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Mitochondrial Dysfunction in Mood Disorders and Metabolic Disease: Uncovering the Role of Biomarkers and Nutrition

Year: 2025
Type: dissertation
Study design: Observational Study
Abstract: Mood and metabolic disorders are increasingly recognized as co-occurring diseases with substantial individual and economic consequences. Researchers argue that these diseases form a ‘metabolic-mood syndrome,’ characterized by a bidirectional relationship and shared pathophysiology, notably mitochondrial dysfunction. This thesis examines two mitochondrial blood-based biomarkers, lactate and circulating cell-free mitochondrial DNA (ccf-mtDNA), to better understand their roles in mood disorders and metabolic diseases and to improve patient stratification and therapeutic targeting. We investigated three cohorts: two French cohorts (FACE-BD & I-GIVE) with bipolar disorder (BD) and 20% with metabolic syndrome (MetS), and a third cohort (SDS2) with type 2 diabetes (T2D), major depressive disorder (MDD) and anxiety. In the FACE-BD cohort, lactate levels were associated with MetS and patient stratification was modeled in mitochondrial-targeted metabolomics when participants were segregated for high lactate levels and MetS. This trend was similar but not significant in the SDS2 cohort. In the I-GIVE cohort, lactate levels were comparable to those with stable BD in the FACE-BD cohort, but significantly higher in those in an acute disease state. Ccf-mtDNA did not model the same patient stratification. Given the critical role of diet in these diseases, we also assessed diet quality and dietary interventions and their associations with these biomarkers. Meat consumption was linked to higher lactate levels, while high-fiber carbohydrate intake was associated with a lower prevalence of MetS in BD. No associations were found with ccf-mtDNA. Our findings suggest the robustness of these biomarkers, especially lactate as a tool for stratification in metabolic psychiatry but further longitudinal studies in larger cohorts are warranted. Future studies should also investigate mitochondrial metabolites highlighted in the BD cohorts. Ccf-mtDNA should be explored as a potential biomarker for immune-related symptomatology in these diseases. Additionally, dietary trials, including ketogenic diets and dietary fat consumption, may provide meaningful data. In conclusion, lactate shows potential as a biomarker and tool for stratifying mood and metabolic disorders, highlighting new personalized therapeutic targets through the utilization of mitochondrial metabolites.
Language: English
Field: Medicine
Open Access status: green
OpenAlex ID: W7133017585
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