Decreased mitochondrial electron transport proteins and increased complement mediators in plasma neural-derived exosomes of early psychosis

Abstract

Potentially neurotoxic systems involved in traumatic and degenerative diseases of the brain were assessed in acute psychosis. Astrocyte-derived exosomes (ADEs) and neuron-derived exosomes (NDEs) were immunoprecipitated from plasma of ten untreated first-episode psychotics (FPs) and ten matched normal controls (Cs). Neural mitochondrial electron transport and complement proteins were extracted, quantified by ELISAs and normalized with levels of CD81 exosome marker. Levels of subunits 1 and 6 of NADH-ubiquinone oxidoreductase (complex I) and subunit 10 of cytochrome b-c1 oxidase (complex III), but not of subunit 1 of cytochrome C oxidase (complex IV) or superoxide dismutase 1 (SOD1) were significantly lower in ADEs and NDEs of FPs than Cs. This dysregulated pattern of electron transport proteins is associated with increased generation of reactive oxygen species. ADE glial fibrillary acidic protein levels were significantly higher in FPs than Cs, indicating a higher percentage of inflammatory astrocytes in FPs. ADE levels of C3b opsonin were significantly higher and those of C5b-9 attack complex was marginally higher in FPs than Cs. A significantly lower ADE level of the C3 convertase inhibitor CD55 may explain the higher levels of C3 convertase-generated C3b. ADE levels of the neuroprotective protein leukemia inhibitory factor (LIF) were significantly lower in FPs than Cs, whereas levels of IL-6 were no different. Plasma neural exosome levels of electron transport and complement proteins may be useful in predicting FP and guiding therapy. SOD mimetics, C3 convertase inhibitors and LIF receptor agonists also may have therapeutic benefits in FP.

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

“…Extracellular vesicle marker CD81-normalized levels of representative proteins in mitochondrial electron transport complexes I and III, but not IV, had been shown to be significantly lower in ADEVs and NDEVs of FP patients than ctls. 11 Existing data relevant to these levels of electron transport complexes suggested that ROS production would, therefore, be higher and ATP generation lower in mitochondria of both types of CNS cells of FP patients than ctls. 16 CD81normalized enzymatic activity of ATP synthase (complex V) was significantly higher for ctl ADEVs than NDEVs and ATP synthase activity in NDEVs of FP patients was not significantly different than that in ctls (Table 2).…”

“…Some of the neural exosome protein abnormalities previously identified in this study group of ten FP patients had suggested neuroinflammation, altered neural mitochondrial electron/proton transport and decreased neural survival mechanisms. 11 Blood was obtained at the same time of day from all participants without fasting.…”

“…Plasma extracellular vesicles or exosomes derived from neurons (NDEVs) and astrocytes (ADEVs) recently have been enriched from first-episode psychosis (FP) patients and matched controls (ctls) to permit quantification of their cargo proteins of potential relevance to schizophrenia. 11 Significant differences between FP patients and ctls were: ADEV levels of immune complement system neurotoxic proteins C3b and C5b-9 were higher and some complement regulatory membrane proteins lower in FP patients, ADEV levels of the neuroprotective protein leukemia inhibitory factor (LIF) were lower in FP patients, and ADEV and NDEV levels of mitochondrial electron transport chain complexes I and III, but not IV, were sufficiently lower in FP patients than ctls to generate more reactive oxygen species (ROS) and less ATP.…”

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

“…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 ]. Currently, there are limited reports on the collection of microglia-derived exosomes (MDE) [ 128 ] because microglia largely share the surface marker with peripheral macrophages.…”