorder (MDD) is increasingly evident, underscored both by mitochondria’s involvement in many mechanisms identified in depression and the high prevalence of MDD in individuals with mitochondrial disorders. Mitochondrial functions and energy metabolism are increasingly considered to be involved in MDD’s pathogenesis.

major depressive disorder mitochondrial functions mitochondriopathy treatment-resistant depression

1. Epidemiology of MDD

At present, an estimated 3.8% of the global population (280 million people) are living with a depressive disorder [1]. Among them, 193 million people suffered from major depressive disorder (MDD), and this number has surged by 26% as a result of the COVID-19 pandemic, reaching a staggering 246 million people. Therefore, studying MDD appears increasingly relevant. MDD is a complex condition with multiple factors and a genetic basis, emerging from an intricate interplay of vulnerability genes and environmental factors that accumulate influence over an individual’s lifetime. Stressful life experiences, particularly those encountered early in life, are proposed to play a pivotal role in influencing brain development. This influence can result in enduring functional changes, potentially contributing to a lifelong susceptibility to mental health afflictions (for review, see [2]).

2. Pathophysiological Hypotheses

Although the precise pathomechanisms underlying MDD development are still not completely understood, various hypotheses have been put forward. One of the oldest and widely accepted hypotheses describes the dysregulation of neurotransmission, especially in the monoaminergic system. Given that treatments restoring monoamines levels within hours only alleviate symptoms after several weeks, some argue that MDD is mainly a result of reduced neuroplasticity resulting from impaired BDNF signaling [3][4]. In line with this theory, Casarotto et al. showed that common antidepressants (ADs) likely exert their clinical effects through their binding to the neurotrophins receptor TRKB [3]. Yet, for primary AD treatments, the remission rate ranges between 30 and 45% [5]. The mechanisms of AD resistance are not completely clear, but a number of predictors for AD response have been identified [6].
Numerous studies link depression and inflammation. MDD patients show elevated peripheral inflammatory factors [7][8]. Inflammation can be caused by stress [8], and stress can result in disturbances in the hypothalamus–pituitary–adrenal axis (HPA), which is strongly associated with MDD [9]. HPA hormones like cortisol can, in turn, affect plasticity, potentially contributing to the development of depression [10]. Understanding these pathways and how they interconnect and participate with the pathophysiology of MDD is crucial for developing new treatments.

3. Mitochondrial Dysfunction in MDD

Mitochondria and energy metabolism have turned into focus in the pathomechanisms of depression [11][12][13][14]. Mitochondrial dysfunction, resulting in decreased energetic capacity, increased oxidative stress, and alterations in signaling, is regarded as a key risk factor for MDD and other psychiatric disorders [12][13][14][15]. Neurons rely heavily on a consistent supply of energy for their proper physiological function. Remarkably, it is estimated that 75% of the total adenosine triphosphate (ATP) consumption in the brain serves to maintain resting membrane potential, which is critical for membrane excitability and neurotransmission [16]. Consequently, neurons are very susceptible to metabolic stress, which can be caused by mitochondrial dysfunction.

4. Mitochondrial Diseases

Mitochondrial diseases (MDs) result from dysfunctional mitochondria and form a group of clinically heterogeneous genetic disorders. MDs are far more frequent than previously assumed. Schaefer et al. estimated a prevalence of 9.2 mitochondrial DNA diseases per 100,000 adults [17]. In children below 16 years of age, the estimated prevalence of MDs ranges from 5 to 15 cases per 100,000 individuals [18]. However, mitochondrial disorders are hard to define in children and induce unspecific symptoms, making misdiagnoses likely and possibly resulting in underdiagnosed MDs [19]. Predominantly, MDs lead to defects in oxidative phosphorylation. Such shortcomings can affect any tissue, although those requiring high levels of energy, such as muscle and brain, are most severely affected. Symptoms can encompass non-neurological or neurological manifestations and typically involve multiple organ systems [18].
The most commonly affected structure in MDs is the nervous system, with symptoms including stroke-like episodes, migraine, epilepsy, spasticity and ataxia, visual impairment, hearing loss, intellectual disability, and fluctuating encephalopathy [20]. Brain dysfunction in MDs can also lead to neuropsychological or psychiatric disturbances. Indeed, Morava et al. showed that 70% of MD patients will experience a major mental illness at some point during their lives [21]. Moreover, Fattal et al. reported depressive behavior in 50% of children with an MD [22].

