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Lower circulating mitochondrial DNA and increased mitokines suggest significant mitochondrial dysfunction in systemic lupus erythematosus with renal involvement

Halfon, Matthieu ; Memon, Ashfaque A LU orcid ; Hedelius, Anna LU ; Pascual, Manuel ; Sundquist, Kristina LU and Ribi, Camillo (2025) In Lupus science & medicine 12(1).
Abstract

BACKGROUND: SLE is associated with significant morbidity, especially in the case of renal involvement. Mitochondrial dysfunction plays a significant role in SLE and may be assessed by measuring mitochondrial DNA (mtDNA) and cytokines reflecting mitochondrial stress (mitokines). Circulating mtDNA is a promising biomarker in SLE and appears to be reduced in severe SLE. However, measuring circulating mtDNA is challenging and reported methods are heterogenous. Our study aimed at evaluating whole blood mtDNA to nuclear DNA (nucDNA) ratio using droplet-digital PCR and circulating mitokines, growth differentiation factor 15 (GDF-15) and fibroblast growth factor 21 in SLE with and without renal involvement.

METHODS: Cross-sectional study... (More)

BACKGROUND: SLE is associated with significant morbidity, especially in the case of renal involvement. Mitochondrial dysfunction plays a significant role in SLE and may be assessed by measuring mitochondrial DNA (mtDNA) and cytokines reflecting mitochondrial stress (mitokines). Circulating mtDNA is a promising biomarker in SLE and appears to be reduced in severe SLE. However, measuring circulating mtDNA is challenging and reported methods are heterogenous. Our study aimed at evaluating whole blood mtDNA to nuclear DNA (nucDNA) ratio using droplet-digital PCR and circulating mitokines, growth differentiation factor 15 (GDF-15) and fibroblast growth factor 21 in SLE with and without renal involvement.

METHODS: Cross-sectional study involving 195 patients with SLE and age-matched healthy volunteers (HV) as control. Biomarkers were compared in patients with and without renal involvement (defined by estimated glomerular filtration rate <60 mL/min or proteinuria >0.5 g/day) and in those with active and inactive SLE.

RESULTS: Compared with HV, patients with SLE displayed lower mtDNA/nucDNA ratios, especially in the case of renal involvement. Accordingly, mitokines were increased in patients with SLE with renal involvement. We found no correlation between mtDNA/nucDNA ratio and global disease activity. Mitokine levels, on the other hand, correlated with disease activity, in particular GDF-15 even after adjusting for renal involvement.

CONCLUSION: Our findings suggest that lower whole blood mtDNA/nucDNA ratio, a surrogate marker for mitochondrial dysfunction, reflects renal damage, while GDF-15 may also reflect disease activity in SLE. Further studies are needed to assess the clinical value of these markers as predictors for active lupus nephritis.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Humans, Female, DNA, Mitochondrial/blood, Male, Adult, Cross-Sectional Studies, Lupus Erythematosus, Systemic/blood, Growth Differentiation Factor 15/blood, Biomarkers/blood, Middle Aged, Mitochondria/metabolism, Lupus Nephritis/blood, Case-Control Studies, Cytokines/blood, Fibroblast Growth Factors/blood, Glomerular Filtration Rate
in
Lupus science & medicine
volume
12
issue
1
article number
e001368
publisher
BMJ Publishing Group
external identifiers
  • pmid:39900408
  • scopus:85217248213
ISSN
2053-8790
DOI
10.1136/lupus-2024-001368
language
English
LU publication?
yes
additional info
© Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.
id
2ab611dd-1404-42da-8c63-969cd4603466
date added to LUP
2025-02-10 14:07:10
date last changed
2025-07-10 15:50:52
@article{2ab611dd-1404-42da-8c63-969cd4603466,
  abstract     = {{<p>BACKGROUND: SLE is associated with significant morbidity, especially in the case of renal involvement. Mitochondrial dysfunction plays a significant role in SLE and may be assessed by measuring mitochondrial DNA (mtDNA) and cytokines reflecting mitochondrial stress (mitokines). Circulating mtDNA is a promising biomarker in SLE and appears to be reduced in severe SLE. However, measuring circulating mtDNA is challenging and reported methods are heterogenous. Our study aimed at evaluating whole blood mtDNA to nuclear DNA (nucDNA) ratio using droplet-digital PCR and circulating mitokines, growth differentiation factor 15 (GDF-15) and fibroblast growth factor 21 in SLE with and without renal involvement.</p><p>METHODS: Cross-sectional study involving 195 patients with SLE and age-matched healthy volunteers (HV) as control. Biomarkers were compared in patients with and without renal involvement (defined by estimated glomerular filtration rate &lt;60 mL/min or proteinuria &gt;0.5 g/day) and in those with active and inactive SLE.</p><p>RESULTS: Compared with HV, patients with SLE displayed lower mtDNA/nucDNA ratios, especially in the case of renal involvement. Accordingly, mitokines were increased in patients with SLE with renal involvement. We found no correlation between mtDNA/nucDNA ratio and global disease activity. Mitokine levels, on the other hand, correlated with disease activity, in particular GDF-15 even after adjusting for renal involvement.</p><p>CONCLUSION: Our findings suggest that lower whole blood mtDNA/nucDNA ratio, a surrogate marker for mitochondrial dysfunction, reflects renal damage, while GDF-15 may also reflect disease activity in SLE. Further studies are needed to assess the clinical value of these markers as predictors for active lupus nephritis.</p>}},
  author       = {{Halfon, Matthieu and Memon, Ashfaque A and Hedelius, Anna and Pascual, Manuel and Sundquist, Kristina and Ribi, Camillo}},
  issn         = {{2053-8790}},
  keywords     = {{Humans; Female; DNA, Mitochondrial/blood; Male; Adult; Cross-Sectional Studies; Lupus Erythematosus, Systemic/blood; Growth Differentiation Factor 15/blood; Biomarkers/blood; Middle Aged; Mitochondria/metabolism; Lupus Nephritis/blood; Case-Control Studies; Cytokines/blood; Fibroblast Growth Factors/blood; Glomerular Filtration Rate}},
  language     = {{eng}},
  month        = {{02}},
  number       = {{1}},
  publisher    = {{BMJ Publishing Group}},
  series       = {{Lupus science & medicine}},
  title        = {{Lower circulating mitochondrial DNA and increased mitokines suggest significant mitochondrial dysfunction in systemic lupus erythematosus with renal involvement}},
  url          = {{http://dx.doi.org/10.1136/lupus-2024-001368}},
  doi          = {{10.1136/lupus-2024-001368}},
  volume       = {{12}},
  year         = {{2025}},
}