Control mechanisms in mitochondrial oxidative phosphorylation

Distribution and activity of mitochondda are key factors in neuronal development, synaptic plasticity and axogenesis. The majority of energy sources, necessary for cellular functions, originate from oxidative phosphorylation located in the inner mitochondrial membrane. The adenosine-5＇- triphosphate production is regulated by many control mechanism-firstly by oxygen, substrate level, adenosine-5＇-diphosphate level, mitochondrial membrane potential, and rate of coupling and proton leak. Recently, these mechanisms have been implemented by ＂second control mechanisms,＂ such as reversible phosphorylation of the tricarboxylic acid cycle enzymes and electron transport chain complexes, aUosteric inhibition of cytochrome c oxidase, thyroid hormones, effects of fatty acids and uncoupling proteins. Impaired function of mitochondria is implicated in many diseases ranging from mitochondrial myopathies to bipolar disorder and schizophrenia. Mitochondrial dysfunctions are usually related to the ability of mitochondria to generate adenosine-5＇-triphosphate in response to energy demands. Large amounts of reactive oxygen species are released by defective mitochondria similarly, decline of antioxidative enzyme activities （e.g. in the elderly） enhances reactive oxygen species production. We reviewed data concerning neuroplasticity, physiology, and control of mitochondrial oxidative phosphorylation and reactive oxygen species production.

Novel approaches in schizophrenia-from risk factors and hypotheses to novel drug targets

Schizophrenia is a severe psychiatric disorder characterized by emotional,behavioral and cognitive disturbances, and the treatment of schizophrenia is oftencomplicated by noncompliance and pharmacoresistance. The search for thepathophysiological mechanisms underlying schizophrenia has resulted in theproposal of several hypotheses to explain the impacts of environmental, genetic,neurodevelopmental, immune and inflammatory factors on disease onset andprogression. This review discusses the newest insights into the pathophysiologyof and risk factors for schizophrenia and notes novel approaches in antipsychotictreatment and potential diagnostic and theranostic biomarkers. The currenthypotheses focusing on neuromediators (dopamine, glutamate, and serotonin),neuroinflammation, the cannabinoid hypothesis, the gut-brain axis model, andoxidative stress are summarized. Key genetic features, including small nucleotidepolymorphisms, copy number variations, microdeletions, mutations andepigenetic changes, are highlighted. Current pharmacotherapy of schizophreniarelies mostly on dopaminergic and serotonergic antagonists/partial agonists, butnew findings in the pathophysiology of schizophrenia have allowed theexpansion of novel approaches in pharmacotherapy and the establishment ofmore reliable biomarkers. Substances with promising results in preclinical andclinical studies include lumateperone, pimavanserin, xanomeline, roluperidone,agonists of trace amine-associated receptor 1, inhibitors of glycine transporters,AMPA allosteric modulators, mGLUR2-3 agonists, D-amino acid oxidase inhibitorsand cannabidiol. The use of anti-inflammatory agents as an add-on therapy ismentioned.