SIRT6 is a key regulator of mitochondrial function in the brain

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.

Integrated Transcriptomic and Proteomic Study of the Mechanism of Action of the Novel Small-Molecule Positive Allosteric Modulator 1 in Targeting PAC1-R for the Treatment of D-Gal-Induced Aging Mice

“…New findings also suggest that the changes observed in SIRT6-deficient brains also occur in the aging human brain, particularly in patients with Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis. SIRT6 is a key regulator of mitochondrial function in the brain and interacts with transcription factor YY1 to influence mitochondrial function [27]. It is accompanied by a decrease in SIRT6 levels and an increase in YY1 levels in aged mice [14].…”

CoCl2‐triggered pseudohypoxic stress induces proteasomal degradation of SIRT4 via polyubiquitination of lysines K78 and K299

“…Moreover, the Sirt4 gene is directly repressed by the lysinespecific demethylase 1 (Lsd1) [50]. Positive regulators of Sirt4 gene expression include E2F1 [51], and interestingly also SIRT6, whose target genes Sirt3 and Sirt4 are downregulated upon SIRT6 deficiency resulting in mitochondrial dysfunction [52]. Lastly, several microRNAs (miR-15a-5p, miR-15b, miR-130b-5p, and miR-497) bind SIRT4 transcripts and thereby modulate SIRT4 protein levels under basal as well as stress-induced and cell aging conditions [8,[53][54][55].…”

SIRT6 regulates protein synthesis and folding through nucleolar remodeling

“…The brSIRT6KO mouse brain transcriptomic dataset was already published in GSE221077. The analysis was as previously described in Smirnov et al (2023) 27 .…”

“…Although neurodegenerative diseases have each a different phenotype, there are many commonalities that we also found when comparing them with SIRT6-de cient models 20,26 . For example, we discovered an additional link between SIRT6 and Alzheimer's, Parkinson's, Huntington diseases and amyotrophic lateral sclerosis (AD, PD, HD and ALS, respectively) through mitochondrial dysfunction 27 . The SIRT6-neurodegeneration link is especially intriguing because another common trait in many age-related brain pathologies is the extreme form of proteostasis loss, manifested in aggregation of speci c proteins -suggesting a role for SIRT6 in proteostasis.…”