Exercise and Mitochondrial Function in Neurodegenerative and Demyelinating Diseases

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.

Keywords

• Exercise
• mitochondria
• Alzheimer’s disease
• Parkinson’s disease
• multiple sclerosis
• amyotrophic lateral sclerosis

Nörodejeneratif ve Demyelinizan Hastalıklarda Egzersiz ve Mitokondriyal Fonksiyon

Abstract

Nörodejeneratif ve demyelinizan hastalıklar, hasta ömrü ve yaşam kalitesi üzerinde büyük bir etki yaratarak yaşam, sağlık ve refah için ciddi bir risk oluşturmaktadır. Bu hastalıkların, merkezi sinir sistemindeki hasarlı ve normal fonksiyonu bozulmuş mitokondrilerle çok yakından ilişkili olduğu gösterilmektedir. Mitokondri, enerji ve reaktif oksijen türlerinin üretimi, hücrelerdeki kalsiyum seviyelerinin düzenlenmesi ve programlanmış hücre ölümünün kontrolü gibi çeşitli biyolojik süreçler için hayati öneme sahiptir. Bununla birlikte, mitokondriyal aktivitedeki değişiklikler, Alzheimer hastalığı (AD), Parkinson hastalığı (PD), multipl skleroz (MS) ve amyotrofik lateral skleroz (ALS) gibi yaygın nörodejeneratif ve demyelinizan hastalıklar için kritiktir. Egzersizin kas fonksiyonunu iyileştirdiği, çeşitli sinyal yolakları ve moleküler mekanizmalar (miyokinler, hücre dışı veziküller ve biyoaktif moleküller vb.) yoluyla kas-beyin etkileşimine katkıda bulunduğu gösterilmiştir. İskelet kasının uyarılması ve antrene edilmesi, mitokondriyal fonksiyon için kanıtlanmış faydaları olan egzersizin çok önemli bir yönüdür. Egzersizin nörodejenerasyonu ve beyin hasarını önlemek için farmakolojik olmayan bir yöntem olduğu artık bilinmektedir. Düzenli egzersiz, nöronların hayatta kalmasını, nöroplastisitesini artırır ve vücudun mitokondri açısından strese verdiği tepkileri iyileştirir. Bu derleme, mitokondriyal biyogenez, dinamikler ve mitofaji dahil olmak üzere normal mitokondriyal fonksiyonun yanı sıra egzersiz ve mitokondriyal fonksiyonun nörodejeneratif ve demyelinizan bozukluklardaki rolü hakkındaki mevcut bilgilere genel bir bakış sunmaktadır. İlerleyen bölümlerde, egzersizin AD, PD, MS ve ALS gibi bozukluklarda mitokondriyal süreçleri nasıl etkilediği de tartışılmıştır

Keywords

• Egzersiz
• mitokondri
• Alzheimer hastalığı
• Parkinson hastalığı
• multipl skleroz
• amyotrofik lateral skleroz

References

1. López-Cuenca I, De Hoz R. Special issue: “Neurodegenerative diseases: recent advances and future perspectives”. Biomedicines. 2024;12:1080.
2. 2. Wu Y, Chen M, Jiang J, et al. Mitochondrial dysfunction in neurodegenerativediseases and drug targets via apoptotic signaling. Mitochondrion. 2019;49:35-45.
3. 3. Rey F, Ottolenghi S, Zuccotti GV, et al. Mitochondrial dysfunctions in neurodegenerative diseases: role in disease pathogenesis, strategies for analysis and therapeutic prospects. Neural Regen Res. 2022;17:754-758.
4. 4. Jordan J, de Groot PW, Galindo MF. Mitochondria: the headquarters in ischemia-induced neuronal death. Cent Nerv Syst Agents Med Chem. 2011;11:98-106.
5. 5. Marques-Aleixo I, Beleza J, Sampaio A, et al. Preventive and therapeutic potential of physical exercise in neurodegenerative diseases. Antioxid Redox Signal. 2021;34:674 693.
6. 6. Burtscher J, Romani M, Bernardo G, et al. Boosting mitochondrial health to counteract neurodegeneration. Prog Neurobiol. 2022;215:102289.
7. 7. Javadov S, Kozlov AV, Camara AKS. Mitochondria in Health and Diseases. Cells. 2020;9:1177.
8. 8. Lane N, Martin W. The energetics of genome complexity. Nature. 2010;467:929-934.

