Abstract

Neurodegenerative and demyelinating diseases have a major impact on patient longevity and quality of life, creating a serious risk to life, health, and well-being. These diseases have been associated with poor and malfunctioning mitochondria in the central nervous system. Mitochondria are vital for several biological processes, including the production of energy and reactive oxygen species, the regulation of calcium levels within cells, and the control of programmed cell death. Alterations in mitochondrial activity have a significant impact on the most prevalent neurodegenerative and demyelinating disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS). Exercise has been shown to improve muscle function and contribute to the muscle-brain interaction via various signaling pathways and molecular mechanisms (myokines, extracellular vesicles, and bioactive molecules etc.). The stimulation and subsequent training of skeletal muscle is a crucial aspect of exercise, with proven benefits for mitochondrial function. It is now known that exercise is a non-pharmacological method of preventing and reversing neurodegeneration and brain deterioration. Regular exercise enhances the survival and neuroplasticity of neurons and improves the body’s reactions to stress in terms of mitochondria. This review presents an overview of current knowledge on the role of normal mitochondrial function, including mitochondrial biogenesis, dynamics, and mitophagy, as well as exercise and mitochondrial function, in neurodegenerative and demyelinating disorders. In the following sections, we also discuss how exercise affects mitochondrial processes in disorders such as AD, PD, MS, and ALS.

Introduction

The prevalence of neurodegenerative and demyelinating diseases is on the rise in parallel with the extension of human life expectancy. These conditions have significant implications for patient survival and quality of life, presenting a substantial hazard to life, health, and well-being (1). The functioning of the brain is dependent on adenosine triphosphate (ATP) levels, which is produced in large quantities by mitochondria through oxidative phosphorylation (OXPHOS). Neurons have a high metabolic demand and limited capacity for regeneration, making them particularly susceptible to the deleterious effects of mitochondrial dysfunction (2).

Mitochondria are indispensable for numerous biological functions, including energy and reactive oxygen species (ROS) production, calcium homeostasis, and cell death (3). Several vital biological processes, including the transportation of proteins, the formation of neuronal cell membrane potentials, and the transmission of signals, are unable to take place in the absence of energy provided by mitochondria (4).

Exercise has been postulated as a non-pharmacological intervention capable of modifying both brain structure and function (5). Regular exercise has significant beneficial effects on mitochondrial structure formation, with high-intensity exercise resulting in greater improvements in OXPHOS efficiency (6).

This review will center on elucidating the functions of mitochondria, as well as examining the impact of exercise-induced improvements in mitochondrial health on neurodegenerative and demyelinating diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS).

Mitochondria and Normal Mitochondrial Function

Mitochondria, which developed through bacterial endosymbiosis, share striking similarities with archeabacterium (7). Although there are different views, an α-proteobacterium was engulfed by a predecessor of the current eukaryotic cell, resulting in the formation of mitochondria (8). Mitochondria are widely acknowledged as primary energy providers for cellular functions (9), with ATP production specifically tied to the efficiency of OXPHOS (10). Vital biological processes, such as protein transport, neuronal cell membrane potential generation, and signal transmission, rely on the energy supplied by mitochondria (4).

Mitochondrial Biogenesis

Healthy cells typically undergo mitochondrial biogenesis, a unique process for maintaining number, function, and energy production (11) (Figure 1). This process requires the synchronized transcription and translation of nuclear and mitochondrial genes located in both the nucleus and mitochondria since more than 90% of mitochondrial proteins are encoded by nuclear genes (12). The processes that comprise mitochondrial biogenesis include the replication of mitochondrial DNA (mtDNA), the synthesis of nuclear-encoded mitochondrial proteins, and the production of the inner and outer mitochondrial membranes (OMMs) and mitochondrial-encoded proteins (13).

Two main routes that control mitochondrial biogenesis are the sirtuin 1 (SIRT1)-peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and the adenosine monophosphate (AMP)-activated kinase (AMPK)-PGC-1α axis (14). Increased cellular energy demand activates the evolutionary cellular sensor known as AMPK, and mitochondrial bioenergetics and AMPK are closely related (15). PGC-1α can be immediately phosphorylated and activated by AMPK. The increase in PGC-1α expression and mitochondrial biogenesis may be due to AMPK activation (16). Additionally, PGC-1α is activated by SIRT1 (17). In an epilepsy model, SIRT1 activation improved hippocampal activity in rats by enhancing the PGC-1α/mitochondrial antioxidant signaling pathway (18).

