Mitochondrial Dysfunction In Beckers Muscular Dystrophy

By Author: Blueoaknx
Total Articles: 26
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Introduction
Beckers Muscular Dystrophy (BMD) is a genetic neuromuscular disorder caused by mutations in the DMD gene, leading to defective dystrophin production. While dystrophin primarily serves as a structural protein, emerging evidence indicates its role in mitochondrial function and cellular metabolism. This article explores mitochondrial dysfunction in BMD, focusing on bioenergetics, oxidative stress, mitochondrial dynamics, and metabolic consequences.
Bioenergetic Impairment
Mitochondria are the primary energy-producing organelles, generating adenosine triphosphate (ATP) through oxidative phosphorylation (OXPHOS). In BMD, mitochondrial bioenergetics are disrupted due to reduced dystrophin-associated glycoprotein complex (DGC) stability, affecting intracellular signaling and energy metabolism. Studies show that muscle fibers from BMD patients exhibit reduced ATP production, mitochondrial membrane potential (ΔΨm) depolarization, and decreased respiratory chain efficiency. Impaired complex I and complex IV activities have been reported, contributing to decreased oxidative phosphorylation and subsequent ...
... muscle weakness.
Oxidative Stress and ROS Accumulation
Mitochondria are a significant source of reactive oxygen species (ROS), which play dual roles as signaling molecules and contributors to oxidative damage. In BMD, excessive ROS production due to dysfunctional electron transport chain (ETC) exacerbates oxidative stress. Studies have demonstrated elevated lipid peroxidation, increased protein carbonylation, and mitochondrial DNA (mtDNA) damage in BMD-affected muscles. Reduced expression of key antioxidant enzymes, such as superoxide dismutase (SOD) and glutathione peroxidase (GPx), further impairs the ability to counteract oxidative damage. The resulting oxidative burden contributes to muscle fiber degeneration, chronic inflammation, and apoptosis.
Mitochondrial Dynamics: Fission and Fusion Imbalance
Mitochondria continuously undergo fission and fusion processes to maintain cellular homeostasis. These dynamics are critical for mitochondrial quality control, ensuring the removal of damaged mitochondria via mitophagy. In BMD, an imbalance between fission and fusion leads to mitochondrial fragmentation and defective turnover. Key regulators such as dynamin-related protein 1 (DRP1) and mitofusin-2 (MFN2) exhibit altered expression, resulting in increased mitochondrial fission and reduced fusion. This dysregulation impairs mitochondrial network integrity, contributing to decreased ATP production and enhanced susceptibility to apoptosis.
Calcium Homeostasis and Mitochondrial Dysfunction
Dystrophin deficiency in BMD disrupts sarcolemmal stability, leading to aberrant calcium (Ca²⁺) handling. Elevated intracellular Ca²⁺ levels induce mitochondrial Ca²⁺ overload, impairing bioenergetic function and promoting mitochondrial permeability transition pore (mPTP) opening. mPTP dysregulation results in mitochondrial swelling, cytochrome c release, and apoptotic cascade activation. Additionally, excessive mitochondrial Ca²⁺ uptake alters ATP synthesis efficiency, exacerbating muscle fiber necrosis and degeneration.
Metabolic Alterations and Energetic Deficits
Skeletal muscle metabolism in BMD is characterized by a shift from oxidative to glycolytic energy production. Defective mitochondrial respiration forces muscle fibers to rely on glycolysis for ATP generation, leading to increased lactate accumulation and metabolic acidosis. This metabolic shift results in early fatigue, reduced endurance, and inefficient energy utilization. Transcriptomic analyses have identified downregulation of genes involved in fatty acid oxidation and tricarboxylic acid (TCA) cycle activity, further confirming the metabolic shift towards glycolysis. Such metabolic alterations compromise muscle function and regeneration capacity, contributing to disease progression.
Mitochondrial Quality Control and Mitophagy Defects
Mitophagy, a selective form of autophagy responsible for degrading damaged mitochondria, is impaired in BMD. The PINK1/Parkin pathway, essential for mitochondrial quality control, is downregulated in dystrophic muscle, leading to the accumulation of dysfunctional mitochondria. Defective mitophagy contributes to mitochondrial swelling, increased oxidative stress, and cellular energy deficits. Additionally, impaired mitophagy reduces the capacity for mitochondrial biogenesis, further exacerbating mitochondrial dysfunction and muscle pathology.
Conclusion
Mitochondrial dysfunction in BMD arises from bioenergetic impairments, oxidative stress, disrupted mitochondrial dynamics, altered Ca²⁺ homeostasis, metabolic deficits, and defective mitophagy. These abnormalities collectively contribute to muscle degeneration and disease progression. Understanding these mitochondrial defects provides valuable insights into the pathophysiology of BMD, emphasizing the need for targeted research to mitigate mitochondrial dysfunction and improve muscle health in affected individuals.

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