9. 9. Harris DA, Das AM. Control of mitochondrial ATP synthesis in the heart. Biochem J. 1991;280:561-573.
10. 10. Hroudová J, Fišar Z. Control mechanisms in mitochondrial oxidative phosphorylation. Neural Regen Res. 2013;8:363-375.
11. 11. Popov LD. Mitochondrial biogenesis: An update. J Cell Mol Med. 2020;24:4892-4899.
12. 12. Ploumi C, Daskalaki I, Tavernarakis N. Mitochondrial biogenesis and clearance: a balancing act. FEBS J. 2017;284:183-195.
13. 13. Li PA, Hou X, Hao S. Mitochondrial biogenesis in neurodegeneration. J Neuroscİ Res. 2017;95:2025-2029.
14. 14. Cantó C, Auwerx J. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol. 2009;20:98-105.
15. 15. Hardie DG. AMP-activated/SNF1 protein kinases: conserved guardians of cellular energy. Nat Rev Mol Cell Biol. 2007;8:774-785.
16. 16. Birkenfeld AL, Lee HY, Guebre-Egziabher F, et al. Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell Metab. 2011;14:184-195.
17. 17. Zhou Y, Wang S, Li Y, et al. SIRT1/PGC-1α signaling promotes mitochondrial functional recovery and reduces apoptosis after intracerebral hemorrhage in rats. Front Mol Neurosci. 2018;10:443.
18. 18. Wang SJ, Zhao XH, Chen W, et al. Sirtuin 1 activation enhances the PGC-1α/ mitochondrial antioxidant system pathway in status epilepticus. Mol Med Rep. 2015;11:521-526.
19. 19. Kondadi AK, Reichert AS. Mitochondrial dynamics at different levels: from cristae dynamics to interorganellar cross talk. Annu Rev Biophys. 2024;53:147-168.
20. 20. García-Peña LM, Abel ED, Pereira RO. Mitochondrial dynamics, diabetes, and cardiovascular disease. Diabetes. 2024;73:151-161.
21. 21. Wang Y, Dai X, Li H, et al. The role of mitochondrial dynamics in disease. MedComm. 2023;4:462.
22. 22. Dominy JE, Puigserver P. Mitochondrial biogenesis through activation of nuclear signaling proteins. Cold Spring Harb Perspect Biol. 2013;5:015008.
23. 23. D’arcy MS. Mitophagy in health and disease. Molecular mechanisms, regulatory pathways, and therapeutic implications. Apoptosis. 2024;29:1415-1428.
24. 24. Tang S, Geng Y, Lin Q. The role of mitophagy in metabolic diseases and its exercise intervention. Front Physiol. 2024;15:1339128.
25. 25. Li S, Zhang J, Liu C, et al. The role of mitophagy in regulating cell death. Oxid Med Cell Longev. 2021;2021:6617256.
26. 26. Onishi M, Okamoto K. Mitochondrial clearance: mechanisms and roles in cellular fitness. FEBS Lett. 2021;595:1239-1263.
27. 27. Liu L, Li Y, Chen G, et al. Crosstalk between mitochondrial biogenesis and mitophagy to maintain mitochondrial homeostasis. J Biomed Sci. 2023;30:86.
28. 28. Hamacher-Brady A, Brady NR. Mitophagy programs: mechanisms and physiological implications of mitochondrial targeting by autophagy. Cell Mol Life Sci. 2016;73:775-795.
29. 29. Wang S, Long H, Hou L, et al. The mitophagy pathway and its implications in human diseases. Signal Transduction Target Ther. 2023;8:304.
30. 30. Uoselis L, Nguyen TN, Lazarou M, et al. Mitochondrial degradation: mitophagy and beyond. Mol Cell. 2023;83:3404-3420.
31. 31. Rogov V, Dötsch V, Johansen T, et al. Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol Cell. 2014;53:167-178.
32. 32. Johri A, Beal MF. Mitochondrial dysfunction in neurodegenerative diseases. J Pharmacol Exp Ther. 2012;342:619-630.
33. 33. Clemente-Suárez VJ, Redondo-Flórez L, Beltrán-Velasco AI, et al. Mitochondria and brain disease: a comprehensive review of pathological mechanisms and therapeutic opportunities. Biomedicines. 2023;77:2488.
34. 34. Liu BH, Xu CZ, Liu Y, et al. Mitochondrial quality control in human health and disease. Mil Med Res. 2024;11:32.
35. 35. Deas E, Wood NW, Plun-Favreau H. Mitophagy and Parkinson’s disease: the PINK1-parkin link. Biochim Biophys Acta. 2011;1813:623-633.
36. 36. Wang W, Zhao F, Ma X, et al. Mitochondria dysfunction in the pathogenesis of Alzheimer’s disease: recent advances. Mol Neurodegener. 2020;15:30.
37. 37. Lau YS, Patki G, Das-Panja K, et al. Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson’s disease with moderate neurodegeneration. Eur J Neurosci. 2011;33:1264-1274.