Mitochondrial Dynamics

A mechanism known as mitochondrial dynamics regulates the size and structure of mitochondria through a repeated fusion and fission cycles (19) (Figure 1). The optic atrophy 1 protein, crucial for maintaining mitochondrial cristae structure, controls fusion on the inner mitochondrial membrane, while mitofusin-1 (MFN-1) and MFN-2 manage fusion on the OMM (20). The main mediator of mitochondrial fission is dynamin-related protein 1 (DRP1). Mitochondrial fission normally occurs in the cytoplasm. Under stress conditions, the four main adaptor proteins that attach cytosolic DRP1 monomers to the OMM are: Mitochondrial fission factor, mitochondrial fission 1 protein and mitochondrial dynamics proteins, which bind DRP1 to the OMM (21). To alleviate cellular dysfunction, prevent tissue deterioration and restore function, strategies aimed at balancing mitochondrial dynamics hold promise.

Mitophagy

The equilibrium between mitochondrial production and degradation determines mitochondrial mass, with mitochondrial biogenesis resulting in increased mitochondrial numbers, while a healthy mitochondrial population depends on the removal of defective mitochondria by mitophagy (22, 23) (Figure 1). After the specific encapsulation of damaged mitochondria by the autophagosome, these mitochondria are transported to the lysosome where they fuse to form mature mitochondrial autolysosomes, which are then degraded by the lysosomes (24). Proteins located in the inner or outer membrane of mitochondria are known as mitophagy receptors, and contain microtubule-associated proteins 1A/1B light chain 3B (LC3)-interaction region (LIR) domain (25). Mitophagy receptor proteins selectively remove damaged mitochondria by interacting with the necessary autophagy protein LC3, mitophagy receptor proteins selectively destroy damaged mitochondria in response to various mitochondrial stresses, including reduction of mitochondrial membrane potential, oxidative stress, and other conditions, by interacting with the essential autophagy protein LC3 (26, 27).

Damage or defect in the mitochondria results in the attachment of specific chemical markers, via the LC3 protein, to facilitate their identification and subsequent removal through a process known as mitophagy (28). Phosphatase and tensin homolog deleted on chromosome 10-induced kinase 1 (PINK1) accumulates on the OMM in the presence of cellular stress or mitochondrial depolarization, which attracts the E3 ubiquitin ligase Parkin (29). The OMM proteins mitofusins and other related proteins are ubiquitinated by the Parkin protein, which then forms polyubiquitin chains that serve as mitophagy signals (30).
The ubiquitin chains are bound by autophagy receptors such as optineurin and sequestosome-1, which interact with LC3 due to their LIR (31). This dual binding enables the mitochondria to be enclosed within an autophagosome for subsequent lysosomal destruction, thus maintaining cellular homeostasis. To fully realize the potential benefits of mitophagy without causing harm, there must be a balance in its activation.

The Effects of Exercise and Mitochondrial Dysfunction in Neurodegenerative and Demyelinating Diseases

The production of ATP and the quality control of mitochondria are of great importance in the context of neurodegenerative and demyelinating diseases, as these conditions are frequently characterized by mitochondrial dysfunction (32). Impaired OXPHOS results in a reduction of ATP levels, which in turn leads to energy deficits in neurons that are highly dependent on a steady energy supply (33). Concurrently, mitochondrial quality control mechanisms, including mitophagy, fission, and fusion, are disrupted, thereby exacerbating the accumulation of damaged mitochondria (34). For example, in PD, mutations in PINK1 and Parkin impair mitophagy, while in AD, altered mitochondrial dynamics contribute to the buildup of dysfunctional organelles (35, 36). An understanding of these processes across various neurodegenerative and demyelinating diseases offers insight into common pathological mechanisms and potential therapeutic targets.

A growing body of research indicates that regular exercise can protect against chronic illnesses, delay the aging process, and improve overall health (37). Exercise induces perturbations in energy homeostasis in skeletal muscle, activating cellular signaling networks that facilitate the adaptation of skeletal muscle to the increased energy and oxygen demands associated with contraction-induced activity (38). High exercise capacity and mitochondrial function are clearly correlated, with mitochondria serving as the primary source of ATP and essential regulators of exercise capacity (39). Additionally, exercise enhances mitochondrial integrity and function by accelerating mitochondrial turnover, promoting efficient mechanisms for managing organelle turnover such as mitophagy and lysosome biogenesis (40). For example, exercise enhances mitochondrial functioning through its various physiological effects. Research indicates that exercise impacts hippocampal mitochondrial function, neuroplasticity, apoptosis, and increases levels of brain-derived neurotrophic factor (BDNF) (41).

