Depression Pathophysiology: Astrocyte Mitochondrial Melatonergic Pathway as Crucial Hub

Abstract

Major depressive disorder (MDD) is widely accepted as having a heterogenous pathophysiology involving a complex mixture of systemic and CNS processes. A developmental etiology coupled to genetic and epigenetic risk factors as well as lifestyle and social process influences add further to the complexity. Consequently, antidepressant treatment is generally regarded as open to improvement, undoubtedly as a consequence of inappropriately targeted pathophysiological processes. This article reviews the diverse array of pathophysiological processes linked to MDD, and integrates these within a perspective that emphasizes alterations in mitochondrial function, both centrally and systemically. It is proposed that the long-standing association of MDD with suppressed serotonin availability is reflective of the role of serotonin as a precursor for the mitochondrial melatonergic pathway. Astrocytes, and the astrocyte mitochondrial melatonergic pathway, are highlighted as crucial hubs in the integration of the wide array of biological underpinnings of MDD, including gut dysbiosis and permeability, as well as developmental and social stressors, which can act to suppress the capacity of mitochondria to upregulate the melatonergic pathway, with consequences for oxidant-induced changes in patterned microRNAs and subsequent patterned gene responses. This is placed within a development context, including how social processes, such as discrimination, can physiologically regulate a susceptibility to MDD. Future research directions and treatment implications are derived from this.

Type I Diabetes Pathoetiology and Pathophysiology: Roles of the Gut Microbiome, Pancreatic Cellular Interactions, and the ‘Bystander’ Activation of Memory CD8+ T Cells

“…The AhR is predominantly expressed in a complex with other proteins in the cytoplasm, with its activation by endogenous and exogenous ligands leading to its translocation to the nucleus, where it forms a dimer that upregulates genes containing the xenobiotic response element. The AhR has complex effects that are partly dependent upon the specific AhR-activating ligand, cell type, and concurrent wider cellular processes [ 36 ]. The AhR is also expressed on the mitochondrial membrane where it can regulate Ca 2+ influx via the voltage-dependent anion channel (VDAC)1 [ 37 ].…”

“…LPS activation of TLR4 induces the transcription factors, NF-κB and YY1, in many cell types, including leukocytes, macrophages, microglia, and astrocytes [ 36 , 47 ]. The induction of pro-inflammatory processes in pancreatic β-cells is intimately linked to NF-κB upregulation [ 31 , 48 , 49 ].…”

“…The tryptophan–melatonin pathway is evident in cells across body organs and tissues, with relevance to a host of diverse medical conditions, including depression [ 36 ], amyotrophic lateral sclerosis [ 7 ], cancers [ 113 ] and dementia [ 97 ]; see Figure 1 . Most tryptophan is derived from dietary sources, although the shikimate pathway in the human gut microbiome is a relevant provider of aromatic amino acids, including tryptophan, as well as tyrosine and phenylalanine [ 7 ].…”

Redefining Autoimmune Disorders’ Pathoetiology: Implications for Mood and Psychotic Disorders’ Association with Neurodegenerative and Classical Autoimmune Disorders

“…The pathophysiological underpinnings of 'autoimmune'/'immune-mediated' disorders overlap with the pathophysiology of most psychiatric conditions, such as mood/anxiety disorders, bipolar disorder and schizophrenia, including increased O&NS [175], suboptimal mitochondrial function [176], circadian dysregulation [177], gut dysbiosis [178] and tryptophan-melatonin pathway dysregulation [4,179] as well as alterations in NK cells and CD8 + T cells [180]. Classical 'autoimmune' disorders, such as multiple sclerosis [181], T1DM [182] and rheumatoid arthritis [183] show elevations in concurrent psychiatric presentations, especially major depressive disorder (MDD).…”

“…Most, if not all, medical conditions are associated with alterations in mitochondrial and metabolic function, including cancer [1], dementias [2], cardiovascular diseases [3], psychiatric disorders [4,5], pulmonary diseases [6] and metabolic disorders [7]. Typically, the mitochondrial dysfunction involves the suppression of mitochondrial energy production from oxidative phosphorylation (OXPHOS), coupled with increased reactive oxygen species (ROS) and the involvement of reactive cells, either systemic immune cells and/or CNS glial cells [8].…”