Mol Psychiatry︱The new discovery of a biomarker for depression-mitochondrial protein in exosomes

Written by Zheng Yuanjia, edited by Zheng Yuanjia, Wang Sizhen’s major depressive disorde (MDD) is an emotional dysfunction caused by abnormalities in the patient’s individual genetic system (genes) or by the drastic changes in the acquired environment.
A series of depression symptoms dominated by depression, the World Health Organization lists it as the world’s largest factor leading to disability [1, 2]
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Although the prevalence and incidence of MDD are high, the current diagnostic methods for MDD are not reliable
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First-line drug therapy is also not completely effective.
Only 27% of patients resolved after the first treatment, and 67% resolved after four complete treatments
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 In order to evaluate and develop new treatment methods well, it is necessary to identify specific biomarkers involved in the pathogenesis of MDD, so as to reveal their related therapeutic targets [3, 4]
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Previous studies have shown that the concentrations of certain neurotransmitters, tryptophan metabolites, endocrine hormones, immune cytokines, growth and neurotrophic factors in the blood of patients with depression are significantly different from those in the control group [5-9], among which, growth And the decline of neurotrophic factors, the rise of immune cytokines and cortisol are positively correlated with response to treatment [5,7]
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However, the changes in these biomarkers lack disease specificity and cannot be used to predict the severity of the disease and the response to treatment
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New research shows that the number, morphology, and electron transfer activity of neuronal mitochondria in mental diseases have changed significantly, and the increase, deletion and mutation of mitochondrial DNA polymorphisms also suggest that mitochondrial abnormalities may be the basic pathogenic mechanism of MDD [10]
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In stress-induced mood disorders, changes in the copy number of mitochondrial DNA and changes in the activity of mitochondrial respiratory chain enzymes can also be observed [11]
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A recent analysis of neuron-derived extracellular vesicles in patients with first-episode psychosis showed that compared with the control group, the levels of mitochondrial electron transport complexes, structural components, and neuroprotective factors were abnormal [14, 15]
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 In September 2021, Edward J.
Goetzl (first author and corresponding author) of the University of California School of Medicine and his collaborators published a titled "Abnormal levels of mitochondrial proteins in plasma neuronal extracellular vesicles in major depressive disorder" on Molecular Psychiatry.
The article compares the difference in functional mitochondrial protein of neuron-derived extracellular vesicles between MDD patients before and after treatment with a specific serotonin reuptake inhibitor (SSRI) and healthy controls of the corresponding age and gender.
It may become a useful biomarker of depression and a drug target
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 Extracellular vesicles are diverse nano-scale membrane vesicles actively released by cells.
Vesicles of similar size can be further classified according to their biogenesis, size and biophysical properties (such as exosomes, microvesicles)
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The author team developed a platform for studying neuronal mitochondrial proteins (MPs) in plasma neuron-derived extracellular vesicles (NDEVs), which are enriched in exosomal subunits.
Therefore, detecting the level of exosomes can also reflect the content of MPs in brain neurons[12,13]
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The authors quantified 14 mammalian neuronal mitochondrial proteins in the plasma NDEVs (including exosomes) of 20 MDD patients who received SSRI treatment before and after and 10 NDEVs in the control group
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The plasma NDEV level of patients with first episode psychosis is significantly different from that of healthy controls [14,15]
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Figure 1 shows the NDEV levels of various neuronal proteins (including the exosomal marker CD81)
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The pre-treatment (R-Bsl) level of CD81 (Figure 1A) in the population that responded to SSRI was slightly increased compared to the normal control (Ctl), and returned to the normal level (R-Tr) after treatment
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Figure 1 NDEV protein levels involved in mitochondrial dynamics and other maintenance functions (Source: Goetzl E.
J et al.
, Mol Psychiatry.
2021) The first type of protein observed in this study is NDEV involved in mitochondrial dynamics and functional maintenance Mitochondrial proteins, including transcription factor TFAM, CYPD regulators of membrane potential, metabolism and pore permeability, MFN2 required for mitochondrial fusion and distribution, and anchoring of mitochondria to axon microtubules and microfilaments in the presynaptic region Tethering proteins SNPH and MY06 (Table 1) [16-20]
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The results showed that the TFAM of the post-treatment (R-Tr) group that responded to SSRI was slightly higher than the normal R-Bsl level (Figure 1B)
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The MFN2 and CYPD levels of the group that did not respond to SSRI before treatment (NR-Bsl) and the R-Bsl group were significantly lower than those of the Ctl group.
After treatment, the CYPD level of R-Tr was significantly higher than that of R-Bsl, while the level of MFN2 The R-Tr level was completely restored to the Ctl level
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The CYPD and MFN2 levels of the group that did not respond to SSRI after treatment (NR-Tr) did not change significantly (Figure 1C, D)
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In addition, the SNPH and MY06 levels of NR-Bsl and R-Bsl were significantly lower than the Ctl group, but the SNPH and MY06 levels of R-Tr after treatment were significantly higher than the Bsl level (the NR-Tr group did not change) (Figure 1E, F) )
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The results of calcium channel/calcium channel enhancing protein LETM1 are similar to MFN2 (Figure 1G)
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The levels of the four above-mentioned NDEVs in patients with first episode psychosis were significantly lower than those in the control group (Table 1)
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The expression levels of SNPH and MY06 in FP were significantly different from those in MDD group
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Table 1 Comparison of baseline mitochondrial NDEV protein levels between first episode psychosis (FP) and untreated MDD (Source: Goetzl E.
J et al.
, Mol Psychiatry.