Effects of Exercise and Mitochondrial Dysfunction in Parkinson’s Disease

PD is defined by the gradual degradation of dopaminergic neurons, which finally results in a dopamine insufficient in the striatum (42). The pathophysiology of PD is closely linked to mitochondrial dysfunction and oxidative stress (43). A decrease in regulators of mitochondrial biogenesis has been demonstrated to result in a suppression of mitochondrial biogenesis in PD (44). Tissue samples from idiopathic PD patients who have post mortem have demonstrated higher mtDNA abnormalities, indicating mitochondrial malfunction in the disease (45). Several factors contribute to PD-associated mitochondrial dysfunction, including impaired mitochondrial biogenesis, elevated generation of ROS, impaired mitophagy, disrupted protein trafficking, and malfunctioning electron transport chain (ETC) (46).

After physical exercise, levels of BDNF, superoxide dismutase (SOD), and catalase increased in PD rats, while oxidative stress indicators for proteins and lipids decreased. These findings indicate that exercise improves oxidative stress markers and modulates the state of the neurochemicals (47) (Figure 2). Exercise training significantly reduced the loss of dopaminergic neurons in PD animals and improved neuronal and behavioral functions, accompanied by increased mitochondrial activity and neurotrophic factor levels in brain regions (37). In rats with PD, exercise training reduced oxidative stress, restore mitochondrial function, and enhanced dopaminergic neuron survival. This process may involve promoting mitochondrial turnover, including fission, fusion, and clearance, along with increasing mitochondria numbers (48). It has been demonstrated that treadmill exercise has shown promise in reducing α-synuclein accumulation in neurons and promoting the translation of biogenesis regulators and nuclear-encoded mitochondrial proteins. This may lead to an increase in mitochondrial biogenesis and the import of nuclear-encoded mitochondrial protein (49). Endurance exercise may be an effective method of enhancing cerebral mitochondrial biogenesis, thereby mitigating neural energy deficiencies in PD. In particular, treadmill training was observed to elevate or restore the levels of biogenesis regulators and import machinery (50).

Effects of Exercise and Mitochondrial Dysfunction in Alzheimer’s Disease

AD is a neurodegenerative disease that affects millions of individuals worldwide and causes the brain to gradually and irreversibly deteriorate. ATP generation, the main energy source for cells, is impaired by mitochondrial dysfunction in AD. Amyloid beta-induced oxidative damage is connected to mitochondrial dysfunction in the early stages of AD (51). It is well established that amyloid beta can migrate to mitochondrial membranes, interfere with the ETC, produce more ROS, damage mitochondria, and impair normal neuron function (52). Increasing evidence suggests that defects in mitochondrial ETC enzymes and reduced efficiency of complex I and complex IV are associated with AD (53).

Exercise has been demonstrated to benefit several prominent symptoms of AD by regulating brain pathways associated with oxidative stress (54) (Figure 2). In addition, it has been shown that regular exercise significantly increases the metabolic rate and thus reduces the ROS level (55). While acute exercise may not have a significant effect on brain mitochondria, sustained exercise may decrease oxidative DNA damage and lipid peroxidation (56). Additionally, there has been evidence of elevation of mitochondrial antioxidant (SOD and catalase) activity in AD animal models treated to prolonged exercise (57). Six-day-a-week swimming exercise preserved the margins and cristae of the mitochondria, increased brain ATP generation, and enhanced synaptic density (58). The evidence suggests that exercise can serve as a therapeutic strategy to alleviate the deleterious effects of AD. These benefits are attributed to exercise’s interactions with mitochondrial functions, including redox balance, enhancement of bioenergetics, apoptosis blocking, and inducement of mitochondrial biogenesis in AD.

Effects of Exercise and Mitochondrial Dysfunction in Multiple Sclerosis

MS is a long-term autoimmune disorder highlighted by demyelination, inflammation, neuronal death, and scarring (59). Mitochondrial dysfunction is increasingly recognized as a significant component of MS pathology, impacting the clinical course of the disease. Damage to mitochondria results in energy deprivation, leading to dysfunction in neuronal signal transmission (60). Oxidative damage, marked by the formation of oxidized lipids, proteins, and DNA, is observed in the process of cellular degeneration within the dynamic and progressively increasing lesions typical of MS (61). Inflammation in MS contributes to energy depletion and mitochondrial dysfunction, further exacerbating neuronal deterioration (62). MS also affects mitochondrial dynamics in neurons, including fission and fusion processes. Defects in mitochondria and subsequent energy failure can disrupt other cellular processes, contributing to increased demyelination and inflammation in affected neurons and tissues (63).

