Major Depression as a Mitochondria-Associated Disease

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.

This entry is adapted from the peer-reviewed paper 10.3390/ijms25020963

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