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Blood-based mitochondrial respiratory chain function in major depression

ABSTRACT: Mitochondrial dysfunction has been implicated in major depressive disorder (MDD). A measure of mitochondrial respiratory chain (RC) enzymatic activity—the Mitochondrial Health Index (MHI)—has previously been found to correlate with stress and emotional states in caregivers. We here report mitochondrial RC activities, mitochondrial DNA copy number (mtDNAcn), and the composite MHI in unmedicated and somatically healthy subjects with MDD (n = 47) and healthy controls (HC) (n = 11). We also explore, in a subset of the MDD sample (n = 33), whether these markers are associated with response to 8 weeks of SSRI treatment. Mitochondrial RC complexes I, II, IV, citrate synthase (CS), mtDNAcn, and the MHI were assayed in peripheral blood mononuclear cells. Treatment response was defined as >50% decrease on the 25-item Hamilton Depression Rating Scale (HRDS-25). There were no significant differences in MHI or any of the mitochondrial markers between MDD subjects and HCs. Compared to SSRI nonresponders, SSRI responders had significantly higher baseline mitochondrial content markers CS (p = 0.02) and mtDNAcn (p = 0.02), and higher complex I activity (p = 0.01). Complex II activity increased significantly over treatment, irrespective of clinical response (p = 0.03). Complex I activity decreased in responders (n = 9), but increased in nonresponders (n = 18) (group x time interaction, p = 0.02). Absolute treatment-associated change in HDRS-25 scores correlated significantly with change in complex I activity between baseline and week 8 (r = 0.47, p = 0.01). Although mitochondrial markers did not distinguish MDD from controls, they did distinguish SSRI responders from nonresponders. If larger studies validate these mitochondrial differences, they may become useful biomarkers and identify new drug targets.

SUBMITTER: Fernstrom J

PROVIDER: S-EPMC8599473 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. To identify a common cellular response to RC disease, systems biology level transcriptome investigations were performed in human RC disease skeletal muscle and fibroblasts. Global transcriptional and post-transcriptional dysregulation in a tissue-specific fashion was identified across diverse RC complex and genetic etiologies. RC disease muscle was characterized by decreased transcription of cytosolic ribosomal proteins to reduce energy-intensive anabolic processes, increased transcription of mitochondrial ribosomal proteins, shortened 5'-UTRs to improve translational efficiency, and stabilization of 3'-UTRs containing AU-rich elements. These same modifications in a reversed direction typified RC disease fibroblasts. RC disease also dysregulated transcriptional networks related to basic nutrient-sensing signaling pathways, which collectively mediate many aspects of tissue-specific cellular responses to primary RC disease. These findings support the utility of a systems biology approach to improve mechanistic understanding of mitochondrial RC disease. To identify a common cellular response to primary RC that might improve mechanistic understanding and lead to targeted therapies for human RC disease, we performed collective transcriptome profiling in skeletal muscle biopsy specimens and fibroblast cell lines (FCLs) of a diverse cohort of human mitochondrial disease subjects relative to controls. Systems biology investigations of common cellular responses to primary RC disease revealed a collective pattern of transcriptional, post-transcriptional and translational dysregulation occurring in a highly tissue-specific fashion. Affymetrix Human Exon 1.0ST microarray analysis was performed on 29 skeletal muscle samples and Fibroblast cell lines from mitochondrial disease patients and age- and gender-matched controls.

Project description:UnlabelledDiagnosing primary mitochondrial respiratory chain (RC) dysfunction has long relied on invasive tissue biopsies, since no blood-based biomarker has been shown to have sufficiently high sensitivity and specificity across the myriad of individual clinical presentations. We sought to determine whether cohort-level evaluation of commonly obtained blood analytes might reveal consistent patterns to discriminate a heterogenous group of primary mitochondrial RC disease subjects both from control individuals and from subjects with pyruvate dehydrogenase deficiency.MethodsFollowing IRB approval, 62 biochemical analyte concentrations or ratios were retrospectively analyzed in three well-defined and intentionally heterogeneous subject cohorts reflective of clinical practice: [1] Primary mitochondrial disease (n=19); [2] pyruvate dehydrogenase deficiency (n=4); and [3] controls (n=27). Blood analyte categories included comprehensive chemistry profile, creatine kinase, lipoprotein profile, lactate, pyruvate, and plasma amino acid profile. Non-parametric analyses were used to compare the median of each analyte level between cohorts.ResultsDisease cohorts differed significantly in their median levels of triglycerides, lactate, pyruvate, and multiple individual plasma amino acids. Primary mitochondrial disease was significantly discriminated at the cohort level from pyruvate dehydrogenase deficiency by greater pyruvate and alanine elevation in pyruvate dehydrogenase deficiency, as well as significantly increased branched chain amino acid (BCAA) levels and increased ratios of individual BCAAs to glutamate in mitochondrial disease. In addition, significant elevation of median blood triglyceride level was seen in the primary mitochondrial disease cohort.ConclusionsBlood metabolite profile analysis can discriminate a heterogeneous cohort of primary mitochondrial disease both from controls and from pyruvate dehydrogenase deficiency. Elevated BCAA levels, either absolutely or when considered relative to the level of glutamate, are common metabolic sequelae of primary mitochondrial RC disease. Prospective study is needed to validate observed plasma metabolite alterations as a potential biomarker of disease both in larger cohorts and at the individual subject level.

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Blood-based mitochondrial respiratory chain function in major depression

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