38. 38. Reisman EG, Hawley JA, Hoffman NJ. Exercise-regulated mitochondrial and nuclear signalling networks in skeletal muscle. Sports Med. 2024;54:1097- 1119.
39. 39. Huertas JR, Casuso RA, Agustín PH, et al. Stay fit, stay young: mitochondria in movement: the role of exercise in the new mitochondrial paradigm. Oxid Med Cell Longev. 2019;7058350.
40. 40. Joseph AM, Adhihetty PJ, Leeuwenburgh C, et al. Beneficial effects of exercise on age-related mitochondrial dysfunction and oxidative stress in skeletal muscle. J Physiol. 2016;594:5105-5123.
41. 41. Seo JH, Park HS, Park SS, et al. Physical exercise ameliorates psychiatric disorders and cognitive dysfunctions by hippocampal mitochondrial function and neuroplasticity in post-traumatic stress disorder. Exp Neurol. 2019;322:113043.
42. 42. Ben-Shlomo Y, Darweesh S, Llibre-Guerra J, et al. The epidemiology of Parkinson’s disease. Lancet. 2024;403:283-292.
43. 43. Magaña JC, Deus CM, Giné-Garriga M, et al. Exercise-boosted mitochondrial remodeling in Parkinson’s disease. Biomedicines. 2022;10:3228.
44. 44. Perier C, Vila M. Mitochondrial biology and Parkinson’s disease. Cold Spring Harb Perspect Med. 2012;2:009332.
45. 45. Henrich MT, Oertel WH, Surmeier DJ, et al. Mitochondrial dysfunction in Parkinson’s disease – a key disease hallmark with therapeutic potential. Mol Neurodegener. 2023;18:83.
46. 46. Prasuhn J, Davis RL, Kumar KR. Targeting mitochondrial impairment in Parkinson’s disease: Challenges and Opportunities. Front Cell Dev Biol. 2021;8:615461.
47. 47. Tuon T, Valvassori SS, Lopes-Borges J, et al. Physical training exerts neuroprotective effects in the regulation of neurochemical factors in an animal model of Parkinson’s disease. Neuroscience. 2012;227:305-312.
48. 48. Chuang CS, Chang JC, Cheng FC, et al. Modulation of mitochondrial dynamics by treadmill training to improve gait and mitochondrial deficiency in a rat model of Parkinson’s disease. Life Sci. 2017;191:236-244.
49. 49. Koo JH, Cho JY. Treadmill exercise attenuates α-synuclein levels by promoting mitochondrial function and autophagy possibly via SIRT1 in the chronic MPTP/P-induced mouse model of Parkinson’s disease. Neurotox Res. 2017;32:473-486.
50. 50. Nhu NT, Cheng YJ, Lee SD. Effects of treadmill exercise on neural mitochondrial functions in Parkinson’s disease: a systematic review of animal studies. Biomedicines. 2021;9:1011.
51. 51. Reddy PH, Beal MF. Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer’s disease. Trends Mol Med. 2008;14:45-53.
52. 52. Aran KR, Singh S. Mitochondrial dysfunction and oxidative stress in Alzheimer’s disease–A step towards mitochondria based therapeutic strategies. Aging and Health Research. 2023;3:100169.
53. 53. Manczak M, Park BS, Jung Y, et al. Differential expression of oxidative phosphorylation genes in patients with Alzheimer’s disease: implications for early mitochondrial dysfunction and oxidative damage. Neuromolecular Med. 2004;5:147-162.
54. 54. Radak Z, Marton O, Nagy E, et al. The complex role of physical exercise and reactive oxygen species on brain. Journal of Sport and Health Science. 2013;2:87-93.
55. 55. Meng Q, Su C-H. The impact of physical exercise on oxidative and nitrosative stress: balancing the benefits and risks. Antioxidants. 2024;13:573.
56. 56. Liu J, et al. Chronically and acutely exercised rats: biomarkers of oxidative stress and endogenous antioxidants. J Appl Physiol (1985). 2000;89:21-28.
57. 57. Bernardo TC, Marques-Aleixo I, Beleza J, et al. Physical exercise and brain mitochondrial fitness: the possible role against Alzheimer’s disease. Brain Pathol. 2016;26:648-663.
58. 58. Pang R, Wang X, Pei F, et al. Regular exercise enhances cognitive function and intracephalic GLUT expression in Alzheimer’s disease Model Mice. J Alzheimers Dis. 2019;72:83-96.
59. 59. Haki M, Al-Biati HA, Al-Tameemi ZS, et al. Review of multiple sclerosis: Epidemiology, etiology, pathophysiology, and treatment. Medicine (Baltimore). 2024;103:37297.
60. 60. Stys PK. General mechanisms of axonal damage and its prevention. J NeurolSci. 2005;233:3-13.
