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Cited by 138Mitochondrial Function and PathologyAlzheimer's disease research and treatmentsDementia and Cognitive Impairment Research

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Sex-associated differences in mitochondrial function in human peripheral blood mononuclear cells (PBMCs) and brain

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Silaidos, C., Pilatus, U., Grewal, R., Matura, S., Lienerth, B., Pantel, J., Eckert, G. P.·2018·Biology of Sex Differences
DOI 10.1186/s13293-018-0193-7PMC PMC6060503
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Abstract

BACKGROUND: Alzheimer's disease (AD) is the most common form of dementia, and it affects more women than men. Mitochondrial dysfunction (MD) plays a key role in AD, and it is detectable at an early stage of the degenerative process in peripheral tissues, such as peripheral mononuclear blood cells (PBMCs). However, whether these changes are also reflected in cerebral energy metabolism and whether sex-specific differences in mitochondrial function occur are not clear. Therefore, we estimated the correlation between mitochondrial function in PBMCs and brain energy metabolites and examined sex-specific differences in healthy participants to elucidate these issues. METHODS: H-magnetic resonance spectroscopy (MRS). RESULTS: We detected sex-associated differences in mitochondrial function. Mitochondrial complexes I, I+II, and IV and uncoupled respiration and electron transport system (ETS) capacity in PBMCs isolated from blood samples of females were significantly (p < 0.05; p < 0.01) higher compared to males. ATP levels in the PBMCs of female participants were approximately 10% higher compared to males. Citrate synthase (CS) activity, a marker of mitochondrial content, was significantly (p < 0.05) higher in females compared to males. Sex-associated differences were also found for brain metabolites. The N-acetylaspartate (NAA) concentration was significantly higher in female participants compared to males in targeted regions. This difference was observed in white matter (WM) and an area with a high percentage (> 50%) of gray matter (GM) (p < 0.05; p < 0.01). The effect sizes indicated a strong influence of sex on these parameters. Sex-associated differences were found in PBMCs and brain, but the determined parameters were not significantly correlated. CONCLUSIONS: Our study revealed sex-associated differences in mitochondrial function in healthy participants. The underlying mechanisms must be elucidated in more detail, but our study suggests that mitochondrial function in PBMCs is a feasible surrogate marker to detect differences in mitochondrial function and energy metabolism in humans and it underscores the necessity of sex-specific approaches in therapies that target mitochondrial dysfunction.

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Crossref · 10.1186/s13293-018-0193-7

