When Powerhouses Falter: How Mitochondrial Mutations May Fuel Multiple Sclerosis
Multiple sclerosis (MS) is one of the most challenging neurodegenerative diseases known to medicine. It is an autoimmune disorder in which the body’s immune system mistakenly attacks the central nervous system (CNS), leading to inflammation, demyelination, and progressive neurodegeneration. MS affects over two million people worldwide and remains the leading cause of non-traumatic neurological disability among young adults.
While researchers have long explored immune and environmental factors, recent discoveries suggest that the root of MS may also lie deep within our cells — in the mitochondria. These tiny powerhouses are responsible for producing the energy that fuels our neurons, and their dysfunction is increasingly recognized as a key driver of neurodegeneration.
Mitochondria: Energy Factories with Their Own Genetic Code
Unlike most cellular organelles, mitochondria have their own genome — a small, circular DNA molecule called mitochondrial DNA (mtDNA). This genome, inherited exclusively from the mother, contains 37 genes that encode essential components of the oxidative phosphorylation (OXPHOS) system, the process by which cells generate ATP, their main energy currency.
However, mtDNA is more vulnerable to mutations than nuclear DNA. It lacks protective histones and has limited DNA repair mechanisms, making it highly susceptible to damage from reactive oxygen species (ROS). Mutations in mtDNA can impair energy production and promote oxidative stress, which in turn damages neurons — a vicious cycle that may underlie the neurodegenerative processes observed in MS.
The Study: Sequencing the Entire Mitochondrial Genome
In this study published in PLOS ONE in 2022, Dr. Ghada Al-Kafaji and colleagues analyzed the entire mitochondrial genome of Saudi individuals to uncover disease-related mutations linked to multiple sclerosis.
The research team examined 47 participants — 23 patients diagnosed with relapsing-remitting MS (RRMS) and 24 healthy controls. Using next-generation sequencing (NGS), they generated high-coverage mtDNA sequences (approximately 10,000x coverage), enabling the detection of even low-level heteroplasmic mutations that might otherwise be missed.
This approach marked one of the first comprehensive mitochondrial genome analyses of MS patients in an Arab population, providing valuable population-specific genetic insights.
Findings: A Landscape of Mitochondrial Mutations
The study identified 3,248 mtDNA variants across all samples — an average of 69 per individual. Importantly, the total number of variants was higher in MS patients compared to controls.
A significant portion of these variants was located in the D-loop region, a non-coding control segment critical for regulating mtDNA replication and transcription. This region’s high variability may influence mitochondrial gene expression and energy metabolism, potentially affecting disease susceptibility.
The majority of mtDNA mutations were homoplasmic, meaning they were present in all mitochondrial copies within a cell. However, a smaller fraction were heteroplasmic, existing alongside normal mtDNA copies — a hallmark of mitochondrial dysfunction often observed in degenerative diseases.
Unique and Deleterious Mutations in MS Patients
Among the mutations identified, 34 missense variants — mutations that alter amino acids in mitochondrial proteins — were found exclusively in MS patients and absent in healthy controls. Seven of these were predicted to be functionally deleterious, meaning they could directly impair protein structure or function.
These deleterious mutations occurred in key mtDNA-encoded genes responsible for the OXPHOS complexes that drive energy production:
MT-ND3 (Complex I) – Mutation 10237T>C
MT-ND6 (Complex I) – Mutation 14484T>C
MT-ND2 (Complex I) – Mutation 5437C>T
MT-CO3 (Complex IV) – Mutation 9288A>G
MT-CYB (Complex III) – Mutations 15431G>A and 15884G>C
MT-ATP8 (Complex V) – Mutation 8490T>C
These complexes are central to the electron transport chain, which fuels ATP synthesis. Mutations that disrupt their subunits can cause reduced energy output and increased oxidative stress, contributing to the neuronal damage seen in MS.
Predicting the Functional Impact: Computational and Structural Insights
To understand how these mutations might affect mitochondrial function, the team employed bioinformatics prediction tools such as PolyPhen, SIFT, CADD, and Mutation Assessor. These programs evaluate whether amino acid substitutions are likely to be benign or damaging based on evolutionary conservation and structural modeling.
The results revealed that several of the identified mutations were highly deleterious. For example, the mutation MT-CO3 Thr28Ala led to the complete loss of stabilizing polar bonds in the protein’s 3D structure. Similarly, MT-ND6 Met64Val and MT-CYB Ala229Thr introduced structural clashes that could destabilize the protein complex and impair its ability to transfer electrons efficiently.
Such disruptions in the OXPHOS system are likely to reduce ATP production and increase ROS generation, setting the stage for energy failure and axonal degeneration — two central features of multiple sclerosis pathology.
Population-Specific Significance and Broader Implications
This study represents the first whole-mitochondrial genome analysis in an Arab MS cohort, shedding light on potential population-specific genetic variants that might influence disease susceptibility.
The discovery of seven previously unreported mutations expands the catalog of mtDNA variants associated with MS and reinforces the hypothesis that mitochondrial dysfunction is not just a consequence of inflammation but may be an initiating factor in disease development.
Moreover, the study underscores the power of next-generation sequencing in uncovering subtle yet impactful mutations that traditional targeted sequencing methods might overlook.
Future Directions: Toward a Mitochondrial Signature of MS
While the findings are promising, the authors emphasize the need for larger and multi-ethnic studies to confirm these results and explore how mtDNA mutations interact with nuclear genes, immune responses, and environmental factors.
Future research could integrate multi-omics approaches — combining genomics, transcriptomics, and metabolomics — to gain a holistic understanding of how mitochondrial dysfunction contributes to neuroinflammation and neurodegeneration in MS.
In the long term, these insights could lead to novel biomarkers for diagnosis or even mitochondria-targeted therapies, opening a new frontier in personalized medicine for multiple sclerosis.
Conclusion: Mitochondria at the Heart of Neurodegeneration
The study by Al-Kafaji and colleagues offers compelling evidence that mitochondrial DNA mutations may play a direct role in the pathogenesis of multiple sclerosis. By identifying novel deleterious variants in energy-related genes, it highlights the intricate connection between cellular metabolism, oxidative stress, and neurodegeneration.
Far from being passive bystanders, mitochondria may be active contributors to MS progression, linking genetics and bioenergetics to immune dysfunction. Understanding and targeting these mitochondrial mechanisms could be key to unraveling — and ultimately treating — the mysteries of multiple sclerosis.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Al-Kafaji G, Bakheit H.F., AlAli F., Fattah M., Alhajeri S., Alharbi M.A., et al. (2022). Next-generation sequencing of the whole mitochondrial genome identifies functionally deleterious mutations in patients with multiple sclerosis. PLOS ONE, 17(2): e0263606. https://doi.org/10.1371/journal.pone.0263606