61. 61. Lassmann H, Van Horssen J. Oxidative stress and its impact on neurons and glia in multiple sclerosis lesions. Biochim Biophys Acta. 2016;1862:506-510.
62. 62. Su K, Bourdette D, Forte M. Mitochondrial dysfunction and neurodegeneration in multiple sclerosis. Front Physiol. 2013;4:169.
63. 63. Mao P, Reddy PH. Is multiple sclerosis a mitochondrial disease? Biochim Biophys Acta. 2010;1802:66-79.
64. 64. Motl RW, Sandroff BM, Kwakkel G, et al. Exercise in patients with multiple sclerosis. Lancet Neurol. 2017;16:848-856.
65. 65. Kent-Braun JA, Ng AV, Castro M, et al. Strength, skeletal muscle composition, and enzyme activity in multiple sclerosis. J Appl Physiol (1985). 1997;83:1998-2004.
66. 66. Wens I, Dalgas U, Vandenabeele F, et al. Multiple sclerosis affects skeletal muscle characteristics. 2014;9:108158.
67. 67. Orban A, Garg B, Sammi MK, et al. Effect of high-intensity exercise on multiple sclerosis function and phosphorous magnetic resonance spectroscopy outcomes. Med Sci Sports Exerc. 2019;51:1380-1386.
68. 68. Kubat GB, Picone P. Skeletal muscle dysfunction in amyotrophic lateral sclerosis: a mitochondrial perspective and therapeutic approaches. NeurolSci. 2024;45:4121-4131.
69. 69. Muyderman H, Chen T. Mitochondrial dysfunction in amyotrophic lateralsclerosis - a valid pharmacological target? Br J Pharmacol. 2014;171:2191- 2205.
70. 70. Sasaki S, Iwata M. Mitochondrial alterations in the spinal cord of patients with sporadic amyotrophic lateral sclerosis. J Neuropathol Exp Neurol. 2007;66:10-6.
71. 71. Wiedemann FR, Manfredi G, Mawrin C, et al. Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients. J Neurochem. 2002;80:616-625.
72. 72. Rego AC, Oliveira CR. Mitochondrial dysfunction and reactive oxygen species in excitotoxicity and apoptosis: implications for the pathogenesis of neurodegenerative diseases. Neurochem Res. 2003;28:1563-1574.
73. 73. Zhou J, Li A, Li X, et al. Dysregulated mitochondrial Ca(2+) and ROS signaling in skeletal muscle of ALS mouse model. Arch Biochem Biophys. 2019;663:249-258.
74. 74. Ferri A, Lanfranconi F, Corna G, et al. Tailored exercise training counteracts muscle disuse and attenuates reductions in physical function in individuals with amyotrophic lateral sclerosis. Front Physiol. 2019;10:1537.
75. 75. Meng L, Li X, Li C, et al. Effects of exercise in patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis. Am J Phys Med Rehabil. 2020;99:801-810.
76. 76. Julian TH, Glascow N, Barry ADF, et al. Physical exercise is a risk factor for amyotrophic lateral sclerosis: Convergent evidence from Mendelian randomisation, transcriptomics and risk genotypes. EBioMedicine. 2021;68:103397.
77. 77. Ragagnin AMG, Shadfar S, Vidal M, et al. Motor neuron susceptibility in ALS/FTD. Front Neurosci. 2019;13:532.
78. 78. Huisman MH, Seelen M, de Jong SW, et al. Lifetime physical activity and the risk of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2013;84:976-981.
79. 79. Flis DJ, Dzik K, Kaczor JJ, et al. Swim training modulates skeletal muscle energy metabolism, oxidative stress, and mitochondrial cholesterol content in amyotrophic lateral sclerosis mice. Oxid Med Cell Longev. 2018;2018:5940748.
80. 80. Siciliano G, Pastorini E, Pasquali L, et al. Impaired oxidative metabolism in exercising muscle from ALS patients. J Neurol Sci. 2001;191:61-65.
81. 81. Lui AJ, Byl NN. A systematic review of the effect of moderate intensity exercise on function and disease progression in amyotrophic lateral sclerosis. J Neurol Phys Ther. 2009;33:68-87.
82. 82. Kilmer DD. Response to aerobic exercise training in humans with neuromuscular disease. Am J Phys Med Rehabil. 2002;81(11 Suppl):148-150.
83. 83. Fowler WM Jr. Role of physical activity and exercise training in neuromuscular diseases. Am J Phys Med Rehabil. 2002:81(11 Suppl):187-195.
84. 84. Siciliano G, Chico L, Lo Gerfo A, et al. Exercise-related oxidative stress as mechanism to fight physical dysfunction in neuromuscular disorders. Front Physiol. 2020;11:451.
85. 85. Scaricamazza S, Salvatori I, Ferri A, et al. Skeletal muscle in ALS: an unappreciated therapeutic opportunity? Cells. 2021;10:525.