The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders

BMC Medicine, Apr 2015

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.

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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 - 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)


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Gerwyn Morris, Michael Berk. The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders, BMC Medicine, 2015, pp. 68, 13, DOI: 10.1186/s12916-015-0310-y