Relationship Between Mitochondria and Muscular Dystrophy
1. Decreased Energy and ATP Production
In Duchenne muscular dystrophy (DMD), there is a marked reduction in the mitochondria’s ability to generate ATP, reaching only about half the level found in healthy muscle.
This energy deficiency is further aggravated by alterations in key enzymes of the Krebs cycle and in respiratory chain complexes, especially Complex I.
2. Altered Localization and Dysfunctional Structural Organization
The absence of dystrophin disrupts the organization of the cytoskeleton—particularly microtubules—leading to incorrect mitochondrial positioning within muscle cells.
This misplacement hinders the efficient delivery of energy where it is most needed.
In addition, oxidative respiration is compromised, with reduced coupling between the electron transport chain and ATP synthesis.
3. Oxidative Stress and Accumulation of Damaged Mitochondria
Muscles affected by DMD show increased production of reactive oxygen species (ROS), which damage proteins, DNA, and mitochondrial membranes.
At the same time, the processes responsible for removing defective mitochondria (autophagy/mitophagy) are impaired, allowing damaged mitochondria to accumulate and worsen muscle injury.
4. Calcium Overload and Impaired Cellular Repair
The fragility of the muscle membrane (due to the absence of dystrophin) allows excessive calcium influx into the cell, which also overloads mitochondria.
This overload decreases their efficiency and hinders muscle repair mechanisms, creating a harmful cascade effect.
5. Alterations in Mitochondrial Dynamics
Proteins responsible for mitochondrial fusion and fission (such as MFN2 and DRP1) are elevated in muscular dystrophy models, possibly as an adaptive response to metabolic stress.
However, this imbalance is also linked to increased oxidative stress and mitochondrial dysfunction.
6. Mitochondria-Centered Therapeutic Opportunities
Understanding the central role of mitochondria in muscular dystrophy opens multiple avenues for treatment:
Modulation of Mitophagy: Certain compounds have shown the ability to restore mitochondrial function and improve muscle regeneration.
Stabilization of the Mitochondrial Permeability Transition Pore (mPTP): Drugs have been shown to improve mitochondrial respiration in human DMD cells.
Reduction of Oxidative Stress: Agents that counteract ROS could protect cellular and mitochondrial integrity.
In Summary
Mitochondrial dysfunction occurs even before visible muscle damage and plays a decisive role in the development and progression of muscular dystrophy.
For this reason, mitochondria represent a promising target in future therapies.
Scientific Articles:
Mitochondria and Reactive Oxygen Species: The Therapeutic Balance of Powers for Duchenne Muscular Dystrophy
PMID: 38607013 | PMCID: PMC11011272 | DOI: 10.3390/cells13070574Defects in Mitochondrial Localization and ATP Synthesis in the mdx Mouse Model of Duchenne Muscular Dystrophy Are Not Alleviated by PDE5 Inhibition
PMCID: PMC3522404 | PMID: 23049075Mitochondrial Bioenergetic Dysfunction in the D2.mdx Model of Duchenne Muscular Dystrophy Is Associated with Microtubule Disorganization in Skeletal Muscle
PMCID: PMC7529311 | PMID: 33002037The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases
PMCID: PMC7600520 | PMID: 33050147Mitochondria Mediate Cell Membrane Repair and Contribute to Duchenne Muscular Dystrophy
PMID: 27834955 | PMCID: PMC5299714 | DOI: 10.1038/cdd.2016.127Metabolic Dysfunction and Altered Mitochondrial Dynamics in the Utrophin-Dystrophin Deficient Mouse Model of Duchenne Muscular Dystrophy
PMCID: PMC4393257 | PMID: 25859846The Role of Mitochondria in Mediation of Skeletal Muscle Repair
https://doi.org/10.3390/muscles2020011Skeletal Muscle Mitochondria Dysfunction in Genetic Neuromuscular Disorders with Cardiac Phenotype
PMCID: PMC8307986 | PMID: 34298968