Targeting Inflammatory-Mitochondrial Response in Major Depression: Current Evidence and Further Challenges

Abstract

The prevalence of psychiatric disorders has increased in recent years. Among existing mental disorders, major depressive disorder (MDD) has emerged as one of the leading causes of disability worldwide, affecting individuals throughout their lives. Currently, MDD affects 15% of adults in the Americas. Over the past 50 years, pharmacotherapy, psychotherapy, and brain stimulation have been used to treat MDD. The most common approach is still pharmacotherapy; however, studies show that about 40% of patients are refractory to existing treatments. Although the monoamine hypothesis has been widely accepted as a molecular mechanism to explain the etiology of depression, its relationship with other biochemical phenomena remains only partially understood. This is the case of the link between MDD and inflammation, mitochondrial dysfunction, and oxidative stress. Studies have found that depressive patients usually exhibit altered inflammatory markers, mitochondrial membrane depolarization, oxidized mitochondrial DNA, and thus high levels of both central and peripheral reactive oxygen species (ROS). The effect of antidepressants on these events remains unclear. Nevertheless, the effects of ROS on the brain are well known, including lipid peroxidation of neuronal membranes, accumulation of peroxidation products in neurons, protein and DNA damage, reduced antioxidant defenses, apoptosis induction, and neuroinflammation. Antioxidants such as ascorbic acid, tocopherols, and coenzyme Q have shown promise in some depressive patients, but without consensus on their efficacy. Hence, this paper provides a review of MDD and its association with inflammation, mitochondrial dysfunction, and oxidative stress and is aimed at thoroughly discussing the putative links between these events, which may contribute to the design and development of new therapeutic approaches for patients.

Figure 1

Flowchart of the search methodology performed.

Figure 2

Danger-Associated Molecular Pattern (DAMP) binds to the Pattern Recognition Receptors (PRRs) expressed on the cytosol or in innate immune cell membranes. The cascade triggered by these PRRs leads to NLRP3 inflammasome and caspase-1 activation, which can activate IL-1β and IL-18. Oxidized mitochondrial DNA (ox-mtDNA) and mitochondrial reactive oxygen species (ROS) also activate the inflammasome. NF-κB, through the transcriptional activation pathway, generates tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). Proinflammatory cytokines IL-1β and IL-18 activate the enzymes IDO and TDO of the kynurenine pathway, degrading tryptophan into kynurenine. These two cytokines further activate KMO, which is the enzyme that directs kynurenine to be degraded to 3HK and quinolinic acid, both neurotoxic agents, over the kynurenic acid, a neuroprotective agent. Kynurenic acid is an NMDA receptor agonist and increases glutamate levels and consequently intracellular calcium. Excessive amounts of ROS are produced over the kynurenine pathway.

Figure 3

The increase of intracellular calcium activates neural nitric oxide synthase (nNOS), causing increased NO levels. This will decrease SIRT3, which acts as a key to control mitochondrial dysfunction. As SIRT3 activity decreases, mitochondrial permeability transition pores (mPTPs) open, which release cytochrome C, causing a decrease in ATP levels and inducing apoptosis. NO can also bind to ROS from the kynurenine pathway, generating peroxynitrite (ONOO), a highly unstable free radical. Reduction of SIRT3 deacetylates complex I NADH dehydrogenase, specifically in the NDUFA9 subunit, which interacts with two other ATP synthase subunits (F0 and F1). When SIRT3 is reduced, PDH activation is inadequate for the citric acid cycle, resulting in low levels of NADH and reduced activity of complex I. In addition, SIRT3 promotes deacetylation of MnSOD, an antioxidant enzyme that scavenges superoxide anion produced over the pathway. Another impaired antioxidant enzyme is GSH, because during the inflammatory process, the enzyme KMO, an enzyme dependent on NADPH, is activated, thus reducing the availability of this coenzyme for antioxidant defense systems. In parallel, TNF-α phosphorylates tyrosine 304 in subunit I of cytochrome C oxidase in complex IV, leading to further mitochondrial damage.