FA likely marked by problems making mitochondrial proteins
Study finds frataxin deficiency leads to low activity of another key protein
A deficiency of frataxin, the protein whose lack causes Friedreich’s ataxia, leads to problems with mitochondrial translation — the molecular process by which new proteins are made in the mitochondria, the so-called powerhouse of the cell responsible for energy production — according to a new study.
The findings specifically indicate that frataxin deficiency leads to low activity of another protein, called METTL17, that’s essential for mitochondrial translation.
“Our findings indicate that at least in cultured cells, FXN deficiency results in a previously under-appreciated deficit in mitochondrial protein synthesis, which appears to be largely downstream of METTL17,” the researchers wrote.
Increasing METTL17 levels in frataxin-deficient cells could improve the cells’ ability to generate energy, the team found — implying that this pathway may be a useful treatment target.
The study, “METTL17 is an Fe-S cluster checkpoint for mitochondrial translation,” was published in Molecular Cell.
Investigating the connections at the molecular level in FA
Friedreich’s ataxia is caused by mutations in the FXN gene, which provides instructions for making the frataxin protein. This protein is known to be essential for mitochondrial health, and it’s been established that frataxin helps to make iron-sulfur (Fe-S) clusters — a type of chemical modification that gets attached to certain mitochondrial proteins.
But exactly how frataxin, Fe-S clusters, and mitochondrial health are connected at the molecular level is not completely understood. To gain insight, a team led by scientists at the Broad Institute, in Massachusetts, conducted a proteomic analysis comparing levels of hundreds of proteins from cells engineered to lack frataxin to control cells.
Frataxin deficiency was found to lead to decreased levels for almost every detected protein known to bind to Fe-S clusters.
“This analysis revealed that depletion of [frataxin] leads to a near universal diminution in Fe-S cluster-binding proteins,” the researchers wrote.
This finding implies that proteins which normally bind to Fe-S clusters aren’t stable without this chemical addition, which sheds new light on the molecular role of Fe-S clusters in protein biochemistry, according to the researchers.
“Although it has long been known that one function of Fe-S clusters … is protein stability our findings show that, in fact, this is a nearly universal role of the cluster,” they wrote.
While mitochondria are most well-known for their role in producing cellular energy, they also have other important cellular functions. Mitochondria store their own DNA, which is used as a template to make mitochondrial proteins via a specialized process called mitochondrial translation.
The researchers’ proteomic screen suggested that frataxin deficiency led to reduced assembly of the mitoribosome, a protein complex that’s critical for mitochondrial translation. A battery of further cell experiments indicated that mitochondrial translation is significantly impaired in cells lacking frataxin.
METTL17 protein key in producing mitochondrial proteins
In further experiments, the researchers zeroed in on the protein METTL17 as the reason for this. METTL17 is necessary to stabilize the mitoribosome, and when frataxin is lacking, METTL17 activity is abnormally low, resulting in unstable mitoribosomes.
“We show that METTL17 deficiency lies downstream of [frataxin] loss and appears to be a key effector of impaired mitochondrial translation,” the scientists wrote.
The researchers actually found that the METTL17 protein itself harbors a Fe-S cluster, which hadn’t been previously known and seems key to promote mitochondrial translation.
“Our work shows that mitochondrial translation is dependent on METTL17 being present with an intact Fe-S cluster,” the team wrote.
Putting the findings together, this study suggests that frataxin deficiency leads to problems with Fe-S clusters, destabilizing many proteins including METTL17. That, in turn, appears to result in abnormalities with mitochondrial translation, ultimately leading to atypical levels of many proteins that are needed for mitochondria to function correctly.
Based on this mechanism, the researchers wondered if increasing METTL17 levels in frataxin-deficient cells could help improve mitochondrial health. They found that increasing METTL17 led to benefits in cellular energy generation, though it didn’t improve cellular growth.
These findings suggest that “METTL17 could hold therapeutic potential” for Friedreich’s ataxia, the researchers concluded. The team stressed, however, that this study was done in cellular models, so additional work is needed to verify if the same mechanisms are at play in animal models and in samples from Friendreich’s ataxia patients.
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