5. Mitochondrial Diseases and Psychiatric Illnesses

Interestingly, in a case series on MD, Anglin et al. reported that 11 out of 12 patients presented treatment-resistant psychiatric illnesses [23]. Furthermore, clinical deterioration upon treatment with psychotropic medication has been shown in patients with MDs [23][24]. Many psychotropic drugs are known to impair mitochondrial functions [25]; although, as Riquin et al. pointed out, “it is challenging to delineate whether mitochondrial dysfunction occurs secondary to pharmaceutical treatment or whether it is a result of the underlying disease process itself” [24]. These observations highlight the need to consider MDs in patients diagnosed with psychiatric illnesses, such as MDD, and to adapt treatment accordingly.

6. Novel Cellular Model Approach

On the one hand, neurons are highly vulnerable to metabolic stress, which can lead to psychiatric illness such as MDD. On the other hand, mitochondrial impairments associated with MDD have been reported in peripheral cells such as muscle cells [26], platelets [27][28], peripheral blood mononuclear cells [29], and fibroblasts [30][31]. As a result, it is becoming increasingly clear that MDD is not merely limited to mental afflictions but also encompasses physical manifestations. This emphasizes the importance to consider MDD-associated pathomechanisms in neuronal as well as non-neuronal cells. Therefore, researchers studied a human cellular model of MDD in order to unravel the molecular pathomechanisms related to mitochondrial dysfunction and bioenergetics imbalance. A model consisting of various types of patient-derived cells represents a unique opportunity to recapitulate many cellular pathophysiological features of MDD as a human-specific disorder.
In a previous study, researchers collected dermal fibroblasts from MDD patients and non-depressed controls and demonstrated a clear mitochondrial impairment, including reduced respiration and ATP content [31]. Researchers then reprogrammed the fibroblasts to induced pluripotent stem cells (iPSCs), which researchers subsequently differentiated from neural progenitor cells (NPCs) and neurons [32]. Like in peripheral cells, researchers observed signs of altered mitochondrial function in the neural lineage including lower respiration rates. The reduced OXPHOS and altered bioenergetic properties most likely contributed to altered physiological function and support their findings in neurons. Indeed, electrophysiological measurements showed significantly lower membrane capacitance, a more depolarized membrane potential, and increased spontaneous electrical activity [32]. Moreover, astrocyte pathology has been reported in human post-mortem brain tissue of MDD patients [33], suggesting that these glial cells also play a role in the etiology of depression.

