In a new paper just published in the peer-reviewed journal Cell Death and Disease, Dr Toiber and her international colleagues have found that SIRT6 is a key regulator of mitochondrial function in the brain
Ben-Gurion University of the Negev life sciences researcher Dr Debra Toiber has uncovered what seems to be a key preventive measure of DNA breakdown, which many believe causes ageing and neurodegenerative diseases. Dr Toiber has been focused on a protein called SIRT6, and she has discovered that it seems to have remarkable properties. Its absence seems to downgrade DNA repair significantly.
“Mitochondrial dysfunction is one of the hallmarks of ageing and one of the main characteristics of multiple neurodegenerative diseases. Many defects are observed in the mitochondria’s efficiency during ageing; however, what initiates these events is unclear,” explains Dr Toiber.
“We found that SIRT6 keeps mitochondria functioning through the transcription regulation of mitochondrial genes,” she says.
Using transcriptomics, metabolomics, and molecular assays, she and her team observed that in the absence of SIRT6 in the brain, nuclear expressed mitochondrial genes are down-regulated, the number of mitochondria per cell decays, there is an increase in Reactive Oxygen Species (ROS) production, and the mitochondrial membrane potential is impaired, causing major metabolic changes.
This effect is partially the result of SIRT6 regulating the expression of the mitochondrial Sirtuins 3 and 4. Importantly, re-introducing SIRT3 and 4 can rescue the membrane potential capacity. Particularly in the brain, during neurodegeneration, mitochondria lose the ability to generate enough Adenosine Triphosphate (ATP), generate toxic ROS, and impair the production of important metabolites for brain functioning.
“Our results show parallel changes in mitochondrial gene expression induced by the lack of SIRT6 in the brain to the changes observed in ageing, Alzheimer’s disease, Parkinson’s disease, and ALS, suggesting that SIRT6 decay in the brain is the driver of these changes,” Dr Toiber notes.
Dr Toiber is a member of the Department of Life Sciences in the Faculty of Natural Sciences and the Zlotowski Center for Neuroscience.
Additional researchers include Dmitrii Smirnov and Ekaterina Khrameeva of the Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Ekaterina Eremenko, Daniel Stein, Shai Kaluski, Yariv Brotman, and Weronika Jasinska of BGU’s Department of Life Sciences, Claudia Consentino of Massachusetts General Hospital Cancer Center, Harvard Medical School, Barbara Martinez-Pastor also of Mass Gen and the Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), and Raul Mostoslavsky of Mass Gen and The Broad Institute of Harvard and MIT.
The research was supported by the David and Inez Myers Foundation, the Israeli Ministry of Science and Technology (MOST), and the Russian Science Foundation (grant number 21-74-10102).