Neural cell‐derived plasma exosome protein abnormalities implicate mitochondrial impairment in first episodes of psychosis

Abstract

Neuroprotective and other functional proteins of mitochondria were quantified in extracts of plasma neural-derived exosomes from ten first-episode psychosis (FP) patients and ten matched psychiatrically normal controls (ctls). Astrocyte-derived extracellular vesicles (ADEVs) and neuron-derived extracellular vesicles (NDEVs) were immunoabsorbed separately from physically precipitated plasma total EVs. Extracted mitochondrial ATP synthase was specifically immunofixed to plastic wells for quantification of catalytic activity based on conversion of NADH to NAD + . Other extracted mitochondrial functional proteins were quantified by ELISAs. All protein levels were normalized with EV content of the CD81 exosome marker. FP patient ADEV level but not NDEV level of mitochondrial ATP synthase activity was significantly lower than that of ctls. FP patient ADEV and NDEV levels of the functionally critical mitochondrial proteins mitofusin 2 and cyclophilin D, but not of transcription factor A of mitochondria, and of the mitochondrial short open-reading frame neuroprotective and metabolic regulatory peptides humanin and MOTS-c were significantly lower than those of ctls. In contrast, FP patient NDEV, but not ADEV, level of the mitochondrial-tethering protein syntaphilin, but not of myosin VI, was significantly higher than that of ctls. The distinctively different neural levels of some mitochondrial proteins in FP patients than ctls now should be correlated with diverse clinical characteristics. Drugs that increase depressed levels of proteins and mimetics of deficient short open-reading frame peptides may be of therapeutic value in early phases of schizophrenia.

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

“…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 SSRI therapy and in NDEVs of 10 matched controls (Table 1 ). Plasma NDEV levels of most of this same group of mitochondrial proteins in patients with a first episode of psychosis (FP) had been shown to differ significantly from those of age- and sex-matched mentally healthy controls [ 16 , 17 ]. NDEV levels of those mitochondrial proteins that were not previously quantified for FP subjects now are presented in the figure legends for comparison with MDD data.…”

“…There are major quantitative differences between alterations in NDEV levels of mitochondrial proteins in MDD and those observed in FP (Table 3 and figure legends) [ 16 , 17 ]. For most of the mitochondrial proteins, baseline level decreases relative to controls in the absence of treatment are only modestly quantitatively different between the two diseases, whereas for TFAM and PGC-1α there are no differences in either condition.…”

“…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 ]. Recent analyses of NDEV proteins in subjects with the first episode of psychosis (FP) revealed abnormalities in levels of mitochondrial electron transport complexes, structural components, tethering elements and neuroprotective factors relative to those of matched controls [ 16 , 17 ]. Now we present here the results of studies of a similar range of MPs in NDEVs of MDD participants before and after therapy with a selective serotonin reuptake inhibitor in comparison with those of psychiatrically normal age- and sex-matched controls.…”

Mitochondrial Electron Transport Chain Protein Abnormalities Detected in Plasma Extracellular Vesicles in Alzheimer’s Disease

“…In addition to biomarkers reflecting amyloidosis, tauopathy, neurodegeneration, and insulin resistance [ 6 , 8 , 9 , 10 , 11 ], EVs and NDEVs contain mitochondrial cargo, including mitochondrial RNAs [ 12 ], that may be used to investigate mitochondrial abnormalities in AD. The study of abnormalities of mitochondrial oxidative phosphorylation and ROS elimination in living humans has recently become possible through assessing plasma NDEV levels of ETC proteins and SOD1, a pursuit initially undertaken in relation to psychosis [ 13 , 14 ].…”

New Insights Regarding Diagnosis and Medication for Schizophrenia Based on Neuronal Synapse–Microglia Interaction

“…This method has already been applied to some neurological diseases, including schizophrenia. Goetzl et al further found a severe reduction in MFN2 and CYPD proteins in the NDE of patients with schizophrenia, suggesting the impairment of mitochondria in the disease [ 126 ]. They collected astrocyte-derived exosomes (ADE) to determine the upregulation of complement proteins; this suggests that complement abnormalities occur in astrocytes in schizophrenia [ 127 ].…”