The potential of targeting cells’ ‘power stations’ to help those living with MND

Motor neuron disease (MND) is characterised by the loss of a specific type of cells in the nervous system that is responsible for sending instructions to muscles – essential for coordinated movement. In consequence, the disease leads to a gradual loss of muscle function and increasing movement impairment. Unfortunately, there is currently a lack of effective treatments for MND, and life expectancy is usually 2-5 years from diagnosis.

Cells need energy to function, particularly motor neurons – the type of cells mainly affected in MND – which have very high energy demands. Mitochondria are structures inside cells often described as the “powerhouses” of the cell. They release energy to keep the cells alive and working properly. When mitochondria become damaged or stop working properly, they are broken down and recycled by the cell so their components can be reused.

This process is called mitophagy (“phagy” means eat). However, this recycling process can sometimes go wrong, leading to the build-up of malfunctioning mitochondria. Previous research has shown that mitochondrial dysfunction and reduced mitophagy are associated with MND. Despite this, mitochondria have been relatively underexplored as a potential therapeutic target in MND.

Why is the study important?

Problems with mitochondria and mitophagy (the mitochondria recycling process) have been noticed with different causes of MND. If this is a common feature, it could be investigated as a therapy target.

What did the authors do and how did they do it?

The researchers investigated whether mitophagy was functioning properly, and what happens when it is increased. This was primarily studied using mice carrying mutations in SOD1, a gene commonly used in MND research, alongside mice carrying other mutations associated with MND. These experiments were used to characterise disease features and changes in mitophagy, and to test the effect of a drug called urolithin A (UA), which is known to increase mitophagy.

The drug was also tested in human cells, and in tiny worms called C. elegans. Although worms are less complex than humans and mice, they share enough biological similarities that diseases and drugs can affect them in comparable ways. Because they have rapid lifespans, experiments can be completed faster than in mice. This makes them useful for early-stage testing before moving to mice.

The researchers examined mitochondria and mitophagy in MND mice. As expected, in mice with mutant SOD1, the number of healthy motor neurons decreased as the disease progressed. Over time, more mitochondria became damaged, while mitophagy declined. The same pattern – including disruption of a specific mitophagy pathway – was also observed in mice carrying a different MND-associated mutation. This suggests that dysfunctional mitochondria is a shared feature of MND.

Human cells treated with the drug UA showed that mitophagy was increased after treatment. However, these cells did not carry MND-associated mutations. To explore the effects in a disease context, the researchers used worms carrying the same SOD1 mutation used in the mice. The worms showed paralysis, reduced swimming ability, loss of motor neurons, and a shorter lifespan. When treated with UA, mitophagy increased and all measures of disease severity improved. In non-mutated worms, UA treatment increased mitophagy, but did not affect the other health measurements.

The researchers tested UA in the SOD1 mice. Treatment delayed symptom onset, slowed the decline in physical ability and muscle function, and fewer motor neurons were lost. However, their lifespan did not significantly increase, weight loss was not significantly slowed, and a general health score reduced faster with treatment as they aged. Importantly, mitophagy did increase with UA treatment in mice through the same pathway identified in earlier experiments.

What do the findings mean going forward for people with the disease?

This study highlights mitophagy as a potential therapeutic target in MND. Although the tested treatment mainly slowed disease progression in mice rather than extending lifespan, it is encouraging that this treatment appears to address a problem seen in MND. An advantage of UA is that it is already being investigated in clinical trials for boosting muscle function in older adults. This may make future testing in MND more straightforward than developing an entirely new drug.

However, additional tests need to be done in people with MND, especially considering some of the varying results between worms and mice. It should also be noted that the worms were treated with the drug from early life and mice from a pre-symptomatic stage of disease (before symptoms are observed) – neither of which is currently feasible for people, who are typically diagnosed with MND after symptoms appear. Further research is needed to explore whether similar treatment later in the disease could be beneficial, potentially across different causes of MND.

This study can be found at https://www.aginganddisease.org/EN/10.14336/AD.2025.1224

Paper title
Pharmacological Activation of Mitophagy Confers Neuroprotective Benefits for Amyotrophic Lateral Sclerosis

Lead author
Sen Huang

Publication details including date of publication
Published in Aging and Disease on 14 December 2025. DOI 10.14336/AD.2025.1224