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Leukocyte cytokine responses in adult patients with mitochondrial DNA defects

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Abstract

Patients with oxidative phosphorylation (OxPhos) defects causing mitochondrial diseases appear particularly vulnerable to infections. Although OxPhos defects modulate cytokine production in vitro and in animal models, little is known about how circulating leukocytes of patients with inherited mitochondrial DNA (mtDNA) defects respond to acute immune challenges. In a small cohort of healthy controls (n = 21) and patients (n = 12) with either the m.3243A > G mutation or single, large-scale mtDNA deletions, we examined (i) cytokine responses (IL-6, TNF-α, IL-1β) in response to acute lipopolysaccharide (LPS) exposure and (ii) sensitivity to the immunosuppressive effects of glucocorticoid signaling (dexamethasone) on cytokine production. In dose–response experiments to determine the half-maximal effective LPS concentration (EC50), relative to controls, leukocytes from patients with mtDNA deletions showed 74–79% lower responses for IL-6 and IL-1β (pIL-6 = 0.031, pIL-1β = 0.009). Moreover, whole blood from patients with mtDNA deletions (pIL-6 = 0.006), but not patients with the m.3243A > G mutation, showed greater sensitivity to the immunosuppressive effects of dexamethasone. Together, these ex vivo data provide preliminary evidence that some systemic OxPhos defects may compromise immune cytokine responses and increase the sensitivity to immune cytokine suppression by glucocorticoids. Further work in larger cohorts is needed to define the nature of immune dysregulation in patients with mitochondrial disease, and their potential implications for disease phenotypes.

Key messages

  • Little is known about leukocyte cytokine responses in patients with mitochondrial diseases.

  • Leukocytes of patients with mtDNA deletions show blunted LPS sensitivity and cytokine responses.

  • Leukocytes of patients with mtDNA deletions are more sensitive to glucocorticoid-mediated IL-6 suppression.

  • Work in larger cohorts is needed to delineate potential immune alterations in mitochondrial diseases.

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Acknowledgements

We thank the patients and healthy volunteers who participated in this study, Johanne Fortune for assistance with phlebotomy, Logan Beharry for assistance with the systematic literature review, and the rest of the MiSBIE Team.

Funding

This work was supported by the Wharton Fund, the Irving Scholars Program, the Baszucki Brain Research Fund, and the National Center for Advancing Translational Sciences through grant numbers UL1TR001873, P30CA013696, and NIH grants R21MH113011 and R01MH119336 to M.P. and M.H. The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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Authors and Affiliations

  1. Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, USA

    Kalpita R. Karan, Caroline Trumpff, Marissa Cross & Martin Picard

  2. Department of Neurology, H. Houston Merritt Center and Columbia Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, NY, USA

    Kristin M. Engelstad, Michio Hirano & Martin Picard

  3. Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA

    Anna L. Marsland

  4. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Peter J. McGuire

  5. New York State Psychiatric Institute, New York, NY, 10032, USA

    Martin Picard

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  1. Kalpita R. Karan
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  2. Caroline Trumpff
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Contributions

K.R.K. and M.P. designed the study. C.T., M.H., M.P. developed the clinical protocol. K.E. and M.H. provided the clinical diagnosis and recruited the patients. M.C. coordinated the study activities and collected the data. K.R.K. performed the LPS stimulation and cytokine measurements. K.R.K. analyzed the data and prepared the figures. K.R.K. and M.P. drafted the manuscript with P.M. All the authors reviewed and edited the final version of this manuscript.

Corresponding author

Correspondence to Martin Picard.

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Informed consent was obtained in compliance with guidelines of the Institutional Review Board of the New York State Psychiatric Institute IRB#7424. All the participants provided informed consent for the study procedures and publication of data.

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The authors declare no competing interests.

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Karan, K.R., Trumpff, C., Cross, M. et al. Leukocyte cytokine responses in adult patients with mitochondrial DNA defects. J Mol Med 100, 963–971 (2022). https://doi.org/10.1007/s00109-022-02206-2

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  • DOI: https://doi.org/10.1007/s00109-022-02206-2

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