An emerging role for mitochondrial dynamics in schizophrenia

Abstract

Abnormal brain development has long been thought to contribute to the pathophysiology of schizophrenia. Impaired dendritic arborization, synaptogenesis, and long term potentiation and memory have been demonstrated in animal models of schizophrenia. In addition to aberrant nervous system development, altered brain metabolism and mitochondrial function has long been observed in schizophrenic patients. Single nucleotide polymorphisms in the mitochondrial genome as well as impaired mitochondrial function have both been associated with increased risk for developing schizophrenia. Mitochondrial function in neurons is highly dependent on fission, fusion, and transport of the organelle, collectively referred to as mitochondrial dynamics. Indeed, there is mounting evidence that mitochondrial dynamics strongly influences neuron development and synaptic transmission. While there are a few studies describing altered mitochondrial shape in schizophrenic patients, as well as in animal and in vitro models of schizophrenia, the precise role of mitochondrial dynamics in the pathophysiology of schizophrenia is all but unexplored. Here we discuss the influence of mitochondrial dynamics and mitochondrial function on nervous system development, and highlight recent work suggesting a link between aberrant mitochondrial dynamics and schizophrenia.

Tracing Early Neurodevelopment in Schizophrenia with Induced Pluripotent Stem Cells

“…Mitochondrial function is regulated in response to a cell’s metabolic demand, but also through neurotransmission, and plays a critical role in development, synapse formation, and plasticity of spines and synapses [ 99 , 101 , 102 ]. As discussed before, Robicsek and coworkers [ 78 ] reported that SCZ iPSCs were impaired in dopaminergic differentiation and glutamatergic maturation.…”

Synaptic Proteome Alterations in the Primary Auditory Cortex of Schizophrenia

“…Subsequent decreases in synaptic mitochondrial and GABA receptors would then reflect homeostatic plasticity downstream of this decreased excitatory drive. Alternatively, presynaptic mitochondria are essential for bouton development (58) and activity (59). Thus, altered mitochondrial transport to the presynaptic compartment could also contribute to synaptic pathology in Sz.…”

The Complex Interaction of Mitochondrial Genetics and Mitochondrial Pathways in Psychiatric Disease

“…Mitochondrial dynamics comprises such processes as mitochondrial fission, fusion, transport within the cell, and mitophagy [106, 107]. Intact mitochondrial dynamics has been linked to normal brain development, while impaired dynamics leads to neuronal injury and developmental dysfunction [108].…”

“…The kinesin-related protein 5 family (KIF5A–C) comprises specific motor proteins that are thought to play a vital role in the transport of mitochondria in the nervous system. Mutations in the genes encoding KIF5A–C have been implicated in a host of neurodevelopmental disorders [115-122], as summarized by Flippo and Strack [107]; however, it is unclear whether these derive from impaired mitochondrial transport or from impaired transport of other organelles via KIF5. Interestingly, KIF5A interacts with DISC1 (disrupted in schizophrenia 1), a protein whose namesake highlights its relation to SCZ and other psychiatric disorders [123, 124].…”

“…Specifically, G72 (also called DAOA) has been shown to regulate mitochondrial fission [128], and DISC1 interacts with many of the transport proteins [124], as discussed. A recent paper by Flippo and Strack [107] reviewed mitochondrial dynamics in the context of SCZ.…”