PMID- 35635577 OWN - NLM STAT- MEDLINE DCOM- 20220608 LR - 20230215 IS - 1432-1440 (Electronic) IS - 0946-2716 (Print) IS - 0946-2716 (Linking) VI - 100 IP - 6 DP - 2022 Jun TI - Leukocyte cytokine responses in adult patients with mitochondrial DNA defects. PG - 963-971 LID - 10.1007/s00109-022-02206-2 [doi] AB - 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-alpha, IL-1beta) 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 (EC(50)), relative to controls, leukocytes from patients with mtDNA deletions showed 74-79% lower responses for IL-6 and IL-1beta (p(IL-6) = 0.031, p(IL-1beta) = 0.009). Moreover, whole blood from patients with mtDNA deletions (p(IL-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. CI - (c) 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature. FAU - Karan, Kalpita R AU - Karan KR AUID- ORCID: 0000-0002-4152-7541 AD - Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, USA. FAU - Trumpff, Caroline AU - Trumpff C AUID- ORCID: 0000-0002-7070-5546 AD - Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, USA. FAU - Cross, Marissa AU - Cross M AD - Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, USA. FAU - Engelstad, Kristin M AU - Engelstad KM AUID- ORCID: 0000-0002-9138-1069 AD - Department of Neurology, H. Houston Merritt Center and Columbia Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, NY, USA. FAU - Marsland, Anna L AU - Marsland AL AUID- ORCID: 0000-0001-8951-7513 AD - Department of Psychology, University of Pittsburgh, Pittsburgh, PA, USA. FAU - McGuire, Peter J AU - McGuire PJ AD - National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. FAU - Hirano, Michio AU - Hirano M AUID- ORCID: 0000-0002-7070-7402 AD - Department of Neurology, H. Houston Merritt Center and Columbia Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, NY, USA. FAU - Picard, Martin AU - Picard M AUID- ORCID: 0000-0003-2835-0478 AD - Department of Psychiatry, Division of Behavioral Medicine, Columbia University Irving Medical Center, New York, NY, USA. martin.picard@columbia.edu. AD - Department of Neurology, H. Houston Merritt Center and Columbia Translational Neuroscience Initiative, Columbia University Irving Medical Center, New York, NY, USA. martin.picard@columbia.edu. AD - New York State Psychiatric Institute, New York, NY, 10032, USA. martin.picard@columbia.edu. LA - eng GR - R01MH119336/MH/NIMH NIH HHS/United States GR - R21 MH113011/MH/NIMH NIH HHS/United States GR - R21MH113011/MH/NIMH NIH HHS/United States GR - R01 MH119336/MH/NIMH NIH HHS/United States GR - P30 CA013696/CA/NCI NIH HHS/United States GR - R01 MH122706/MH/NIMH NIH HHS/United States GR - UL1TR001873/TR/NCATS NIH HHS/United States GR - UL1 TR001873/TR/NCATS NIH HHS/United States GR - P30CA013696/TR/NCATS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20220530 PL - Germany TA - J Mol Med (Berl) JT - Journal of molecular medicine (Berlin, Germany) JID - 9504370 RN - 0 (Cytokines) RN - 0 (DNA, Mitochondrial) RN - 0 (Glucocorticoids) RN - 0 (Interleukin-6) RN - 0 (Lipopolysaccharides) RN - 7S5I7G3JQL (Dexamethasone) SB - IM MH - Animals MH - Cytokines MH - *DNA, Mitochondrial/genetics MH - Dexamethasone/pharmacology MH - Glucocorticoids/pharmacology MH - Humans MH - Interleukin-6 MH - Leukocytes MH - Lipopolysaccharides MH - *Mitochondrial Diseases/genetics PMC - PMC9885136 MID - NIHMS1864549 OTO - NOTNLM OT - 3243A > G OT - Cytokine OT - Glucocorticoid OT - Inflammation OT - Inflammation Suppression OT - Interleukin OT - Mitochondrial disease OT - mtDNA deletion COIS- Declarations Competing interests The authors declare no competing interests. EDAT- 2022/06/01 06:00 MHDA- 2022/06/09 06:00 PMCR- 2023/01/30 CRDT- 2022/05/31 12:41 PHST- 2021/12/21 00:00 [received] PHST- 2022/05/06 00:00 [accepted] PHST- 2022/04/11 00:00 [revised] PHST- 2022/06/01 06:00 [pubmed] PHST- 2022/06/09 06:00 [medline] PHST- 2022/05/31 12:41 [entrez] PHST- 2023/01/30 00:00 [pmc-release] AID - 10.1007/s00109-022-02206-2 [pii] AID - 10.1007/s00109-022-02206-2 [doi] PST - ppublish SO - J Mol Med (Berl). 2022 Jun;100(6):963-971. doi: 10.1007/s00109-022-02206-2. Epub 2022 May 30.