Mitochondrial Function in Nervous System

Mitochondria could produce the main energy of most cell currency in ATP through a multi-step process; this is essential for neuronal function. Mitochondria are critical for many cellular processes, including energy production, amino acid biosynthesis, metal, ion homeostasis, iron-sulfur cluster synthesis, generation and detoxification of reactive oxygen species (ROS), and apoptosis. All these mitochondrial functions vary across cells within a given central nervous system (CNS) region. Defects in genes controlling these functions attract increasing attention as causes of neurological diseases and neurodegenerative disorders.

Fig.1. Schematic of intermediate mitochondrial metabolism showing the relationships between pyruvate and fatty acid metabolism and ATP synthesis. (DiMauro, 2008)

Mitochondrial Retrograde Signaling

There are many roles of mitochondrial activity in neurogenesis and neuronal differentiation. Also, the response of mitochondrial retrograde can be activated in the nervous system. Thus, mis-regulation of retrograde mitochondrial signaling can lead to profound effects on neuronal activity and survival. Modulation of retrograde mitochondrial signaling has therapeutic potential in a range of diseases linked to mitochondrial dysfunction. For instance, drugs that inhibit main regulators of retrograde mitochondrial signaling could be effective in common neurodegenerative conditions.

Mitochondria Dysfunction and Neurodegeneration

Mitochondria are increasingly seen as important determinants for neurodegeneration. Mitochondrial dysfunction is the main process that leads to neuronal injury and death following acute CNS insults. Mitochondrial dysfunction is also believed to contribute to many neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). Cell death in many neurodegenerative diseases usually occurs by apoptosis, more commonly by the intrinsic mitochondrial pathway than by the extrinsic cell-signaling pathway.

Fig.2. The role of mitochondrial dynamics in neuron development. (Flippo, 2017)

Mitochondrial Function and Dynamics in Schizophrenia

The pathology of schizophrenia is related to impaired brain development and connectivity. In addition to aberrant nervous system development, recent work suggests that aberrant mitochondrial dynamics could also contribute to abnormal connectivity in the brains of schizophrenic patients. In support, impaired mitochondrial function is observed in schizophrenic patients. Single nucleotide polymorphisms in the mitochondrial genome and impaired function of mitochondria are connected with an increased risk for developing schizophrenia. Due to the mitochondrial fission/fusion enzymes evaluated as potential drug targets for treating neurological disorders, further insights into the role of mitochondria in brain development may lead to new therapies for schizophrenia and other psychiatric disorders.

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References

1. DiMauro, S.; Schon, E. A. Mitochondrial disorders in the nervous system. Annu. Rev. Neurosci. 2008, 31, 91-123.
2. Flippo, K. H.; Strack, S. An emerging role for mitochondrial dynamics in schizophrenia. Schizophrenia research. 2017, 187, 26-32.