Mitochondria, The Powerhouse of the Cell? Perhaps Not If You Have ALS

Annabelle Yan -

In the United States, baseball plays a large part in sports culture and has captivated families around the nation for decades. In its most popular days, news of baseball greats often overlapped with daily headlines, which is why you’ve probably heard of Lou Gehrig’s disease, or ALS (amyotrophic lateral sclerosis). ALS is a neurological disease in which the loss of motor neurons in the cortex and the spinal cord causes progressive paralysis [1]. Gehrig, a widely renowned first baseman known as the Iron Horse, deteriorated rapidly at only 36 years old and died less than two years after his diagnosis. The exact cause of the disease is unknown, but its consequences are well-researched: mild symptoms such as slurring words and twitching limbs quickly give way to an absence of muscle control. This impairs the ability to eat, move, speak, or breathe, and eventually leads to complete paralysis [1]. A person with ALS remains conscious until the end of their life, so bitter expectations for a patient are shared by families around the world. While medication and therapies can slow symptoms and decrease discomfort, there is no current cure [1]. However, researchers are hoping to learn more about the underlying mechanisms of ALS to create treatments targeting dysfunctional systems. 

A recent study from the National Autonomous University of Mexico published in the journal Neuroscience identified a role of mitochondria damage in cell death from AMPA-induced excitotoxicity, a key feature of ALS [2]. AMPA-induced excitotoxicity is a phenomenon where over-activation of glutamate receptors leads to neuronal dysfunction and cell death [3]. Glutamate is a neurotransmitter responsible for a large portion of brain signaling in the central nervous system, but prolonged excitation can be toxic to cells [4]. ALS patients commonly exhibit raised levels of glutamate in their cerebrospinal fluid, which heavily affects the functionality of mitochondria, limiting the energy they can produce for cells to use [5].

Figure 1: These five rows show the gradual progression of mitochondrial degeneration. Control motor neurons (MNs) show a homogeneous cytoplasmic density and a well-defined shape. As the degeneration progresses, the endoplasmic reticulum and cytoplasm begin to swell and vacuolize until stage 4, where MNs begin to rupture and disintegrate [2]

Interested in the role of AMPA-induced excitotoxicity, researchers observed mitochondrial alterations in an in vivo (in a live organism) chronic model of motor neuron degeneration in male rats [2]. The chronic administration of AMPA, a compound that mimics glutamate activity, was found to induce gradual changes in the structure of spinal motor neurons and their mitochondria. Specifically, mitochondria were found to swell and change from an elongated to a circular shape, and mitochondrial DNA was damaged in rats. It is now believed that the observed decreases in mitochondrial energy production because of AMPA-excitotoxicity are due to dysfunctional and deformed mitochondria. These mitochondrial alterations disrupt proper motor neuron activity and are associated with early muscular dysfunction and the onset of ALS, even before motor neuron loss [2].

Understanding the complex degenerative process of motor neurons is crucial for developing effective ALS treatment. This study explored the role of mitochondrial damage and early muscle dysfunction in ALS, particularly the mechanisms downstream of toxic protein aggregation [2]. By identifying how AMPA-induced excitotoxicity disrupts mitochondrial structure and energy production in motor neurons, this study suggests that mitochondrial alterations may drive disease progression and offers a new avenue for targeted interventions before motor neuron loss becomes irreversible. Better knowledge of the intricacies of ALS ultimately brings hope for therapies that address ALS at a cellular level, potentially improving quality of life and even preventing its debilitating effects for millions of patients like Lou Gehrig.

Reference: 

[1] Brotman, R. G., Moreno-Escobar, M. C., Joseph, J., Munakomi, S., & Pawar, G. (2024). Amyotrophic Lateral Sclerosis. In StatPearls. StatPearls Publishing.

[2] Ramirez-Jarquin, U. N., Lopez-Huerta, V. G., & Tapia, R. (2023). Characterization of Mitochondria Degeneration in Spinal Motor Neurons Triggered by Chronic Over-activation of α-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid Receptors in the Rat Spinal Cord in Vivo. Neuroscience, 521, 31–43. https://doi.org/10.1016/j.neuroscience.2023.04.005

[3] Jensen, J. B., Schousboe, A., & Pickering, D. S. (1998). AMPA receptor mediated excitotoxicity in neocortical neurons is developmentally regulated and dependent upon receptor desensitization. Neurochemistry international, 32(5-6), 505–513. https://doi.org/10.1016/s0197-0186(97)00130-7

[4] Dong, X. X., Wang, Y., & Qin, Z. H. (2009). Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta pharmacologica Sinica, 30(4), 379–387. https://doi.org/10.1038/aps.2009.24

[5] Hillen, A. E. J., & Heine, V. M. (2020). Glutamate Carrier Involvement in Mitochondrial Dysfunctioning in the Brain White Matter. Frontiers in molecular biosciences, 7, 151. https://doi.org/10.3389/fmolb.2020.00151