Mitochondria in Neurons

What is Mitochondria?

Mitochondria are vital ATP-generating organelles and central for cellular processes such as intracellular Ca²⁺ signaling and apoptotic cell death. The outer mitochondrial membrane is regulated permeable for ions and small molecules. The inner mitochondrial membrane forms a tight barrier between the mitochondrial matrix and the neuronal cytoplasm. It is also equipped with ion channels and transporters, like the Ca²⁺ uniporter and mitochondrial enzyme systems. Because of the change dynamically in the mitochondria reflecting the cell’s metabolic state, mitochondrial dysfunction has some effects on the integrity of cells and is critically involved in degenerative diseases.

Roles of Mitochondria in Neurons

Neurons primarily rely on oxidative phosphorylation to produce ATP essential for the excitability and survival of neurons. In addition, neurons require mitochondria for Ca²⁺ homeostasis and maintenance of their action potential to establish membrane excitability and execute the complex neurotransmission and plasticity processes. Therefore, by generating energy and regulating subcellular Ca²⁺ and redox homeostasis, mitochondria may play essential roles in controlling fundamental neuron developmental and function processes, including neuronal survival and differentiation, neurite outgrowth, neurotransmission, and dendritic remodeling.

• Developmental Roles for Mitochondria

Diverse molecular mechanisms modulate neurogenesis, and recently, interests in studying the mechanisms of neurogenesis have expanded to the mitochondrial role. Mitochondria has the role of supporting the different bioenergetic requirements of highly proliferative neural stem cells and postmitotic neurons. In addition, signals that influence mitochondrial biogenesis and functions, including nitric oxide and BDNF, may regulate the proliferation and differentiation of neural cells in the developing and adult brain. The newborn neurons then grow an axon and dendrites and eventually form synapses. After axons and dendrites differentiate, mitochondrial motility and functions may influence their growth and synaptic connectivity.

• Mitochondrial Transport and Turnover

Due to complex cytoskeletal transport mechanisms, individual mitochondria are highly mobile and move in neuron cells; however, the percentage of motile mitochondria decreases as neurons differentiate and maturate. The proper transport of mitochondria is critical to neuron health and the homeostasis of the cell. Consequently, mitochondria need to be transported and require docking mechanisms, which must be tightly regulated to respond rapidly to synaptic activity. Disruption of the transport can lead to impaired synaptic transmission. This impaired positioning accelerates neurodegeneration. Thus, good coordination in mitochondrial transport must be in place for proper neuronal function.

Fig.1 Schematic representation of the mitochondrial transport machinery. (Vanhauwaert, 2019)

• Mitochondrial dynamics in neuronal development

Mitochondrial dynamics and their potential are related to developmental brain diseases in neuronal development, described in the animal brain recently. Morphological changes of mitochondria illustrate the maturation of mitochondria and reflect the metabolic shift of cells for an increase in bioenergetics. If mitochondria cannot reach the signal exchanging center, the neuronal function will be impaired. Mitochondria dynamics are essential for neuronal functions since they regulate mitochondrial location, morphology, number, and function.

Fig.2 Mitochondrial proteins, functions, and dynamics. (Son, 2018)

Mitochondria and Neurological Diseases

The improper distribution and movement of mitochondria in neurons can lead to neuronal dysfunction, neurodegenerative and neuropsychiatric disorders. Damaged mitochondria, highly harmful to the neuron, must be rapidly repaired or eliminated, even when they are left at terminals exceptionally far away from the soma. Disturbances in mitochondrial functions and signaling may play roles in Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, psychiatric disorders, stroke, and amyotrophic lateral sclerosis. Thus, studies for mechanisms of mitochondrial dysfunctions lead to novel approaches to prevent and treat neurological disorders.

Fig.3 Pathogenesis of disease. (Devine, 2018)

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References

1. Vanhauwaert, R.; et al. Surveillance and transportation of mitochondria in neurons. Current opinion in neurobiology. 2019, 57, 87-93.
2. Son, G.; Han, J. Roles of mitochondria in neuronal development. BMB reports. 2018, 51(11), 549.
3. Devine, M. J.; Kittler, J. T. Mitochondria at the neuronal presynapse in health and disease. Nature Reviews Neuroscience. 2018, 19(2), 63.