Abnormal levels of mitochondrial proteins in plasma neuronal extracellular vesicles in major depressive disorder

Vinod H Srihari,Edward J Goetzl,Laura Goetzl,George R Heninger,Owen M Wolkowitz,Victor I Reus,Dimitrios Kapogiannis,Synthia H Mellon

doi:10.1038/s41380-021-01268-x

Abstract

To characterize neuronal mitochondrial abnormalities in major depressive disorder (MDD), functional mitochondrial proteins (MPs) extracted from enriched plasma neuron-derived extracellular vesicles (NDEVs) of MDD participants (n = 20) were quantified before and after eight weeks of treatment with a selective serotonin reuptake inhibitor (SSRI). Pretreatment baseline NDEV levels of the transcriptional type 2 nuclear respiratory factor (NRF2) which controls mitochondrial biogenesis and many anti-oxidant gene responses, regulators of diverse neuronal mitochondrial functions cyclophilin D (CYPD) and mitofusin-2 (MFN2), leucine zipper EF-hand containing transmembrane 1 protein (LETM1) component of a calcium channel/calcium channel enhancer, mitochondrial tethering proteins syntaphilin (SNPH) and myosin VI (MY06), inner membrane electron transport complexes I (subunit 6) and III (subunit 10), the penultimate enzyme of nicotinamide adenine dinucleotide (NAD) generation nicotinamide mononucleotide adenylytransferase 2 (NMNAT2), and neuronal mitochondrial metabolic regulatory and protective factors humanin and mitochondrial open-reading frame of the 12S rRNA-c (MOTS-c) all were significantly lower than those of NDEVs from matched controls (n = 10), whereas those of pro-neurodegenerative NADase Sterile Alpha and TIR motif-containing protein 1 (SARM1) were higher. The baseline NDEV levels of transcription factor A mitochondrial (TFAM) and the transcriptional master-regulator of mitochondrial biogenesis PPAR γ coactivator-1α (PGC-1α) showed no differences between MDD participants and controls. Several of these potential biomarker proteins showed substantially different changes in untreated MDD than those we reported in untreated first-episode psychosis. NDEV levels of MPs of all functional classes, except complex I-6, NRF2 and PGC-1α were normalized in MDD participants who responded to SSRI therapy (n = 10) but not in those who failed to respond (n = 10) by psychiatric evaluation. If larger studies validate NDEV MP abnormalities, they may become useful biomarkers and identify new drug targets.

Highlights

Major depressive disorder (MDD) is ranked by the World Health Organization as the single largest contributor to global disability [1, 2]
We have developed a platform for investigations of neuronal mitochondrial proteins (MPs) found in plasma neuron-derived extracellular vesicles (NDEVs) enriched for exosomes at levels that reflect those in brain neurons [14, 15]
Fourteen mammalian neuron mitochondrial proteins were quantified in plasma neuron-derived extracellular vesicles (NDEVs, that include exosomes) of 20 MDD participants before and after an eight-week course of selective serotonin reuptake inhibitor (SSRI) therapy and in NDEVs of 10 matched controls (Table 1)

Summary

Introduction

Major depressive disorder (MDD) is ranked by the World Health Organization as the single largest contributor to global disability [1, 2]. Evaluation of new therapeutic approaches should include specific biomarkers that objectively identify the involvement of pathogenic mechanisms underlying MDD and may reveal relevant molecular targets [4, 5]. Investigations of blood-based biomarkers in MDD have begun to increase our understanding of relevant pathophysiology and alterations in the clinical course. Blood levels of growth and neurotrophic factors are decreased, whereas those of immune cytokines and cortisol show increases that positively correlate with poor responses to psychological and pharmacological therapy [6, 8]. Despite quantitatively striking changes in concentrations of some blood-based biomarkers in MDD, these alterations often have lacked disease specificity and any predictive capability regarding changes in severity or responses to treatment of the MDD. One recently emerging technology relies on analyses of blood mRNAs to track and predict the course and severity of depression and mania, as well as to identify potentially beneficial drug treatments [11]

Methods

Results

Conclusion