It is well documented that people with MS benefit from regular exercise, which improves motor function, reduces fatigue, and enhances cardiorespiratory fitness (64) (Figure 2). Mitochondrial enzymes in individuals with MS have shown reduced succinate dehydrogenase activity across all types of muscle fibers, suggesting a greater reliance on anaerobic rather than aerobic oxidative ATP production compared to healthy individuals (65). Changes in muscle fiber dimensions and composition associated with MS are accompanied by alterations in muscle mitochondrial content (66). A cross-sectional study found a positive correlation between walking performance and physical activity levels in people with MS. The study results indicated that walking performance correlates positively with brain volume, fatigue levels, cognitive processing speed, and tract integrity (67).

Effects of Exercise and Mitochondrial Dysfunction in Amyotrophic Lateral Sclerosis

ALS, characterized by motor neuron atrophy in the nervous system, is the most common form of motor neuronopathy in adults (68). Substantial evidence links ALS pathology to progressive changes in mitochondrial structure, bioenergetics, and calcium homeostasis (69). Motor neurons derived from ALS patients exhibit altered structural features and mitochondrial clustering, characterized by enlarged and vacuolated organelles (70). ALS patients also demonstrate reduced activity in all complexes of the ETC, including complexes I, II, III, and IV (71). Excessive production of ROS in ALS contributes to oxidative damage across cellular components, particularly affecting mitochondria, which are highly susceptible to such damage (72). Furthermore, increased ROS generation promotes muscle atrophy in ALS (73).

It has been demonstrated that regular exercise can have beneficial effects on muscular strength and oxidative capacity in healthy individuals. Therefore, exercise can be regarded as a potentially viable therapeutic option for patients suffering from ALS (74) (Figure 2). Clinical trials suggest that exercise can enhance lung function and functional capacity in ALS patients, primarily demonstrated over the long term, with limited benefits observed in the short or medium term (75). It has previously been debatable whether exercise increases the risk of ALS (76). In ALS, it is the type IIB muscle fibers that are most vulnerable to the disease’s progression. These fibers are responsible for anaerobic activity, and there is evidence that ALS is particularly associated with strenuous exercise (76-78). It has been demonstrated that swimming exercise results in modifications to the structure and function of mitochondria, which can be attributed to alterations in the concentration of mitochondrial cholesterol (79). Furthermore, numerous studies have indicated that individuals with ALS exhibit abnormal physiological responses to exercise (80). Prolonged periods of high-intensity exercise have been shown to exacerbate several adverse effects on the body, including motor neuron denervation, irreversible strength loss, and muscle degeneration (81). It has been suggested that moderate exercise programs may be beneficial for people with ALS, potentially impacting free radical balance and muscle fiber oxidation (82, 83).

It is possible that excessive exercise may overload the antioxidant systems of ALS patients, which are already compromised, and increase the generation of ROS (84). This could result in further harm to nearby tissues and neurons. Moreover, the capacity to recuperate muscles following strenuous exercise is compromised by the progressive loss of motor neurons and ensuing muscular atrophy associated with ALS (85). The progression of the disease may be accelerated by overexertion, which can lead to increased fatigue and accelerate the degeneration of motor neurons (85). The findings of research conducted on animals and observations made by patients indicate that moderate, tailored exercise may improve quality of life and potentially slow the progression of symptoms (83). However, excessive or uncontrolled exercise has been shown to have adverse effects (81). It is therefore imperative that exercise regimens are tailored to the individual and designed to avoid overexertion to effectively manage ALS.

Conclusion

Exercise has been recognized as a non-pharmacological intervention with neuroprotective effects in neurodegenerative and demyelinating disorders. Its mechanism involves modulating multiple brain pathways, with mitochondria being a significant target organelle affected by physical activity. Exercise plays a crucial role in preventing and treating neurodegenerative and demyelinating diseases by interacting with mitochondrial mechanisms, including redox control, bioenergetics, reduced apoptosis, stimulation of mitochondrial biogenesis, and modulation of mitochondrial dynamics and mitophagy.

It is of the utmost importance that future studies concentrate on elucidating the complex relationships between human activity and mitochondrial function, particularly in the context of neurodegenerative and demyelinating disorders. An investigation into the influence of exercise on mitochondrial biogenesis, dynamics and quality control may facilitate the development of targeted treatment approaches. One promising avenue of research is the utilization of wearable technology, such as sensors, to monitor mitochondrial biomarkers and physiological responses in real-time. These techniques may enable the precise measurement of mitochondrial responses to various exercise regimens, aiding in the optimization of duration and intensity for maximal benefit. These advancements may pave the way for the development of personalized therapies that enhance outcomes while reducing risks for susceptible groups.

Footnotes