‘Iron overload’ in mitochondria linked to heart damage in FA: Mouse study
Findings may pave way toward new treatment strategies, researchers say
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Abnormal buildup of iron in mitochondria, the powerhouses of cells, may contribute to heart damage in Friedreich’s ataxia, according to a new study done in a mouse model.
Data also indicate that heart cells have reduced ability to recycle damaged mitochondria in Friedreich’s ataxia. Collectively, the findings shed new light on the molecular underpinnings of the disease and may pave the way toward new treatment strategies, researchers said.
The study, “Mitochondrial iron overload is associated with lysosomal dysfunction-mediated mitophagy impairment in the heart of Friedreich’s ataxia,” was published in Mitochondrion.Â
Heart damage a leading cause of mortality among FA patients
Mitochondria are cellular structures that are vital for energy production. To efficiently generate energy, mitochondria require many nutrients, including small amounts of iron. But too much iron building up inside mitochondria, known as mitochondrial iron overload, can disrupt energy production.
Friedreich’s ataxia is a genetic disease marked by problems with mitochondrial function due to a deficiency of a protein called frataxin. Although it’s well established that the frataxin protein is essential for mitochondrial health, scientists still don’t fully understand the mechanisms by which frataxin deficiency leads to mitochondrial damage across different cells in the body.
To learn more, scientists at the University of Massachusetts Lowell conducted a series of experiments using a mouse model that lacks frataxin in heart cells but has it in all other organs. This allowed the researchers to examine specifically how frataxin deficiency affects the heart.
Of note, heart damage is a leading cause of mortality among people with Friedreich’s ataxia.
Our data support a strong relationship between mitochondrial iron overload and [mitochondrial membrane] structural abnormalities.
The scientists found that, in the absence of frataxin protein, iron builds up abnormally in mitochondria in the hearts of the Friedreich’s ataxia mouse model, consistent with mitochondrial iron overload.
Detailed imaging experiments specifically suggested that iron clumps up in mitochondria, forming jagged structures that alter the structure of the delicate membranes needed to produce energy efficiently. The end result is that mitochondrial energy production is dampened.
“Our data support a strong relationship between mitochondrial iron overload and [mitochondrial membrane] structural abnormalities,” the researchers wrote.
Further studies urged to help prove a cause-and-effect relationship
The researchers noted that these imaging experiments don’t definitively prove a cause-and-effect relationship, adding that “future studies are warranted to investigate whether reversal of mitochondrial iron overload restores [mitochondrial membrane] structure and mitochondrial function.”
The researchers also noticed that, although mitochondrial energy production was reduced, mice actually had more individual mitochondria in their heart cells.
Further experiments indicated that frataxin deficiency leads to an increase in the production of new mitochondria in heart cells. At the same time, however, these cells show marked reductions in mitophagy — the process by which damaged mitochondria get cleared away and recycled.
“In parallel with [iron clumps and structural changes to mitochondrial membranes], we also found that mitochondrial quantity and quality controls are markedly changed under cardiac frataxin deficiency,” the researchers wrote.
The scientists said these changes in mitochondrial production and clearance likely also contribute to heart damage in Friedreich’s ataxia, highlighting the need for further studies to better understand these mechanisms. Such research may pave the way toward new strategies to treat Friedreich’s ataxia.
