Predicting Mitochondrial Dynamic Behavior in Genetically Defined Neurodegenerative Diseases Part 2

3. Mitochondrial Dysdynamism in Genetic Neurological Diseases

Conceptually, it is easy to appreciate how mitochondrial dynamic dysfunction can manifest as a neurodegenerative disease. 

Neurodegenerative diseases are a type of disease that gradually develops with age, and common ones include Alzheimer's disease, Parkinson's disease, Huntington's disease, etc. These diseases have a great impact on the physical and mental health of patients and also pose great difficulties to the patient's families and society.

Studies have shown that neurodegenerative diseases are closely related to memory. People with neurodegenerative diseases such as Alzheimer's disease often experience symptoms such as memory loss and cognitive decline, which may greatly affect their quality of life and workability.

However, we cannot think that these diseases are hopeless because of the impact of neurodegenerative diseases on memory. In fact, through proper treatment and rehabilitation training, patients' memory and cognitive abilities can be improved. At the same time, there are also some measures to prevent diseases, such as maintaining a healthy lifestyle, doing proper physical exercise, and actively interacting with others.

In general, although neurodegenerative diseases can have a great impact on people's physical and mental health, we should always maintain a positive attitude, help patients and their families cope with the disease together, improve their quality of life, and let them not lose confidence in difficulties and face the future bravely. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because it has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

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Electrically excitable neurons have high metabolic requirements to maintain electrochemical membrane potentials and drive synaptic release and reuptake of neurotransmitters. 

Indeed, the neurological system has one of the highest metabolic rates of all organ systems; human brains, comprise only ~2% of total body weight, but consume ~20% of total oxygen (a marker for ATP production by mitochondrial respiration) [35,36]. 

Therefore, any genetic or environmental event that compromises mitochondrial fitness has the potential to adversely impact the neurological system. 

In addition to high metabolic needs, neurons have a unique structural feature making them exceptionally vulnerable to mitochondrial dysfunction: neurons are long. Sciatic nerve motor and sensory neurons originating in the lumbar spine of a six-foot-tall person may extend ~three feet before they terminate in the feet. 

Mitochondrial-derived ATP is required throughout the neuron, and because ATP undergoes rapid spontaneous degradation by hydrolysis, it must be generated locally by resident mitochondria according to physiological needs. The length of neuronal processes presents a formidable physical obstacle to effective mitochondrial delivery. 

For this reason, neurons (especially the long peripheral nerves innervating the upper and lower extremities) are susceptible to damage from factors that diminish mitochondrial transport [37–39]. 

Mitochondrial dysmotility is a common finding in human genetic neurodegenerative diseases, especially peripheral neuropathies (vide infra). The most common mitochondrial abnormality in these syndromes is mitochondrial morphological shortening or fragmentation. 

In most conditions, the underlying abnormality in mitochondrial dynamics is increased DRP1-mediated mitochondrial fission [40–43]. However, an impairment of MFN-mediated mitochondrial fusion is increasingly recognized as an accompanying or alternative mechanism for observed mitochondrial fragmentation [44–47]. 

This is an important distinction because increased mitochondrial fission does not necessarily provoke mitochondrial dysfunction, whereas suppressing mitochondrial fusion interrupts complementation-mediated mitochondrial repair and causes respiratory/metabolic dysfunction (vide supra) [21,22]. Moreover, mitochondrial respiratory dysfunction is damaging both because it impedes ATP production and because uncoupling of oxidative phosphorylation from ATP synthesis produces neuro- and mito-toxic reactive oxygen species (ROS). 

Thus, mitochondrial dysdynamism can initiate a vicious cycle of mitochondrial degeneration in which a primary impairment in the ability of individual mitochondria to undergo fusion-mediated repair evokes accelerated organelle senescence manifested in part by increased production of toxic ROS, which further injures the index organelle and can damage other members of the mitochondrial collective, which have a similar dynamic impairment. 

Mitochondrial damage provokes more mitochondrial damage (Figure 3). 

Unless this feed-forward cycle is interrupted, mitochondrial degeneration can spread throughout the neuron, depriving it of ATP required for synaptic transmission and neuronal repair, and exposing it to ROS that will degrade nuclear DNA and damage essential proteins [48]. 

Because mitochondrial dysmotility and degeneration tend to be most severe distally, the ultimate consequence is neuronal die-back [49,50] or, if mitochondrial damage is more uniform, apoptotic neuron death [51,52]. 

