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Mitochondrial dysfunction in blood cells from amyotrophic lateral sclerosis patients

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Abstract

Mitochondrial dysfunction is implicated in amyotrophic lateral sclerosis, where the progressive degeneration of motor neurons results in muscle atrophy, paralysis and death. Abnormalities in both central nervous system and muscle mitochondria have previously been demonstrated in patient samples, indicating systemic disease. In this case–control study, venous blood samples were acquired from 24 amyotrophic lateral sclerosis patients and 21 age-matched controls. Platelets and peripheral blood mononuclear cells were isolated and mitochondrial oxygen consumption measured in intact and permeabilized cells with additions of mitochondrial substrates, inhibitors and titration of an uncoupler. Respiratory values were normalized to cell count and for two markers of cellular mitochondrial content, citrate synthase activity and mitochondrial DNA, respectively. Mitochondrial function was correlated with clinical staging of disease severity. Complex IV (cytochrome c-oxidase)-activity normalized to mitochondrial content was decreased in platelets from amyotrophic lateral sclerosis patients both when normalized to citrate synthase activity and mitochondrial DNA copy number. In mononuclear cells, complex IV-activity was decreased when normalized to citrate synthase activity. Mitochondrial content was increased in amyotrophic lateral sclerosis patient platelets. In mononuclear cells, complex I activity declined and mitochondrial content increased progressively with advancing disease stage. The findings are, however, based on small subsets of patients and need to be confirmed. We conclude that when normalized to mitochondria-specific content, complex IV-activity is reduced in blood cells from amyotrophic lateral sclerosis patients and that there is an apparent compensatory increase in cellular mitochondrial content. This supports systemic involvement in amyotrophic lateral sclerosis and suggests further study of mitochondrial function in blood cells as a future biomarker for the disease.

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Abbreviations

ALS:

Amyotrophic lateral sclerosis

BSA:

Bovine serum albumin

BZD:

Benzodiazepines

CI:

Complex I

CII:

Complex II

CIV:

Complex IV

CNS:

Central nervous system

CS:

Citrate synthase

EDTA:

Ethylenediaminetetraacetic acid

EGTA:

Ethyleneglycoltetraacetic acid

ETS:

Electron transport system

FCCP:

Carbonyl cyanide p-(trifluoromethoxy) phenylhydrazone

HEPES:

4-(2-hydroxyethyl)-1-Piperazineethanesulfonic acid

mtDNA:

Mitochondrial DNA

OXPHOS:

Respiration associated with ATP synthesis by oxidative phosphorylation

PBMC:

Peripheral blood mononuclear cell

PSMA:

Progressive spinal muscular atrophy

SD:

Standard deviation

SSRI:

Selective serotonin re-uptake inhibitor

TMPD:

Tetramethylphenylenediamine

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Acknowledgments

The authors would like to thank Eleonor Åsander-Frostner and Albana Shahini for technical support, and Katarina Johansson for help with patient identification and recruitment. Funding: Swedish Research Council (2011-3470), Swedish government project and salary funding for clinically oriented medical research (ALF-grants).

Conflicts of interest

Johannes Ehinger, Magnus J. Hansson and Eskil Elmér own shares in NeuroVive Pharmaceutical AB, a public company active in the field of mitochondrial medicine. Saori Morota, Johannes Ehinger, Magnus J. Hansson and Eskil Elmér received salary support from NeuroVive Pharmaceutical AB during parts of the study. Gesine Paul has no conflict of interest to disclose.

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Authors and Affiliations

  1. Mitochondrial Medicine, Department of Clinical Sciences, Lund University, BMC A13, 221 84, Lund, Sweden

    Johannes K. Ehinger, Magnus J. Hansson & Eskil Elmér

  2. Division of Cancer Biology, Group for Research of Molecular Functions and Targets, National Cancer Center, Tokyo, Japan

    Saori Morota

  3. Translational Neurology Group, Department of Clinical Sciences, Lund University, Lund, Sweden

    Gesine Paul

  4. Department of Otorhinolaryngology, Head and Neck Surgery, Skåne University Hospital, Lund, Sweden

    Johannes K. Ehinger

  5. Department of Clinical Neurophysiology, Skåne University Hospital, Lund, Sweden

    Eskil Elmér

  6. Department of Clinical Physiology, Skåne University Hospital, Lund, Sweden

    Magnus J. Hansson

  7. Department of Neurology, Skåne University Hospital, Lund, Sweden

    Gesine Paul

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  1. Johannes K. Ehinger
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  2. Saori Morota
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  4. Gesine Paul
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  5. Eskil Elmér
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Correspondence to Johannes K. Ehinger.

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Ehinger, J.K., Morota, S., Hansson, M.J. et al. Mitochondrial dysfunction in blood cells from amyotrophic lateral sclerosis patients. J Neurol 262, 1493–1503 (2015). https://doi.org/10.1007/s00415-015-7737-0

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  • DOI: https://doi.org/10.1007/s00415-015-7737-0

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