Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress

Prabakaran, Sudhakaran; Swatton, Jane E.; Ryan, Margaret M.; Huffaker, Stephen J.; Huang, Jeffrey T.‐J.; Griffin, Jules; Wayland, Matthew T.; Freeman, Tracy A.; Dudbridge, Frank; Lilley, Kathryn S.; Karp, Natasha A.; Hester, Svenja; Tkachev, Dmitri; Mimmack, Michael L.; Yolken, Robert H.; Webster, Maree J.; Torrey, Ε. Fuller; Bahn, Sabine

doi:10.1038/sj.mp.4001532

Cited by 482 publications

(289 citation statements)

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“…Our study and another two studies (Table 3) also found another protein related to oxidative stress, peroxiredoxin-1 (PRDX1), to be downregulated, reinforcing the concept of a reduced response to oxidative stress [58,59].…”

Section: Resultssupporting

confidence: 79%

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

Saia-Cereda

Cassoli

Schmitt

et al. 2015

Eur Arch Psychiatry Clin Neurosci

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Schizophrenia is an incurable and debilitating mental disorder that may affect up to 1% of the world population. Morphological, electrophysiological, and neurophysiological studies suggest that the corpus callosum (CC), which is the largest portion of white matter in the human brain and responsible for inter-hemispheric communication, is altered in schizophrenia patients. Here, we employed mass spectrometry-based proteomics to investigate the molecular underpinnings of schizophrenia. Brain tissue samples were collected postmortem from nine schizophrenia patients and seven controls at the University of Heidelberg, Germany. Because the CC has a signaling role, we collected cytoplasmic (soluble) proteins and submitted them to nano-liquid chromatography-mass spectrometry (nano LC-MS/MS). Proteomes were quantified by label-free spectral counting. We identified 5678 unique peptides that corresponded to 1636 proteins belonging to 1512 protein families. Of those proteins, 65 differed significantly in expression: 28 were upregulated and 37 downregulated. Our data increased significantly the knowledge derived from an earlier proteomic study of the CC. Among the differentially expressed proteins are those associated with cell growth and maintenance, such as neurofilaments and tubulins; cell communication and signaling, such as 14-3-3 proteins; and oligodendrocyte function, such as myelin basic protein and myelin-oligodendrocyte glycoprotein. Additionally, 30 of the differentially expressed proteins were found previously in other proteomic studies in postmortem brains; this overlap in findings validates the present study and indicates that these proteins may be markers consistently associated with schizophrenia. Our findings increase the understanding of schizophrenia pathophysiology and may serve as a foundation for further treatment strategies.

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Section: Resultssupporting

confidence: 79%

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

Saia-Cereda

Cassoli

Schmitt

et al. 2015

Eur Arch Psychiatry Clin Neurosci

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“…Mitochondria being the major source and target of ROS, play a pivotal role during ageing and neurodegenerative diseases (Prabakaran et al 2004;Balaban et al 2005;Lin and Flint Beal 2006). It is evident that CR is effective at mitochondria to lower the ROS levels (Bevilacqua et al 2004) by modulating respiratory chain activities and enhanced biogenesis of mitochondria with low membrane potential (Barja 2004;Lopez-Lluch et al 2006).…”

Section: Introductionmentioning

confidence: 99%

Modulation of oxidative phosphorylation machinery signifies a prime mode of anti-ageing mechanism of calorie restriction in male rat liver mitochondria

et al. 2009

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Mitochondria being the major source and target of reactive oxygen species (ROS) play a crucial role during ageing. We analyzed ageing and calorie restriction (CR)-induced changes in abundance of rat liver mitochondrial proteins to understand key aspects behind the age-retarding mechanism of CR. The combination of blue-native (BN) gel system with fluorescence Difference Gel Electrophoresis (DIGE) facilitated an efficient analysis of soluble and membrane proteins, existing as monomers or multi-protein assemblies. Changes in abundance of specific key subunits of respiratory chain complexes I, IV and V, critical for activity and/or assembly of the complexes were identified. CR lowered complex I assembly and complex IV activity, which is discussed as a molecular mechanism to minimize ROS production at mitochondria. Notably, the antioxidant system was found to be least affected. The GSH:GSSG couple could be depicted as a rapid mean to handle the fluctuations in ROS levels led by reversible metabolic shifts. We evaluated the relative significance of ROS generation against quenching. We also observed parallel and unidirectional changes as effect of ageing and CR, in subunits of ATP synthase, cytochrome P450 and glutathione S-transferase. This is the first report on such 'putatively hormetic' ageing-analogous effects of CR, besides the age-retarding ones.

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“…In anxiety this is supported by -omics findings in mouse models [21,22,33]. Proteomics and metabolomics studies in schizophrenia [19,34,35,36,37] and depression [38] have also reported alterations for protein and metabolite oxidative stress markers.…”

Section: Proteomics and Metabolomics Studies In Psychiatric Disordersmentioning

confidence: 50%

What Have Mass Spectrometry-Based Proteomics and Metabolomics (Not) Taught Us about Psychiatric Disorders?

Turck

Filiou

2015

Complex Psychiatry

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Understanding the molecular causes and finding appropriate therapies for psychiatric disorders are challenging tasks for research; -omics technologies are used to elucidate the molecular mechanisms underlying brain dysfunction in a hypothesis-free manner. In this review, we will focus on mass spectrometry-based proteomics and metabolomics and address how these approaches have contributed to our understanding of psychiatric disorders. Specifically, we will discuss what we have learned from mass spectrometry-based proteomics and metabolomics studies in rodent models and human cohorts, outline current limitations and discuss the potential of these methods for future applications in psychiatry.

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Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress

Cited by 482 publications

References 0 publications

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

Proteomics of the corpus callosum unravel pivotal players in the dysfunction of cell signaling, structure, and myelination in schizophrenia brains

Modulation of oxidative phosphorylation machinery signifies a prime mode of anti-ageing mechanism of calorie restriction in male rat liver mitochondria

What Have Mass Spectrometry-Based Proteomics and Metabolomics (Not) Taught Us about Psychiatric Disorders?

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