References

  1. World Health Organization. World Mental Health Report: Transforming Mental Health for All; World Health Organization: Geneva, Switzerland, 2022.
  2. Lopizzo, N.; Bocchio Chiavetto, L.; Cattane, N.; Plazzotta, G.; Tarazi, F.I.; Pariante, C.M.; Riva, M.A.; Cattaneo, A. Gene-environment interaction in major depression: Focus on experience-dependent biological systems. Front. Psychiatry 2015, 6, 68.
  3. Casarotto, P.C.; Girych, M.; Fred, S.M.; Kovaleva, V.; Moliner, R.; Enkavi, G.; Biojone, C.; Cannarozzo, C.; Sahu, M.P.; Kaurinkoski, K.; et al. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell 2021, 184, 1299–1313.e19.
  4. Liu, W.; Ge, T.; Leng, Y.; Pan, Z.; Fan, J.; Yang, W.; Cui, R. The Role of Neural Plasticity in Depression: From Hippocampus to Prefrontal Cortex. Neural Plast. 2017, 2017, 6871089.
  5. Fava, M.; Rush, A.J. Current status of augmentation and combination treatments for major depressive disorder: A literature review and a proposal for a novel approach to improve practice. Psychother. Psychosom. 2006, 75, 139–153.
  6. El-Hage, W.; Leman, S.; Camus, V.; Belzung, C. Mechanisms of antidepressant resistance. Front. Pharmacol. 2013, 4, 146.
  7. Sluzewska, A. Indicators of Immune Activation in Depressed Patients. In Cytokines, Stress, and Depression; Dantzer, R., Wollman, E.E., Yirmiya, R., Eds.; Springer: New York, NY, USA, 1999; pp. 59–73.
  8. Maydych, V. The Interplay Between Stress, Inflammation, and Emotional Attention: Relevance for Depression. Front. Neurosci. 2019, 13, 384.
  9. Vreeburg, S.A.; Hoogendijk, W.J.G.; van Pelt, J.; DeRijk, R.H.; Verhagen, J.C.M.; van Dyck, R.; Smit, J.H.; Zitman, F.G.; Penninx, B.W.J.H. Major Depressive Disorder and Hypothalamic-Pituitary-Adrenal Axis Activity: Results from a Large Cohort Study. Arch. Gen. Psychiatry 2009, 66, 617–626.
  10. Stokes, P.E. The potential role of excessive cortisol induced by HPA hyperfunction in the pathogenesis of depression. Eur. Neuropsychopharmacol. 1995, 5, 77–82.
  11. Moretti, A.; Gorini, A.; Villa, R.F. Affective disorders, antidepressant drugs and brain metabolism. Mol. Psychiatry 2003, 8, 773–785.
  12. Klinedinst, N.J.; Regenold, W.T. A mitochondrial bioenergetic basis of depression. J. Bioenerg. Biomembr. 2015, 47, 155–171.
  13. Manji, H.; Kato, T.; Di Prospero, N.A.; Ness, S.; Beal, M.F.; Krams, M.; Chen, G. Impaired mitochondrial function in psychiatric disorders. Nat. Rev. Neurosci. 2012, 13, 293–307.
  14. Gardner, A.; Boles, R.G. Beyond the serotonin hypothesis: Mitochondria, inflammation and neurodegeneration in major depression and affective spectrum disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 2011, 35, 730–743.
  15. Monzel, A.S.; Enriquez, J.A.; Picard, M. Multifaceted mitochondria: Moving mitochondrial science beyond function and dysfunction. Nat. Metab. 2023, 5, 546–562.
  16. Berndt, N.; Holzhutter, H.G. The high energy demand of neuronal cells caused by passive leak currents is not a waste of energy. Cell Biochem. Biophys. 2013, 67, 527–535.
  17. Schaefer, A.M.; McFarland, R.; Blakely, E.L.; He, L.; Whittaker, R.G.; Taylor, R.W.; Chinnery, P.F.; Turnbull, D.M. Prevalence of mitochondrial DNA disease in adults. Ann. Neurol. 2008, 63, 35–39.
  18. Gorman, G.S.; Chinnery, P.F.; DiMauro, S.; Hirano, M.; Koga, Y.; McFarland, R.; Suomalainen, A.; Thorburn, D.R.; Zeviani, M.; Turnbull, D.M. Mitochondrial diseases. Nat. Rev. Dis. Primers 2016, 2, 16080.
  19. Koenig, M.K. Presentation and diagnosis of mitochondrial disorders in children. Pediatr. Neurol. 2008, 38, 305–313.
  20. Finsterer, J. Central nervous system manifestations of mitochondrial disorders. Acta Neurol. Scand. 2006, 114, 217–238.
