Energy production complex in mitochondria may be FA target

Findings shed light on role of frataxin in metabolic dysfunctions in FA

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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An illustration of mitochondria.

A deficiency in the frataxin protein, which is the underlying cause of Friedreich’s ataxia (FA), alters a process in a large protein structure in mitochondria critical for energy production, a cell-based study suggests.

Specifically, this deficiency affects the formation of iron-sulfur clusters — which are specialized molecules needed for the function of several proteins — in respiratory complex I, the first and largest component of the respiratory chain.

“Our data point to a structural and functional interaction of frataxin with complex I and open a perspective to explore therapeutic rationales for [FA] targeted to this respiratory complex,” researchers wrote.

The study, “Human frataxin, the Friedreich ataxia deficient protein, interacts with mitochondrial respiratory chain,” was published in the journal Cell Death & Disease.

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FA results in deficiency in frataxin that’s needed for function of mitochondria

People with FA carry mutations in the FXN gene that result in a deficiency of frataxin, a protein needed for the function of mitochondria, or the cellular organelles that produce energy. A lack of frataxin impairs energy production, particularly in nerve and muscle cells, leading to the onset of ataxia, or a lack of muscle control during voluntary movements.

Frataxin loss in FA is known to disrupt the assembly of iron-sulfur protein clusters, or the molecules needed for the function of several proteins. Three such proteins include respiratory complexes I, II, and III of the electron transport chain. These proteins form a series of associated complexes within mitochondria that shuttle electrons and ultimately drive energy generation via the synthesis of adenosine triphosphate.

In the study, scientists at the University of Padova, in Italy, investigated whether frataxin directly interacted with complexes I, II, and III to gain further insights into frataxin’s function and its role in FA.

Using a fluorescence technique that detects the proximity of proteins within cells, the team confirmed that frataxin is close to the respiratory complexes I, II, and III in healthy heart and nerve cells. Consistent with frataxin deficiency in FA, the same fluorescent signals were significantly reduced in both types of cells derived from an FA patient.

Next, when an antibody that binds to frataxin was mixed with cell extracts and then isolated, all three complexes were isolated at the same time, demonstrating “frataxin interacts with complexes I, II and III,” the researchers wrote.

In mitochondria isolated from FA cells, the decreased level of frataxin specifically affected the iron-sulfur cluster content of complex I, with associated signals dropping between 37% and 52% compared with controls. The researchers noted the production of complex I protein components was also lower in FA cells.

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Other complexes not affected by decrease in frataxin levels

In contrast, the other complexes were not affected, “pointing to a specific susceptibility of complex I to frataxin decrease,” the scientists noted.

Finally, cells derived from FA patients were modified to produce Nqo15, a frataxin-like protein originating in a bacteria called Thermus thermophilus. The shape of this protein is very similar to human frataxin, according to the researchers.

Experiments demonstrated energy production with FA cells was improved with Nqo15 production, suggesting a “functional interaction of human frataxin with the mitochondrial respiratory complex I,” the researchers added.

“Our findings shed new light on the role of frataxin in the metabolic dysfunctions leading to [FA],” the researchers concluded. These findings “could pave the way to future therapeutic strategies in the disease treatment focused on respiratory complex I.”