Self-cannibalising mitochondria discovery may lead to ALS treatment target

Scientists have discovered a new phenomenon in the brain that could explain the development of early stages of neurodegeneration seen in diseases such as Amyotrophic lateral sclerosis (ALS). According to the researchers, their finding presents a drug target for these conditions. 

The discovery was so novel, the scientists from Northwestern Medicine, US needed to coin a new term to describe it: mitoautophagy, a collection of self-destructive mitochondria in diseased upper motor neurons of the brain that begin to disintegrate from within at a very early age.

The phenomenon is observed mainly in one of the most common pathologies observed in neurodegenerative diseases, TDP-43 pathology, which is seen in more than 90 percent of ALS cases. 

“I think we have found the culprit that primes neurons to become vulnerable to future degeneration: suicidal mitochondria,” said senior study author Hande Ozdinler, associate professor of neurology at Northwestern University Feinberg School of Medicine. “The mitochondria basically eat themselves up very early in the disease. This occurs selectively in the neurons that will soon degenerate in patients’ brains.”

Using a process called immuno-coupled electron microscopy, the scientists investigated the cellular events that go wrong inside the neurons which become vulnerable to disease. They observed the self-destruction of mitochondria only in the diseased neurons and especially within the context of TDP-43 pathology.

Mitochondria create and maintain energy in the cells. In the diseased upper motor neurons, mitochondria self-destruct first by elongating, then forming a ring-like structure, until they finally disintegrate from the inside out. It is a type of degeneration never been seen before and it is different from previously described stages of mitochondrial degeneration.

These self-destructive mitochondria could become a future target for drug therapies to treat ALS and other neurodegenerative diseases in which a person’s movement is affected, Ozdinler said. 

“Many of the drugs currently on the market that target the health and the integrity of mitochondria may well be repurposed and considered for neurodegenerative diseases in the future,” Ozdinler said. “Maybe we don’t need to reinvent the wheel to cure ALS and other neurodegenerative diseases.

“To overcome neurodegeneration, we need to improve the health and the stability of mitochondria. If we improve the health of the mitochondria early, we may even eliminate protein aggregate formation, a pathology broadly observed in many diseases.”

The study was published in Frontiers in Cellular Neuroscience.