  21. Morava, E.; Gardeitchik, T.; Kozicz, T.; de Boer, L.; Koene, S.; de Vries, M.C.; McFarland, R.; Roobol, T.; Rodenburg, R.J.; Verhaak, C.M. Depressive behaviour in children diagnosed with a mitochondrial disorder. Mitochondrion 2010, 10, 528–533.
  22. Fattal, O.; Link, J.; Quinn, K.; Cohen, B.H.; Franco, K. Psychiatric comorbidity in 36 adults with mitochondrial cytopathies. CNS Spectr. 2007, 12, 429–438.
  23. Anglin, R.E.; Tarnopolsky, M.A.; Mazurek, M.F.; Rosebush, P.I. The psychiatric presentation of mitochondrial disorders in adults. J. Neuropsychiatry Clin. Neurosci. 2012, 24, 394–409.
  24. Riquin, E.; Duverger, P.; Cariou, C.; Barth, M.; Prouteau, C.; Van Bogaert, P.; Bonneau, D.; Roy, A. Neuropsychological and Psychiatric Features of Children and Adolescents Affected With Mitochondrial Diseases: A Systematic Review. Front. Psychiatry 2020, 11, 747.
  25. Chan, S.T.; McCarthy, M.J.; Vawter, M.P. Psychiatric drugs impact mitochondrial function in brain and other tissues. Schizophr. Res. 2020, 217, 136–147.
  26. Gardner, A.; Johansson, A.; Wibom, R.; Nennesmo, I.; von Dobeln, U.; Hagenfeldt, L.; Hallstrom, T. Alterations of mitochondrial function and correlations with personality traits in selected major depressive disorder patients. J. Affect. Disord. 2003, 76, 55–68.
  27. Hroudova, J.; Fisar, Z. Control mechanisms in mitochondrial oxidative phosphorylation. Neural Regen. Res. 2013, 8, 363–375.
  28. Sjovall, F.; Ehinger, J.K.; Marelsson, S.E.; Morota, S.; Frostner, E.A.; Uchino, H.; Lundgren, J.; Arnbjornsson, E.; Hansson, M.J.; Fellman, V.; et al. Mitochondrial respiration in human viable platelets—Methodology and influence of gender, age and storage. Mitochondrion 2013, 13, 7–14.
  29. Karabatsiakis, A.; Bock, C.; Salinas-Manrique, J.; Kolassa, S.; Calzia, E.; Dietrich, D.E.; Kolassa, I.T. Mitochondrial respiration in peripheral blood mononuclear cells correlates with depressive subsymptoms and severity of major depression. Transl. Psychiatry 2014, 4, e397.
  30. Garbett, K.A.; Vereczkei, A.; Kalman, S.; Wang, L.; Korade, Z.; Shelton, R.C.; Mirnics, K. Fibroblasts from patients with major depressive disorder show distinct transcriptional response to metabolic stressors. Transl. Psychiatry 2015, 5, e523.
  31. Kuffner, K.; Triebelhorn, J.; Meindl, K.; Benner, C.; Manook, A.; Sudria-Lopez, D.; Siebert, R.; Nothdurfter, C.; Baghai, T.C.; Drexler, K.; et al. Major Depressive Disorder is Associated with Impaired Mitochondrial Function in Skin Fibroblasts. Cells 2020, 9, 884.
  32. Triebelhorn, J.; Cardon, I.; Kuffner, K.; Bader, S.; Jahner, T.; Meindl, K.; Rothhammer-Hampl, T.; Riemenschneider, M.J.; Drexler, K.; Berneburg, M.; et al. Induced neural progenitor cells and iPS-neurons from major depressive disorder patients show altered bioenergetics and electrophysiological properties. Mol. Psychiatry 2022.
  33. Rajkowska, G.; Stockmeier, C.A. Astrocyte pathology in major depressive disorder: Insights from human postmortem brain tissue. Curr. Drug Targets 2013, 14, 1225–1236.
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Subjects: Cell Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Iseline Cardon
,
Sonja Grobecker
,
Selin Kücükoktay
,
Stefanie Bader
,
Tatjana Jahner
,
Caroline Nothdurfter
,
Kevin Koschitzki
,
Mark Berneburg
,
Bernhard H. F. Weber
,
Heidi Stöhr
,
Marcus Höring
,
Gerhard Liebisch
,
Frank Braun
,
Tanja Rothammer-Hampl
,
Markus J. Riemenschneider
,
Rainer Rupprecht
,
Vladimir M. Milenkovic
,
Christian H. Wetzel
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Revisions: 2 times (View History)
Update Date: 16 Jan 2024
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