This paradigm can explain why such genetically and etiologically diverse neurodegenerative diseases as amyotrophic lateral sclerosis, Huntington's disease, and Charcot–MarieTooth disease share common phenotypes of mitochondrial degeneration and neuron loss.

Charcot–Marie–Tooth disease type 2A (CMT2A) is the only neurodegenerative syndrome unambiguously caused by mitochondrial dynamic dysfunction. This slowly progressive pediatric peripheral neuropathy is linked to ~100 different loss-of-function mutations of the MFN2 gene that encodes one of the two outer mitochondrial membrane mitofusin proteins [50,53]. 

Clinically, autosomal dominant CMT2A typically manifests in toddlers as difficulty walking and delayed progress in ambulation; rare autosomal recessive CMT2A has a similar presentation [54]. 

The disease progresses during childhood and adolescence, culminating in disabling neurogenic muscular atrophy of the distal upper and lower extremities most often requiring wheelchairs for mobility and hand and foot splints to prevent secondary skeletal abnormalities [55,56]. 

The underlying neuropathology is progressive neuronal "die-back", described as retrograde degeneration from the distal synapses of long peripheral motor and sensory nerves. In most instances die-back stops at approximately the knee and elbow, producing characteristic distal neurogenic muscle atrophy that spares proximal extremities. 

Axonal mitochondria in (directly reprogrammed) human CMT2A neurons or neurons from mice expressing human CMT2A MFN2 mutants exhibit fragmentation, depolarization (dissipated ∆Ψm), and severe hypomotility [57]. 

Mitochondria in CMT2A neuronal soma are abnormally aggregated, forming characteristic "clumps" [58], and mitochondria can be lost from CMT2A neuronal neuromuscular junctions [57,58]. 

Mitochondrial fragmentation in CMT2A is the direct effect of dominant suppression of mitochondrial fusion by MFN2 mutants, while loss of inner membrane ∆Ψm is likely a secondary effect of impaired fusion-mediated mitochondrial repair (vide supra). 

The exact mechanism for mitochondrial dysmotility in CMT2A is unclear, although there is evidence that MFN2 normally binds to and may therefore modulate mitochondrial Miro that couples mitochondria to the Milton/Trak transport apparatus [59].

 Pharmacological activation of endogenous normal MFN1 and MFN2 (which appear functionally overlapping for mitochondrial fusion and motility), can improve mitochondrial abnormalities produced by CMT2A MFN2 mutants in neurons [25] and reverse neuromuscular degeneration in CMT2A mice [57].

Abnormalities in mitochondrial morphology and mitofusin expression/function are equally prominent in amyotrophic lateral sclerosis (ALS) [38,60] and Huntington's disease [41,61], although the primary genetic causes of these diseases are not mutations in mitochondrial genes. 

ALS is an etiologically diverse upper and lower motor neuron neuropathy. Familial ALS with an identifiable genetic cause occurs in 1 out of every 10 cases [62], and mitochondrial fragmentation and impaired mitochondrial transport are typical [38,60,63,64]. By contrast, Huntington's disease (HD) is a central nervous system cognitive and motor disorder caused by an expanded number of CAG repeats in the huntingtin (HTT) gene [65]. 

Mitochondrial fragmentation and depolarization are hallmarks of this condition [41], although it is not clear whether the mitochondrial abnormalities are principal contributing factors that provoke neuronal death or reflect collateral damage that is a consequence of other primary abnormalities [66]. 

Mutations of the inner mitochondrial membrane fusion protein, optic atrophy 1 (OPA1), cause dominant optic atrophy (DOA) in approximately half of cases, primarily affecting retinal ganglion cells [67–69]. 

An excess of mitochondrial fission relative to fusion in retinal ganglion cell axons from OPA1 mutant mice and patient fibroblasts is evidenced by prototypical mitochondrial fragmentation [70–72]. 

Mutations of dynamin-like protein 1, which is a central effector of mitochondrial fission, are also linked to DOA. 

In contrast to OPA1 mutations that interrupt mitochondrial fusion, DNM1L mutations produce a relatively excessive mitochondrial fusion versus fission, with elongated/tubular mitochondria in patient-derived fibroblasts [20]. 

Thus, the balance between mitochondrial fusion and fission, rather than the absolute activity of either process, appears critical to neuronal health.

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