Extensive respiratory chain defects in inhibitory interneurones in patients with mitochondrial disease
Open accessAbstract
Aims: Mitochondrial disorders are among the most frequently inherited cause of neurological disease and arise due to mutations in mitochondrial or nuclear DNA . Currently, we do not understand the specific involvement of certain brain regions or selective neuronal vulnerability in mitochondrial disease. Recent studies suggest γ‐aminobutyric acid ( GABA )‐ergic interneurones are particularly susceptible to respiratory chain dysfunction. In this neuropathological study, we assess the impact of mitochondrial DNA defects on inhibitory interneurones in patients with mitochondrial disease. Methods: Histochemical, immunohistochemical and immunofluorescent assays were performed on post‐mortem brain tissue from 10 patients and 10 age‐matched control individuals. We applied a quantitative immunofluorescent method to interrogate complex I and IV protein expression in mitochondria within GABA ergic interneurone populations in the frontal, temporal and occipital cortices. We also evaluated the density of inhibitory interneurones in serial sections to determine if cell loss was occurring. Results: We observed significant, global reductions in complex I expression within GABA ergic interneurones in frontal, temporal and occipital cortices in the majority of patients. While complex IV expression is more variable, there is reduced expression in patients harbouring m.8344 A > G point mutations and POLG mutations. In addition to the severe respiratory chain deficiencies observed in remaining interneurones, quantification of GABA ergic cell density showed a dramatic reduction in cell density suggesting interneurone loss. Conclusions: We propose that the combined loss of interneurones and severe respiratory deficiency in remaining interneurones contributes to impaired neuronal network oscillations and could underlie development of neurological deficits, such as cognitive impairment and epilepsy, in mitochondrial disease.
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The discrepancies in COX1 versus COX4 effects may stem from differences in using intracellular optical density measurements corrected to porin expression, along with the specific neuronal subtype and brain regions examined.
“These discrepancies may stem from differences in using intracellular optical density measurements corrected to porin expression, along with the specific neuronal subtype and brain regions examined. 21 , 66”
From High vulnerability of medial prefrontal pyramidal neurons in post-stroke, vascular, Alzheimer's disease, and aging-related dementias (2026) · cites this paper as [21]
The Results (Respiratory chain deficient inhibitory interneurones) report COX1 optical densities measured within GAD65-67-positive interneurones relative to porin; the Methods (Post-mortem brain tissue) identify the frontal, temporal and occipital cortices examined. The paper does not compare COX1 with COX4 or assess whether these methodological and sampling differences explain the cited discrepancies. (LLM, conf=0.82)
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Jobson, D. D., Hase, Y., Walker, L., Polvikoski, T., Khundakar, A. A., Allan, L., & Kalaria, R. N. (2026) · Alzheimer's & Dementia · doi:10.1002/alz.71151 · Cited by 2 · see citing works
“21,64–66 However, we found that COX1-positive neurons were minimally affected ( ≈ 8% lower) compared to COX4 across the dementias.”
- Authors
- Lax, N. Z., Grady, J., Laude, A., Chan, F., Hepplewhite, P. D., Gorman, G., Whittaker, R. G., Ng, Y., Cunningham, M. O., & Turnbull, D. M.
- Affiliations
- Wellcome Centre for Mitochondrial Research (GB)
- Newcastle University (GB)
- Wellcome Trust Centre for Mitochondrial Research Institute of Neuroscience Newcastle University Newcastle upon Tyne UK
- Royal Victoria Infirmary (GB)
- Venue
- Neuropathology and Applied Neurobiology
- Publisher
- Wiley
- Published
- 2015-05-30
- Volume
- 42
- Issue
- 2
- Pages
- 180-193
- ISSN
- 0305-1846 (ISSN-L)
- 1365-2990
- PMC
- PMC4772453
- OpenAlex
- W1554609063
- Cited by
- 61
- References
- 33
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 7 · 2020: 7 · 2019: 6 · 2018: 5 · 2017: 1 · 2016: 5 · 2015: 4
- FWCI
- 2.17
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Neuropathology and Applied Neurobiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Aston Publications Explorer (Aston University) (acceptedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- The Wellcome Trust (074454/Z/04/Z)
- Newcastle upon Tyne Hospitals NHS Foundation Trust
- UK NHS Specialist Commissioners
- UK Medical Research Council (G0400074)
- MRC Edinburgh Sudden Death Brain Bank
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- mitochondrial disease, respiratory chain deficiency, GABAergic interneurons, complex I, cytochrome c oxidase, POLG mutations, interneuron loss, epilepsy, cognitive impairment, neuronal network oscillations
- MeSH terms
- Adult, Aged, Autopsy, Brain, Electron Transport Complex IV, Female, Fluorescent Antibody Technique, Humans, Immunohistochemistry, Interneurons, Male, Middle Aged, Mitochondrial Diseases, Electron Transport Complex I, Young Adult, GABAergic Neurons
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