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Fig. 1 Target region and representative 1H spectrum from a GM voxel of the target yellow marked target region. Positions of the choline (Cho), creatine (Cr), and N-acetylaspartate (NAA) are marked in the spectrum. The red (broken) line shows the results of the LC mode-fitting procedure. The dotted line is the baseline as estimated by the LC Model. GM = gray matter
Fig. 1 Target region and representative 1H spectrum from a GM voxel of the target yellow marked target region. Positions of the choline (Cho), creatine (Cr), and N-acetylaspartate (NAA) are marked in the spectrum. The red (broken) line shows the results of the LC mode-fitting procedure. The dotted line is the baseline as estimated by the LC Model. GM = gray matterCC BY · PubMed Central
Fig. 2 a Mitochondrial content marker CS activity was significantly higher in isolated PBMCs of females than those of males. Data represent means ± SEM; n = 21; unpaired t test with Welch’s correction; η2 = 0.29; p = 0.04; (*p < 0.05); CS = citrate synthase, PBMC = peripheral blood mononuclear cells. b Respiration of isolated PBMCs from healthy male and female participants in high-resolution respirometry. Values are normalized to international units (IU) of citrate synthase activity. The addition of a substance or inhibitor into the oxygraph chamber is indicated with a cross. Data represent means ± SEM; n = 19; unpaired t test with Welch’s correction were calculated for every state; p values and effect power are shown in Table 2; (*p < 0.05; **p < 0.01); PBMCs = peripheral blood mononuclear cells. c Cell count normalized ATP levels in isolated PBMCs of female and male participants. Data represent means ± SEM; n = 24; unpaired t test with Welch’s correction; η2 = 0.04; p = 0.4; PBMCs = peripheral blood mononuclear cells
Fig. 2 a Mitochondrial content marker CS activity was significantly higher in isolated PBMCs of females than those of males. Data represent means ± SEM; n = 21; unpaired t test with Welch’s correction; η2 = 0.29; p = 0.04; (*p < 0.05); CS = citrate synthase, PBMC = peripheral blood mononuclear cells. b Respiration of isolated PBMCs from healthy male and female participants in high-resolution respirometry. Values are normalized to international units (IU) of citrate synthase activity. The addition of a substance or inhibitor into the oxygraph chamber is indicated with a cross. Data represent means ± SEM; n = 19; unpaired t test with Welch’s correction were calculated for every state; p values and effect power are shown in Table 2; (*p < 0.05; **p < 0.01); PBMCs = peripheral blood mononuclear cells. c Cell count normalized ATP levels in isolated PBMCs of female and male participants. Data represent means ± SEM; n = 24; unpaired t test with Welch’s correction; η2 = 0.04; p = 0.4; PBMCs = peripheral blood mononuclear cellsCC BY · PubMed Central
Fig. 3 NAA concentrations in the a GM and b WM regions of male and female subjects. Concentrations are given in millimoles per tissue water volume. Female subjects show a significantly higher concentration. Data represent means ± SEM; n = 24; unpaired t test with Welch’s correction; a η2 = 0.35; p = 0.009; b η2 = 0.25; p = 0.01 (*p < 0.05; **p < 0.01); GM = gray matter, WM = white matter
Fig. 3 NAA concentrations in the a GM and b WM regions of male and female subjects. Concentrations are given in millimoles per tissue water volume. Female subjects show a significantly higher concentration. Data represent means ± SEM; n = 24; unpaired t test with Welch’s correction; a η2 = 0.35; p = 0.009; b η2 = 0.25; p = 0.01 (*p < 0.05; **p < 0.01); GM = gray matter, WM = white matterCC BY · PubMed Central
Fig. 4 Correlation between citrate synthase (CS) activity and N-acetylaspartate (NAA) concentration of males in a gray matter (GM) and b white matter (WM) and females in c GM and d WM. Correlation between ATP levels and NAA concentrations of males in e GM and f WM and females in g GM and h WM. n = 22–24; p values and Pearson r are shown in Table 3
Fig. 4 Correlation between citrate synthase (CS) activity and N-acetylaspartate (NAA) concentration of males in a gray matter (GM) and b white matter (WM) and females in c GM and d WM. Correlation between ATP levels and NAA concentrations of males in e GM and f WM and females in g GM and h WM. n = 22–24; p values and Pearson r are shown in Table 3CC BY · PubMed Central

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Research works printed but not linked: 1

  1. Kuklinski B. Mitochondrien: Symptome, diagnose und therapie. 1st ed; 2015. Aurum.

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Metadata

Authors
Silaidos, C., Pilatus, U., Grewal, R., Matura, S., Lienerth, B., Pantel, J., & Eckert, G. P.
Affiliations
  • Justus-Liebig-Universität Gießen (DE)
  • Goethe University Frankfurt (DE)
Corresponding author
Eckert, G. P.
ORCID
Venue
Biology of Sex Differences
Publisher
Springer Science and Business Media LLC
Published
2018-07-25
Volume
9
Issue
1
Pages
34-34
ISSN
2042-6410 (ISSN-L)
DOI
10.1186/s13293-018-0193-7
PMC
PMC6060503
OpenAlex
W2884114748
Cited by
137
References
69
Citations by year
2026: 10 · 2025: 23 · 2024: 27 · 2023: 21 · 2022: 18 · 2021: 17 · 2020: 16 · 2019: 4 · 2018: 1
FWCI
3.38
Type
journal article
Language
en
Open access
Licence
Locations
  • Biology of Sex Differences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • University writing server of the Justus Liebig University Giessen (Justus-Liebig-Universität Gießen) (submittedVersion, cc-by)
  • Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
sex differences, mitochondrial function, mitochondrial dysfunction, peripheral blood mononuclear cells, brain energy metabolism, Alzheimer's disease, mitochondrial protein complexes, uncoupled respiration, electron transport chain, ATP, citrate synthase, N-acetylaspartate, white matter, gray matter, magnetic resonance spectroscopy, surrogate markers
MeSH terms
Adenosine Triphosphate, Adult, Aspartic Acid, Brain, Citrate (si)-Synthase, Female, Humans, Leukocytes, Mononuclear, Male, Mitochondria, Sex Characteristics, Cell Respiration, Young Adult

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