Deficient mitochondrial respiration has been found to impair sirtuin 3 activity in dorsal root ganglia (DRG) in Friedreich ataxia (FA) mouse and cell models, according to an article preprint posted on bioRxiv. The study has not yet been peer-reviewed.

To evaluate the effects of frataxin deficiency in DRG neurons, the study authors analyzed primary cultures of frataxin-deficient DRGs and DRGs from the new mouse model. This mouse is a carrier of the I151F point mutation equivalent to the human I154F pathological mutation and presents with human-like low frataxin levels, biochemical alterations, and neurological deficits starting at 23 weeks of age.

According to the results, frataxin deficiency resulted in lower activity and levels of the electron transport complexes I and II in both primary cultures of DRG neurons and DRGs from the new mouse model. This has been associated with a reduced NAD+/NADH ratio and impaired sirtuin 3, a mitochondrial NAD+-dependent deacetylase.

The researchers established alpha-tubulin to be the major acetylated protein from DRG homogenates whose levels were increased in the new model of mice compared to wild-type mice. The acetylation of mitochondrial superoxide dismutase, a sirtuin 3 substrate, was increased in frataxin-deficient DRG neurons.

Read more about FA complications

As the acetylation of superoxide dismutase inactivates the enzyme and higher levels of mitochondrial superoxide anion were detected, the researchers proceeded with analyzing oxidative stress markers. The level of hydroxynonenal bound to proteins was elevated, as well as the accumulation of Fe2+ in the mitochondria of cells with decreased frataxin. A sirtuin 3 activator, honokiol, was successful at reestablishing normal mitochondrial respiration.

“We propose that because neurons have a high energy requirement, and fewer antioxidant systems compared to other tissues, the decay in the electron transport chain results in decreased sirtuin 3 activity and protein hyperacetylation, thus comprising a negative feedback contributing to neuron lethality,” Sanz-Alcázar and colleagues noted.

Patients with FA experience progressive limb and gait ataxia, dysarthria, decreased tendon reflex and Babinski reflex, and impaired position and vibration senses. Since DRG neurons have the highest levels of frataxin, they are one of the most affected cellular types in the early stages of disease development.


Sanz-Alcázar A, Britti E, Delaspre F, et al. Deficient mitochondrial respiration impairs sirtuin activity in dorsal root ganglia in Friedreich ataxia mouse and cell models. BioRxiv. Published online February 3, 2023. doi:10.1101/2023.02.01.526688