Faulty cellular connections disrupting energy production in brain cells

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neurone disease (MND).The primary type of cell may be affected in ALS are called motor neurons; these are  like electrical wires carrying messages from the brain to the muscles. When someone has ALS, these  brain cells (motor neurons) gradually stop working and die, causing progressive weakness that affects everyday activities like walking, speaking, eating, and eventually breathing. Scientists have discovered several processes that contribute to the death of these nerve cells, such as the following:

• Nerve cells usually turn on for short periods of time, however when they are forced to stay constantly active, they become damaged over time.
• defective proteins that don’t fold properly can clump together, creating harmful buildup in the motor neuron cells.
• Faulty connections in these cells can lead to disruption of energy production. Causing brain cells to die.
• Disfunction in the “mitochondria” which are the energy making centres of the cell, are also a contributing factor to the development of ALS.

Why is the study important?

This new study is important because it  uncovered a crucial piece of the puzzle in understanding how ALS damages nerve cells, particularly focusing on how cells get their energy. Scientists have discovered that in ALS, there’s a breakdown in communication between different parts of the nerve cell – specifically between the energy factory (mitochondria) and another important cell structure, the part of the cell that makes the building blocks for proteins (endoplasmic reticulum). This communication problem leads to a significant change in how cells use fuel to enable them to function. Instead of properly using sugar (fuel), which is their normal energy source, the cells are forced to switch to burning fat for energy – similar to an engine trying to run on the wrong type of fuel.

This different incorrect fuel choice creates toxic waste products that damage the cells further. Before this discovery, scientists knew cells were dying in ALS but didn’t fully understand the underlying reasons. Now that they’ve identified this energy factory fuel problem, they now have a new target for potential treatments. If scientists can find ways to fix the communication breakdown between these cell parts, then they might be able to help cells use the right fuel again, potentially slowing down or preventing some of the damage caused by ALS. This discovery opens up new possibilities for treatments that could help keep nerve cells alive longer and potentially improve the lives of people living with ALS.

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

The researchers conducted their  research (study) using both mice and human brain cells that were grown in the lab. They focused on examining a critical connection point inside cells called the mitochondria-associated ER membrane (MAM) – a specialised region where two key structures inside the cell meet and interact.

These two structures are the cell’s energy-producing centre (mitochondria) and the (ER).This connection point is vital because it allows these two cellular components to coordinate their activities and regulate cell function. The scientists wanted to understand what happens when the communication at this connection point (MAM) becomes disrupted, particularly how it affects the cell’s ability to process different energy sources like sugar (glucose) and fats (fatty acids).

This interaction is crucial because when these cellular components fail to communicate properly, it can lead to problems with energy production, protein processing, which is the cell’s ability to make, and arrange proteins correctly. The proper functioning of both the energy-producing mitochondria and the protein-making ER, along with their ability to communicate through the MAM, is essential for maintaining healthy cell function and hence preventing cell death.

The researchers discovered several important changes happening in cells affected by ALS.

First, they found that a crucial connection point in cells, called the MAM, was damaged and not working properly. This damaged connection led to major changes in how cells produced their energy. The cell’s power plants (mitochondria) were forced to switch from using their preferred fuel source of sugar (glucose) to relying more heavily on fats (fatty acids). This switch to using fats resulted in the cells producing energy less efficiently, much like an engine running on the wrong type of fuel.

As a result of this inefficient energy production, the cells began producing more harmful substances called “reactive oxygen species” (a harmful byproduct that damages healthy cells), which caused additional damage to cell components. The researchers also found an important enzyme complex, which is a group of proteins that work together for a specific task. Specifically, the dysfunction complex was (complex I) located in the mitochondria had stopped working properly, further reducing the cell’s ability to produce energy effectively.

Together, these findings show how problems with the MAM connection point can trigger a chain reaction of energy production problems in cells affected by ALS, ultimately leading to cell damage and dysfunction.

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

This research reveals how altered interactions between mitochondria and the ER and MAM can drive metabolic changes in the body’s biochemical processes due to ALS. When these cellular components stop working together properly, nerve cells struggle to produce sufficient energy to function properly. By identifying these problems, researchers can work on developing treatments that restore these critical cellular functions . For people with ALS, this research offers hope for future treatments that could help maintain daily functions and personal independence for longer. The goal is to keep nerve cells healthy and working properly, which could make a real difference in how the disease progresses.

This study can be found at
https://pubmed.ncbi.nlm.nih.gov/39753538/ 

Paper title
Altered mitochondria-associated ER membrane (MAM) function shifts mitochondrial metabolism in amyotrophic lateral sclerosis (ALS)

Lead author
Delfina Larrea, Estela Area-Gomez

Publication details including date of publication
Nature Communications. 2025 Jan 3;16(1):379