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

Abstract

Although previously restricted to a limited number of medical conditions, there is a growing appreciation that ‘autoimmune’ (or immune-mediated) processes are important aspects of a wide array of diverse medical conditions, including cancers, neurodegenerative diseases and psychiatric disorders. All of these classes of medical conditions are associated with alterations in mitochondrial function across an array of diverse cell types. Accumulating data indicate the presence of the mitochondrial melatonergic pathway in possibly all body cells, with important consequences for pathways crucial in driving CD8+ T cell and B-cell ‘autoimmune’-linked processes. Melatonin suppression coupled with the upregulation of oxidative stress suppress PTEN-induced kinase 1 (PINK1)/parkin-driven mitophagy, raising the levels of the major histocompatibility complex (MHC)-1, which underpins the chemoattraction of CD8+ T cells and the activation of antibody-producing B-cells. Many factors and processes closely associated with autoimmunity, including gut microbiome/permeability, circadian rhythms, aging, the aryl hydrocarbon receptor, brain-derived neurotrophic factor (BDNF) and its receptor tyrosine receptor kinase B (TrkB) all interact with the mitochondrial melatonergic pathway. A number of future research directions and novel treatment implications are indicated for this wide collection of poorly conceptualized and treated medical presentations. It is proposed that the etiology of many ‘autoimmune’/‘immune-mediated’ disorders should be conceptualized as significantly determined by mitochondrial dysregulation, with alterations in the mitochondrial melatonergic pathway being an important aspect of these pathoetiologies.

Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses

“…Melatonin is often described as a homeostatic regulator due to its long evolutionary association with mitochondrial function [ 25 ], with melatonin effects partly dependent on the nature of the dynamic metabolic interactions in a given microenvironment and the intracellular metabolic function of a given cell. For example, melatonin increases mitophagy and PTEN-associated kinase 1 (PINK1)/parkin to suppress CD8 + T cell chemoattraction in “immune-mediated” conditions, such as Parkinson’s disease [ 2 , 89 ], but suppresses mitophagy in cancer cells [ 90 ], whilst also derepressing CD8 + T cells [ 60 ]. However, melatonin generally has suppressive effects on pro-inflammatory responses by Th1 and Th17 cells, whilst potentiating Treg [ 91 ], in contrast to GR effects [ 81 , 82 ].…”

“…It is such dysregulation of a given microenvironment’s homeostatic interactions that is proposed to underpin the emergence of autoimmune/immune-mediated conditions, such as type 1 diabetes mellitus (T1DM) [ 147 ] and Parkinson’s disease [ 148 ]. In such “immune-mediated” conditions, the homeostatic dysregulation seems powerfully determined by alterations in mitochondrial melatonergic pathway function, enhanced oxidative stress and the suppression of PINK1 driven mitophagy, coupled to the upregulation of major histocompatibility complex 1 (MHC-1) that chemoattracts CD8 + T cells to destroy pancreatic β-cells and substantia nigra pars compacta dopamine neurons, in the examples given [ 2 ]. Systemic processes therefore regulate the nature of local microenvironment homeostatic interactions, with differential effects on mitochondrial function in different cell types, including via intercellular processes regulating the tryptophan-melatonin pathway.…”

“…There is a growing interest in role of mitochondrial function in determining core aspects of intracellular and intercellular interactions across diverse medical conditions, including autoimmune/immune-mediated disorders [ 1 , 2 ] and neurodegenerative/neuropsychiatric disorders [ 3 – 5 ]. The importance of mitochondrial function and alterations in tumor cellular metabolism have been appreciated since the time of Warburg to be an important determinant of cancer pathogenesis and pathophysiology [ 6 ].…”

“…Although primarily known for its release by the pineal gland at night, the melatonergic pathway is evident in every body cell investigated to date, primarily within mitochondria [ 22 ]. The regulation of the tryptophan-melatonin pathway is increasingly recognized as an important aspect of intercellular interactions in a given microenvironment, being a significant target as to how one cell influences and modulates the function of a neighboring cell [ 2 ]. Variations in the regulation of the mitochondrial melatonergic pathway are also an important determinant of cell phenotypic and plasticity responses and therefore of the dynamic interactions occurring in a given microenvironment, including within the immune cells and other cells of the tumor microenvironment [ 8 ].…”

Role of the Night-Time Systemic Processes and the Astrocyte Tryptophan-Melatonin Pathway in the Regulation of α-Synuclein and Wider Parkinson’s Disease Pathophysiology

“…A growing number of diverse medical conditions 2 are now proposed to be 'autoimmune'/'immune-mediated' disorders, including Alzheimer's disease [3,6] and amyotrophic lateral sclerosis (ALS) [7], as well as PD [8]. Recent work indicates that alterations in mitochondrial interactions in a given microenvironment can leave one cell type susceptible to elimination by 'immune-mediated' processes, which is typically mediated by CD8 + T cells and to a lesser extent by natural killer (NK) cells [9]. Such cell elimination arises from a decrease in mitophagy in association with suppressed levels of PTEN-induced kinase (PINK)1 and parkin, leading to an increase in oxidative stress induction of major histocompatibility complex (MHC)-I, which triggers the chemoattraction of CD8 + T cells to eliminate SNpc dopamine neurons [9].…”