2021) In addition to the above neuronal mitochondrial protein, the second category observed in this study Protein is a class of proteins that play an important role in energy production, including: inner membrane electrotransfer complex NADH dehydrogenase complex I-6 (Complex I-6) and cytochrome b-c1 complex III-10 (Complex III -10), nicotinamide mononucleotide adenosine transferase 2 (NMNAT2), and SARM1 with significant NAD enzyme activity (Table 1) [21, 22]
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The levels of NR-Bsl and R-Bsl in Complex I-6 and Complex III-10 were significantly lower than those in the corresponding control group (Figure 2 A, B)
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Among them, Complex III-10 in R-Tr can be completely reversed by treatment, while Complex I-6 does not change significantly
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The Complex III-10 protein level in the NR-Tr group was not affected by the treatment, while the Complex I-6 protein level was significantly reduced
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The two main enzymes that determine the concentration of mitochondrial NADH/NAD+ are NMNAT2 and SARM1.
Compared with Ctls, the NMNAT2 level of the NR-Bsl and R-Bsl groups was significantly reduced (Figure 2C), while the SARM1 level was significantly increased (Figure 2D)
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In the R-Tr group, the two protein levels were normalized, but there was no change in the NR-Tr group
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Figure 2 The level of NDEV protein involved in mitochondrial energy production (Source: Goetzl E.
J et al.
, Mol Psychiatry.
2021) The third type of neuronal mitochondrial protein is involved in metabolic regulation and cell survival, including nerves encoded by mitochondrial ribosomal RNA The protective protein Humanin and the neuronal metabolism regulator protein MOTS-c (Table 1, Figure 3A, B) [23-25]
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In the R-Bsl group, the two protein levels were significantly lower than Ctls, which can be reversed after treatment in the R-Tr group
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However, in the group that did not respond to SSRI, the MOTS-c level of the NR-Bsl group was significantly reduced, and there was no change after treatment, while the Humanin baseline did not change, but it further decreased after treatment
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 The fourth type of neuronal mitochondrial protein mainly regulates mitochondrial biogenesis by influencing mitochondrial DNA replication [26], including transcription factors PGC-1α and NRF2 (Table 1)
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There was no difference in the level of PGC-1α between the groups.
NRF2 was statistically different between the NR-Bsl group and the R-Bsl group, but there was no statistical difference between the NR-Tr group and the R-Tr group (Figure 3C, D )
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Figure 3 The level of NDEV protein involved in mitochondrial biogenesis (Source: Goetzl E.
J et al.
, Mol Psychiatry.
2021) Conclusion and discussion, inspiration and prospects of this study Protein observations indicate that MDD and first episode psychosis are related to many abnormalities of neuronal mitochondria, including its biogenesis, structure, metabolism, energy production and peptide production, as well as the protection and regulation of normal physiological processes of neurons by these peptides
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After MDD treatment is successful, most of the mitochondrial protein NDEV levels can be normalized, but in the group that does not respond to treatment, these proteins cannot be repaired and improved well, which also makes it impossible to clearly identify the specific mitochondrial protein.
Pathological mechanism or drug target
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However, these changes in NDEV protein may be used to reflect the severity of the disease or an indicator of response to treatment, or may indicate the early onset or recurrence of the disease
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 Another limitation of this study is that this result is based on the preliminary results of a small number of patients.
It is difficult to draw a meaningful correlation between the severity of MDD or first episode psychosis and the abnormal level of one or more mitochondrial proteins in NDEVs.
Therefore, Large-scale controlled studies are also needed to make further observational studies on correlations and identify particularly useful biomarkers and potential new drug targets
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Original link: https://doi.
org/10.
1038/s41380-021-01268-x Selected articles from previous issues [1] Science | Breakthrough! Astrocyte Ca2+ induces ATP release to regulate myelin axon excitability and conduction velocity [2] Neurosci Bull︱Shen Ying’s team reveals the three-dimensional heterogeneity of the cerebellar nucleus to thalamus projection [3] J Neurosci︱ Cao Junli’s group Reveal the loop mechanism of the anterior cingulate gyrus to regulate mirror pain [4] Nat Commun︱Non-human primate (monkey marmoset) autism model reveals the biological abnormalities in the early development of human diseases [5] Cell Discovery︱ Ma Yuanwu/Shen Bin’s team realized the precise editing of rat mitochondrial DNA for the first time [6] Dev Cell︱ Lactic acid promotes peripheral nerve damage and repair B side: Long-term lactic acid metabolism of axons can lead to oxidative stress and axon degeneration [7] Nat Commun︱ Selective inhibition of microglia activation is expected to alleviate the transmission of pathological α-syn [8] Science︱ Serotonin helps overcome cocaine addiction? [9] Mol Psychiatry︱ Gao Tianming’s research group reveals the different roles of astrocytes and neurons in synaptic plasticity and memory [10] Sci Transl Med︱ Xiang Xianyuan and others reveal the brain’s immune cells crazy sugar phagocytosis, helping nerves Early diagnosis of degenerative diseases [11] A new mechanism of Mol Cell︱ Alzheimer's disease: Tau protein oligomerization induces nuclear cell transport of RNA binding protein HNRNPA2B1 and mediates enhancement of m6A-RNA modification [12] Cereb Cortex | Li Tao project The group reported the abnormality of the cortical myelin covariation network with the deep characteristics of the cerebral cortex in schizophrenia [13] Cell︱ hand in hand, advance and retreat together! Microglia form a cellular connection network and work together to degrade pathological α-syn.
Recommended high-quality scientific research training courses [1] Discount countdown ︱ Near-infrared brain function data processing class (online: 11.
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