SIRT6 is a key regulator of mitochondrial function in the brain

Cell Death Dis. 2023 Jan 18;14(1):35. doi: 10.1038/s41419-022-05542-w.

Dmitrii Smirnov ¹ ² ³, Ekaterina Eremenko ¹ ², Daniel Stein ¹ ², Shai Kaluski ¹ ², Weronika Jasinska ¹, Claudia Cosentino ⁴, Barbara Martinez-Pastor ⁴ ⁵, Yariv Brotman ¹, Raul Mostoslavsky ⁴ ⁶, Ekaterina Khrameeva ⁷, Debra Toiber ⁸ ⁹

Affiliations

1 Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.
2 The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel.
3 Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, 121205, Russia.
4 The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA, 02114, USA.
5 Molecular Oncology Program, Spanish National Cancer Research Center (CNIO), Madrid, 28029, Spain.
6 The Broad Institute of Harvard and MIT, Cambridge, MA, 02142, USA.
7 Center for Molecular and Cellular Biology, Skolkovo Institute of Science and Technology, Moscow, 121205, Russia. [email protected].
8 Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel. [email protected].
9 The Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva, 8410501, Israel. [email protected].

PMID: 36653345 DOI: 10.1038/s41419-022-05542-w

Abstract

The SIRT6 deacetylase has been implicated in DNA repair, telomere maintenance, glucose and lipid metabolism and, importantly, it has critical roles in the brain ranging from its development to neurodegeneration. Here, we combined transcriptomics and metabolomics approaches to characterize the functions of SIRT6 in mouse brains. Our analysis reveals that SIRT6 is a central regulator of mitochondrial activity in the brain. SIRT6 deficiency in the brain leads to mitochondrial deficiency with a global downregulation of mitochondria-related genes and pronounced changes in metabolite content. We suggest that SIRT6 affects mitochondrial functions through its interaction with the transcription factor YY1 that, together, regulate mitochondrial gene expression. Moreover, SIRT6 target genes include SIRT3 and SIRT4, which are significantly downregulated in SIRT6-deficient brains. Our results demonstrate that the lack of SIRT6 leads to decreased mitochondrial gene expression and metabolomic changes of TCA cycle byproducts, including increased ROS production, reduced mitochondrial number, and impaired membrane potential that can be partially rescued by restoring SIRT3 and SIRT4 levels. Importantly, the changes we observed in SIRT6-deficient brains are also occurring in aging human brains and particularly in patients with Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis disease. Overall, our results suggest that the reduced levels of SIRT6 in the aging brain and neurodegeneration initiate mitochondrial dysfunction by altering gene expression, ROS production, and mitochondrial decay.

Name
Email *

	Sorry, but the email address you supplied was invalid.