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Cited by 245Mitochondrial Function and PathologyParkinson's Disease Mechanisms and TreatmentsCoenzyme Q10 studies and effects

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The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders

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Morris, Gerwyn, Berk, Michael·2015·BMC Medicine
DOI 10.1186/s12916-015-0310-yPMC PMC4382850
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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.

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Crossref · 10.1186/s12916-015-0310-y

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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 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.CC BY · PubMed Central
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.
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.CC BY · PubMed Central

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Research works printed but not linked: 6

  1. Lutz NW, Viola A, Malikova I, Confort-Gouny S, Ranjeva JP, Pelletier J, et al. High-resolution 1 H NMR spectroscopy reveals differences in CSF metabolic profiles for MS patients with inflammatory vs. non-inflammatory plaques. Proc Intl Soc Mag Reson Med. 2006;14:1986.
  2. Boris M, Goldblatt A, Galanko J, James SJ. Association of MTHFR gene variants with autism. J Am Phys Surg. 2004;9:106–8.
  3. Mostafa GA, El-Gamal HA, El-Wakkad ASE, El-Shorbagy OE, Hamza MM. Polyunsaturated fatty acids, carnitine and lactate as biological markers of brain energy in autistic children. Int J Child Neuropsychiatry. 2005;2:179–88.
  4. Behan WMH, More IAR, Downie I, Gow JW. Mitochondrial studies in the chronic fatigue syndrome. EOS Riv Immunol Immunofarmacol. 1995;15:36–9.
  5. Behan WMH, Gow JW, Simpson K, More IAR, Downie I, Holt IJ, et al. Mitochondrial findings in the chronic fatigue syndrome. J Pathol. 1994;173:SI7.
  6. Rajasekaran A, Venkatasubramanian G, Berk M, Debnath M. Mitochondrial dysfunction in schizophrenia: Pathways, mechanisms and implications. Neuroscience & Biobehavioral Reviews. 2015;48:10–21. doi:10.1016/j.neubiorev.2014.11.005. · DOI

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Metadata

Authors
Morris, G., & Berk, M.
Affiliations
The Royal Melbourne Hospital (AU)
Corresponding author
Morris, Gerwyn
ORCID
Morris, Gerwyn
Venue
BMC Medicine
Publisher
Springer Science and Business Media LLC
Published
2015-04-01
Volume
13
Issue
1
Pages
68-68
ISSN
1741-7015 (ISSN-L)
DOI
10.1186/s12916-015-0310-y
PMC
PMC4382850
OpenAlex
W1978853745
Cited by
245
References
507
Citations by year
2026: 15 · 2025: 15 · 2024: 16 · 2023: 18 · 2022: 16 · 2021: 16 · 2020: 30 · 2019: 19 · 2018: 31 · 2017: 31 · 2016: 34 · 2015: 4
FWCI
14.47
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion, cc-by)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
Funders
National Health and Medical Research Council (1059660)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Coenzyme Q10 studies and effects
Keywords
mitochondrial dysfunction, oxidative metabolism, neuroimmunological diseases, neuropsychiatric disorders, chronic oxidative stress, reactive oxygen species, reactive nitrogen species, glutathione, inflammatory cytokines, systemic inflammation, multiple sclerosis, Parkinson's disease, bipolar disorder, schizophrenia, depression, autism spectrum disorder, chronic fatigue syndrome
MeSH terms
Autistic Disorder, Mental Disorders, Bipolar Disorder, Depressive Disorder, Female, Humans, Mitochondria, Multiple Sclerosis, Parkinson Disease, Schizophrenia, Neuroimmunomodulation, Fatigue Syndrome, Chronic, Oxidative Stress, Mitochondrial Diseases

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