SIRT6 regulates mitochondrial function within the brain
The exact mechanism of mitochondrial dysfunction remains unknown, even though it is a well-known marker for aging and neurodegenerative disease. The decline of SIRT6 during aging and Alzheimer’s [18, 23], as well as in the disease itself [18, 46], could be the key mechanism that leads to the degeneration of mitochondrial function. This claim is supported by the changes that are induced at the metabolite levels due to the SIRT6 knockout: metabolites associated with mitochondrial energy systems (in particular OXPHOS, and TCA cycle), are overrepresented in the differentially abundant metabolites. All these metabolites were downregulated in SIRT6-KO, in line with the mitochondrial dysfunction discussed in aging. The dramatic decline in NAD+ was associated with both pro-senescence mechanisms and limited neuroprotective activities of sirtuins.
In our gene expression analysis, we found that the majority of mitochondrial-related genes differentially expressed were downregulated. We measured mitochondrial membrane potential in SIRT6 KO cells, as they were highly enriched in mitochondrial respiratory chains complexes. This was because we suspected that reduced gene expression could indicate the loss mitochondria. The two measured characteristics were both significantly reduced, validating that mitochondrial oxidative biogenesis and mitochondrial phosphorylation are impaired in SIRT6 deficient brains. The average reduction in mtDNA gene transcription (19.7% in SIRT6 KO) was in agreement with the reduction in mitochondrial content (21.8%). This suggests that mitochondrial biogenesis is the primary cause of the transcriptional dysregulation observed in mitochondria after SIRT6 knockout.
SIRT3 levels and SIRT4 levels were downregulated significantly in SIRT6 deficient brains. This can partially restore the membrane potential. Both are located in mitochondria, and both have an impact on mitochondrial pathways that relate to redox balance, cellular metabolism, and mitochondrial metabolism [38]. They also play important roles in ROS balance, mitochondria metabolism, and lifespan [50-52]. Our analysis and that of publicly available gene-expression data [39] confirms SIRT6 transcriptionally controls SIRT3 or SIRT4. Our analysis also indicates that SIRT6 controls mitochondrial gene transcription through the transcriptional factor YY1. In the past, we have shown that SIRT6 forms a complex with YY1 that regulates many genes that are shared [24]. Our analysis of the YY1 ChiIP-seq [53] data suggests that SIRT6 regulates mitochondrial processes in coordination with YY1.
Source:
https://www.nature.com/articles/s41419-022-05542-w
