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

The DOI matches its Crossref record; 507 of the 507 references it cites were found in a registry or an index.

The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders

Open access
Morris, Gerwyn, Berk, Michael·2015·BMC Medicine
DOI 10.1186/s12916-015-0310-yPMC PMC4382850
Open this paper in CoChat — free accountOpen PDF

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.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1186/s12916-015-0310-y

Cites

507 of 507 references verified0 citation errors · 0 not checkable

Statistics

Figures

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

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

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

Cited by

Sorted by citations

See all 245

Related

See all

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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review