The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders
Morris and Berk BMC Medicine
The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders
Gerwyn Morris
Michael Berk
Background: Mitochondrial dysfunction and defects in oxidative metabolism are a characteristic feature of many chronic illnesses not currently classified as mitochondrial diseases. Examples of such illnesses include bipolar disorder, multiple sclerosis, Parkinson's disease, schizophrenia, depression, autism, and chronic fatigue syndrome. Discussion: While the majority of patients with multiple sclerosis appear to have widespread mitochondrial dysfunction and impaired ATP production, the findings in patients diagnosed with Parkinson's disease, autism, depression, bipolar disorder schizophrenia and chronic fatigue syndrome are less consistent, likely reflecting the fact that these diagnoses do not represent a disease with a unitary pathogenesis and pathophysiology. However, investigations have revealed the presence of chronic oxidative stress to be an almost invariant finding in study cohorts of patients afforded each diagnosis. This state is characterized by elevated reactive oxygen and nitrogen species and/or reduced levels of glutathione, and goes hand in hand with chronic systemic inflammation with elevated levels of pro-inflammatory cytokines. Summary: This paper details mechanisms by which elevated levels of reactive oxygen and nitrogen species together with elevated pro-inflammatory cytokines could conspire to pave a major road to the development of mitochondrial dysfunction and impaired oxidative metabolism seen in many patients diagnosed with these disorders.
Autism; Bipolar disorder; Schizophrenia; Chronic fatigue syndrome; Cytokines; Depression; Immune dysfunction; Inflammatory; Mitochondrial dysfunction; Multiple sclerosis; Nitric oxide; Oxidative stress; Parkinson's disease; Peroxynitrite; Psychiatry; Neurology
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Background
Syndromic or non-syndromic mitochondrial diseases,
classified as cytopathies or encephalomyopathies, arise as
a result of mutations in mitochondrial or nuclear DNA
[1]. However, mitochondrial dysfunction and impaired
bioenergetics are implicated in the pathogenesis of many
chronic illnesses, mainly neuroimmune or autoimmune in
nature, despite these not being currently categorized as
primary mitochondrial diseases [1-5]. Mitochondrial
dysfunction with concomitant oxidative stress is evidenced
in the brains and periphery of many patients with the
diagnoses of multiple sclerosis (MS) [6], chronic fatigue
syndrome (CFS) [6], Parkinsons disease (PD) [7], and
autism [8].
* Correspondence:
1Tir Na Nog, Bryn Road seaside 87, Llanelli, Cardiff, Wales SA152LW, UK
Full list of author information is available at the end of the article
Mitochondrial dysfunction in such individuals may
well result from the presence of oxidative stress, as there
is now ample evidence implicating oxidative stress as
one of the major contributing factors in the
development of mitochondrial dysfunction and compromised
bioenergetic performance [9-13]. In fact, the causative role
of chronic oxidative stress in the development of
mitochondrial damage and localized or systemic bioenergetic
failure has now been established beyond reasonable doubt
[4,14-16]. Chronic oxidative stress develops in a cellular
environment whenever production of reactive nitrogen
species (RNS) and reactive oxygen species (ROS) exceeds
the clearance ability of the cells antioxidant defenses
such as the glutathione (GSH) and thioredoxin systems
[17-19]. ROS and RNS are natural products of oxidative
phosphorylation [18,20]. These reactive species can also
be generated by activated inflammatory cells, including
macrophages and microglia [21-24]. Oxidative stress and
chronic inflammation are inextricably interconnected.
Oxidative stress activates a number of transcription
factors, such as NF-kappaB and activated protein 1, leading
to the production of pro-inflammatory cytokines (PICs),
various chemokine species, and activation and
proliferation of lymphocytes. The activation of other immune cells
in turn leads to the production of more ROS and RNS,
principally in the form of superoxide, nitric oxide (NO),
and peroxynitrite [24-27]. The tissue damage
characteristic of chronic inflammation is mediated directly by
macrophages, neutrophils, and eosinophils via the production of
PICs [28]. This intricate bidirectional self-amplifying and
self-sustaining relationship between the development of
chronic oxidative stress and chronic systemic
inflammation is sometimes described as an autotoxic loop [25,29].
ROS and RNS can also contribute to the development
of chronic oxidative stress and inflammation via the
oxidative and nitrosative modification of proteins, lipids, and
DNA, resulting in modification of DNA bases and tertiary
protein structure, lipid peroxidation of cell membranes,
and the production of highly reactive aldehydes and
ketones. The net result of these processes is the indirect and
direc (...truncated)