Mitochondrial Biomarkers and Metabolic Syndrome in Bipolar Disorder
Authors: Zachos Kassandra A. , Choi Jaehyoung , Godin Ophelia , Chernega Timofei , Kwak Haejin Angela , Jung Jae H. , Aouizerate Bruno , Aubin Valérie , Bellivier Frank , Belzeaux R Raoul , Courtet Philippe , Dubertret Caroline , Etain Bruno , Haffen Emmanuel , Lefrere A Antoine , Llorca Pierre-Michel , Olié Emilie , Polosan Mircea , Samalin Ludovic , Schwan Raymund , Roux Paul ,   the FondaMental Academic Centers of Expertise in Bipolar Disorders (FACE-BD) Collaborators, Barau Caroline , Richard Jean Romain , Tamouza Ryad , Leboyer Marion , Andreazza Ana C. 
Published: December 2023

AbstractImportanceExamining translatable mitochondrial blood-based biological markers to identify its association with metabolic diseases in bipolar disorder.ObjectiveTo test whether mitochondrial metabolites, mainly lactate, and cell-free circulating mitochondrial DNA are associated with markers of metabolic syndrome in bipolar disorder, hypothesizing higher lactate but unchanged cell-free circulating mitochondrial DNA levels in bipolar disorder patients with metabolic syndrome.DesignIn a cohort study, primary testing from the FondaMental Advanced Centers of Expertise for bipolar disorder was conducted, including baseline plasma samples and blinded observers for all experimentation and analysis.SettingThe FondaMental Foundation coordinate a multicenter, multidisciplinary French networks aiming at creation of cohorts to improve identification of homogeneous subgroups of psychiatric disorders toward personalized treatments.ParticipantsThe FACE-BD primary testing cohort includes 837 stable bipolar disorder patients. The I-GIVE validation cohort consists of 235 participants: stable and acute bipolar patients, non-psychiatric controls, and acute schizophrenia patients. Participants were randomly selected based on biosample availability.ExposuresAll patients underwent the standard primary care within their center. No intentional exposures were part of this study.Main Outcome and MeasuresThe primary outcome modelled an association with lactate and metabolic syndrome in this population. Reflectivea priorihypothesis.ResultsMultivariable regression analyses show lactate association with triglycerides (Est= 0.072(0.023), p = 0.0065,), fasting glucose (Est = 12(0.025), p= 0.000015) and systolic (Est= 0.003(0.0013), p= 0.031) and diastolic blood pressure (Est = 0.0095±0.0017, p= 1.3e-7). Significantly higher levels of lactate were associated with presence of metabolic syndrome (Est = 0.17±0.049, p=0.00061) after adjusting for potential confounding factors. Mitochondrial-targeted metabolomics identified distinct metabolite profiles in patients with lactate presence and metabolic syndrome, differing from those without lactate changes but with metabolic syndrome. Circulating cell-free mitochondrial DNA was not associated with metabolic syndrome.Conclusion & RelevanceThis thorough analysis mitochondrial biomarkers indicate the associations with lactate and metabolic syndrome, whereas circulating cell-free mitochondrial DNA is limited in the context of metabolic syndrome. This study is relevant to improve the identification and stratification of bipolar patients with metabolic syndrome and provide potential personalized-therapeutic opportunities.Key PointsQuestionCan lactate, a mitochondrial metabolite, indicate metabolic syndrome in bipolar disorder?FindingIn 837 stable bipolar disorder patients, we found high lactate levels significantly associated with metabolic syndrome, unlike circulating cell-free mitochondrial DNA. This pattern also appeared in acute bipolar and schizophrenia cases. Mitochondrial-targeted metabolomics distinguishes patients with high lactate and metabolic syndrome from those without lactate changes, but presence of metabolic syndrome.MeaningThis research underscores lactate as a potential biomarker for identifying bipolar disorder patients with metabolic syndrome. It opens new avenues for personalized treatment strategies, leveraging mitochondrial metabolite profiling to improve patient stratification and therapeutic outcomes.