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Mitochondria kill themselves to protect neurons from an early death

Read time: 5 mins
Mitochondria kill themselves to protect neurons from an early death

Voluntary movements, like lifting your hand to wave, are executed through precise coordination between different brain areas. Sometimes, due to the loss of neurons in the brain, some individuals cannot coordinate such voluntary movements and are said to be suffering from a condition called ataxia. A type of ataxia, known as the spinocerebellar ataxia, involves the loss of neurons from the spinal cord and cerebellum. These brain areas are responsible for controlling movement and balance. Caused by an inherited genetic mutation, the disease progresses slowly and manifests in children when they are twelve or thirteen years old.

In a recent study, researchers from the Indian Association for the Cultivation of Science, Kolkata, Indian Institute of Science Education and Research (IISER) Pune, and Indian Institute of Technology Gandhinagar, point out how neural cells alter themselves to survive spinocerebellar ataxia. The study, published in the journal Science Advances, found that these neurons got rid of their energy-producing machinery. The study was funded by the Wellcome Trust/ Department of Biotechnology India Alliance and the Department of Science and Technology.

The DNA, present in the nucleus of the cell, is a coiled structure. It holds the recipe for producing all the vital proteins needed for the proper functioning of the body. To make these proteins, the DNA needs to unwind through the help of an enzyme called topoisomerase 1 (TOP1), which binds to the DNA at specific sites. This binding creates a cut and results in the DNA uncoiling, after which, another enzyme called tyrosyl-DNA phosphodiesterase 1 (TDP1) removes TOP1 from the binding sites. The cut DNA heals and coils back again. However, in individuals with SCAN-1, a genetic mutation results in a faulty version of TDP1. As a result, it cannot completely heal the nick made during the unwinding of the DNA, damaging it in the process and triggering cell death.

The TOP1-TDP1 interplay occurs within the cell nucleus and also in the mitochondria, which have their own DNA. Mitochondria are powerhouses producing the energy required for the cell. Under normal conditions, the mitochondrial DNA is nicked by TOP1 to assist in replication, and after that, TDP1 heals the cut. The researchers of the current study wondered if the mutated enzyme TDP1 also jeopardized the energy machinery of the cell in patients with spinocerebellar ataxia. They developed a cellular system using embryonic cells from mice to study this process. These immature cells had no TDP1 enzyme of their own but were genetically engineered to produce the mutant TDP1.

"We choose to work on fibroblasts, which gives a clear picture of the mutant gene knock-in cellular models," says Dr. Benu Brata Das, the corresponding author of the study. He is an associate professor and a Wellcome Trust Intermediate Fellow at the Indian Association of Cultivation of Science, Kolkata. "We also used cells derived from patients with SCAN1 and differentiated human neuronal cells expressing SCAN1-mutant TDP1 to address our questions", he points out.

The researchers used the anti-cancer drug called Irinotecan or mitoSN-38 to lock TOP1 on the mitochondrial DNA.  Accumulated TOP1 on mitochondrial DNA damages it permanently which induces cell death in cancerous tissues. In this study, however, the aim was to check whether the mutant TDP1 enzyme efficiently removed the accumulated topoisomerase complex. 

The researchers found that the mutated TDP1 enzyme was unable to cure the DNA damage, and the DNA remained bound to large quantities of TOP1. As a result, the mitochondrial DNA was damaged in patients with spinocerebellar ataxia with axonal neuropathy. 

Under such conditions of stress, the mitochondria may split up to let go of its deteriorated DNA. This process is known as fission and is the only way to generate new mitochondria. Alternatively, to maintain a balance in the number of mitochondria, these energy powerhouses can fuse to create a single mitochondrion. As a result, mitochondria exist in the form of a dynamic network and undergo fission or fusion to maintain equilibrium.

The researchers marked the mitochondrial network using fluorescent proteins. They observed that these proteins moved slowly across the mitochondrial network when the cells harboured mutated TDP1. Besides, there was an increase in the mitochondrial fission proteins, suggesting that in the diseased conditions, increased fission disrupts the mitochondrial network.

The researchers hypothesized that a damaged mitochondrial network might activate the cell's cleaning process. This process, called autophagy, involves confining the broken cellular components within a membrane to degrade them. The rate of formation of these membrane-covered structures had almost doubled in the diseased cells. Interestingly, the study found that mutation in the TDP1 enzyme results in smaller mitochondria with shorter DNA, and were poor in generating proteins essential for energy production. Would this mean that neurons are deprived of energy in SCAN1?

"Essentially, the autophagy is a mechanism that protects the healthy mitochondria from damaged ones. Therefore, under this situation, the fewer healthy mitochondria, can partially fulfil the energy demand", says Dr Das.

For a cell, damage to the DNA is the final nail in the coffin. TDP1 enzyme forms an essential part of the machinery that repairs this damage and aids cell survival. But how does a mutation in a single protein lead to large scale neurodegeneration?

"Mutation of DNA repair proteins leads to gross chromosomal changes. The accumulation of DNA double-strand breaks cause neurodegeneration, cancer, and accelerates ageing phenotypes. Experiments from our lab, and other studies, establish that damaged DNA in the neurons, if not repaired properly, facilitates the onset of neurodegeneration. Taken together, what matters is how you maintain the DNA in neurons because they don't divide but are a critical part of the brain. The death of neurons is directly correlated with the dysfunctional brain", he sums up.


This article has been run past the researchers, whose work is covered, to ensure accuracy.