The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders

Abstract

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.

Figure 1

Schematic representation of the inhibitory effects of NO and ONOO- on the ETC, enzymes of the tricarboxylic cycle and antioxidant enzymes. NO and peroxynitrite inhibit the mitochondrial respiration via different mechanisms: NO itself causes selective, rapid, potent, but readily reversible inhibition of cytochrome oxidase and increased production of RNS within the intermembrane space. On the other hand, excessive levels of peroxynitrite and other RNS leads to slow, weak non-selective, but essentially irreversible inhibition of a wide range of mitochondrial components. Peroxynitrite inhibits Complex I, Complex II, cytochrome oxidase ATP synthase, MnSOD, aconitase, creatine kinase, and a plethora of other proteins playing an essential role in energy production. In addition, peroxynitrite is a potent oxidant capable of inducing peroxidation of mitochondrial membrane lipid components, hence increasing membrane permeability and disrupting the potential difference between the inner and outer membrane and inducing mitochondrial membrane transition. Inhibition of ATP production and electron chain dysfunction leads to the production of ever increasing production of ROS and RNS leading to a vicious circle culminating in eventual bioenergetic failure and often cellular necrosis or apoptosis.

Figure 2

Mitochondrial ultrastructural damage and impaired capacity for energy generation in an environment of chronic nitro-oxidative stress. Excessive levels of peroxynitrite cause oxidative and peroxidative damage to lipids and proteins, leading to profound ultrastructural damage, including disrupted cristae, loss of outer membrane integrity, mitochondrial permeability transition, and uncoupling of ETC activity from oxidative phosphorylation.