NDR White Paper Issue 20: Can Elamipretide target mitochondrial dysfunction in ALS?

Updated: Jun 21

Amyotrophic lateral sclerosis (ALS) is associated with mitochondrial dysfunction and weight loss.

Mitochondria are the powerhouse of the cell, generating 90% of energy production in cells. The predominant physiological function of mitochondria is the generation of ATP, adenosine triphosphate, by chemical reactions called oxidative phosphorylation. The site of the ATP producing reactions, controlled by the electron transport chain, are within the inner folds of the inner mitochondrial membrane. Abnormalities in this process are collectively termed, mitochondrial dysfunction.


Mitochondria contain two major membranes. The outer mitochondrial membrane fully surrounds the inner membrane, leaving a small intermembrane space between the two membranes. The outer membrane has many protein-based pores that are big enough to allow the passage of ions and molecules as large as a small protein. In contrast, the inner membrane has much more restricted permeability. The inner membrane is also loaded with proteins involved in electron transport and ATP synthesis. This membrane surrounds the mitochondrial matrix, where the citric acid cycle produces the electrons that travel from one protein complex to the next in the inner membrane. At the end of this electron transport chain, the final electron acceptor is oxygen.


The total outward and inward proton currents exactly balance under steady-state conditions. The dominant pathway of proton re-entry during active ATP synthesis is the ATP synthase. In addition to proton re-entry through the ATP synthase, all mitochondria possess a parallel endogenous proton leak that is critical for limiting the pH and electrical gradient between the cytoplasm and the matrix. Coupled respiration, is the coupled part of respiratory oxygen flux that pumps protons across the inner mitochondrial membrane to be utilized by the phosphorylation system to produce ATP. Constitutive mitochondrial electron leak and consequent free radical generation is a significant aspect of mitochondrial metabolism. A second type of proton leak in the mitochondria is inducible, regulated protonlike mediated by uncoupling proteins.


One of NDR's research projects looked for an upregulation of uncoupling proteins in tissue from ALS patients when compared to clinically normal patients. We didn’t find an increase in uncoupling proteins.


The energy production process in mitochondria mainly involves the metabolism of lipids, or fats. One of the essential lipids involved in the process is cardiolipin. Without sufficient cardiolipin, mitochondria are misshapen and cannot produce enough energy for the cell. This means the cells become inactive and eventually die. Cells that require a lot of energy to function, like muscle and brain cells, are particularly vulnerable to mitochondrial dysfunction. Interestingly, cardiolipin participates in inflammation.


Dysfunctional mitochondria can have an impaired ability to produce ATP and can generate increased levels of reactive oxygen species, or ROS, a major contributor to oxidative stress. Low levels of ROS are important signaling molecules in the cell while high levels of ROS can damage proteins and membrane lipids within the cell. Cardiolipin in particular is highly susceptible to oxidative damage, which can result in disrupted mitochondrial structure and a cycle of increasing ROS generation that leads to inflammation, fibrosis, senescence and cell death implicated in neurodegenerative diseases.


Elamipretide, is a peptide compound that readily penetrates cell membranes, and targets the inner mitochondrial membrane where it binds reversibly to cardiolipin. In preclinical and clinical studies, Elamipretide increases mitochondrial respiration, improves electron transport chain function and ATP production and reduces formation of pathogenic ROS levels. This Elamipretide-cardiolipin association has been shown to normalize the structure of the inner mitochondrial membrane, thereby improving mitochondrial function. Functional benefit is achieved through improvement of ATP production and interruption and potential reversal of damaging oxidative stress.


The drug Elamipretide is a mitochondria-targeted drug that reversibly binds cardiolipin on the inner mitochondrial membrane and improves coupling of the electron transport chain. Elamipretide triacetate is in clinical trials for some recognized mitochondrial diseases.

A project at NDR involved isolating adipose stem from an sALS patient. The cells were fully characterized and found to be abnormal in their proliferation, lipid accumulation, and energy metabolism. A measurable parameter was the extracellular production of ATP. Several chemicals were used to evaluate the capacity to rescue abnormal metabolism and mitochondrial dysfunction including Elamipretide. Elamipretide did not rescue these cells.


What's on the horizon for mitochondrial rescue?

SBT-272, in the pipeline at Stealth BioTherapeutics, is an innovative peptidomimetic being investigated as a potential therapy for neurodegenerative illnesses that are associated with mitochondrial dysfunction. In preclinical experiments, the administration of SBT-272 to defective mitochondria led to an increase in the generation of adenosine triphosphate (ATP) and a decrease in the levels of reactive oxygen species (ROS).


In comparison to Elamipretide, Stealth’s first-in-class lead chemical, SBT-272 exhibits much higher mitochondrial uptake, significantly higher concentrations in the brain, and significantly enhanced oral bioavailability. In a mouse model of ALS that shows progressive neurodegenerative disease characterized by the deterioration of motor neurons and the atrophy of muscle tissue, treatment with SBT-272 was associated with a dose-dependent delay in the onset of neurological disease, a reduction in systemic markers of neurodegeneration, and a prolonged lifespan.


ALS is one of the most common forms of neurodegenerative disease. SBT-272 is presently being investigated in a further preclinical model of ALS, as well as in a preclinical model indicative of activity in multiple system atrophy (MSA). MSA is a neurological condition that can result in parkinsonism, cerebellar ataxia, dysautonomia, and other motor and non-motor symptoms. It is thought that mitochondrial dysfunction has a role in the course of neurodegenerative disorders such as ALS and MSA, as well as other conditions such as Parkinson’s disease, Huntington’s disease, and Alzheimer’s disease.

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