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Published on: May 21, 2020
Rapamycin reduces oxidative stress in frataxin-deficient yeast cells
Carlo M T Marobbio1, Isabella Pisano, Vito Porcelli
1Laboratory of Biochemistry and Molecular Biology, Department of Pharmaco-Biology, University of Bari, Via E. Orabona 4, 70125 Bari, Italy.
Abstract:
Friedreich ataxia (FRDA) is a common form of ataxia caused by decreased expression of the mitochondrial protein frataxin. Oxidative damage of mitochondria is thought to play a key role in the pathogenesis of the disease. Therefore, a possible therapeutic strategy should be directed to an antioxidant protection against mitochondrial damage. Indeed, treatment of FRDA patients with the antioxidant idebenone has been shown to improve neurological functions. The yeast frataxin knock-out model of the disease shows mitochondrial iron accumulation, iron-sulfur cluster defects and high sensitivity to oxidative stress. By flow cytometry analysis we studied reactive oxygen species (ROS) production of yeast frataxin mutant cells treated with two antioxidants, N-acetyl-L-cysteine and a mitochondrially-targeted analog of vitamin E, confirming that mitochondria are the main site of ROS production in this model. Furthermore we found a significant reduction of ROS production and a decrease in the mitochondrial mass in mutant cells treated with rapamycin, an inhibitor of TOR kinases, most likely due to autophagy of damaged mitochondria.
Insights
Friedreich ataxia (FRDA) research shows that mitochondria are the primary source of oxidative damage. Antioxidants and rapamycin can reduce this damage, offering potential therapeutic avenues for FRDA patients.
Area of Science:
- Biochemistry
- Cell Biology
- Neuroscience
Background:
- Friedreich ataxia (FRDA) is a genetic neurodegenerative disorder linked to reduced mitochondrial frataxin expression.
- Mitochondrial dysfunction and oxidative stress are central to FRDA pathogenesis.
- Current therapeutic strategies focus on antioxidant protection, with idebenone showing promise.
Purpose of the Study:
- To investigate reactive oxygen species (ROS) production in a yeast model of FRDA.
- To evaluate the efficacy of antioxidants in mitigating mitochondrial damage in FRDA.
- To explore the impact of rapamycin on ROS production and mitochondrial mass in FRDA.
Main Methods:
- Utilized a yeast frataxin knock-out model to mimic FRDA.
- Employed flow cytometry to measure ROS production in yeast cells.
- Treated cells with N-acetyl-L-cysteine, a vitamin E analog, and rapamycin.
Main Results:
- Confirmed mitochondria as the primary site of ROS production in the FRDA yeast model.
- Demonstrated that N-acetyl-L-cysteine and the vitamin E analog reduced ROS levels.
- Observed a significant decrease in ROS production and mitochondrial mass with rapamycin treatment, suggesting autophagy.
Conclusions:
- Mitochondrial oxidative stress is a key feature of FRDA, as evidenced by the yeast model.
- Antioxidants can ameliorate mitochondrial damage in FRDA.
- Rapamycin's ability to reduce ROS and mitochondrial mass highlights the role of autophagy in managing mitochondrial damage in FRDA.
