Received November 11, 2021; Revised December 20, 2021; Accepted December 22, 2021
SIRT3 is a protein lysine deacetylase with a prominent role in the maintenance of mitochondrial integrity, which is a vulnerable target in many diseases. Intriguingly, cellular aging is reversible just by SIRT3 overexpression, which raises many questions about the role of SIRT3 in the molecular anti-aging mechanisms. Therefore, functions of SIRT3 were analyzed through the interaction network of 407 substrates collected by data mining. Results of the pathway enrichment and gene function prediction confirmed functions in the primary metabolism and mitochondrial ATP production. However, it also suggested involvement in thermogenesis, brain-related neurodegenerative diseases Alzheimer’s (AD), Parkinson’s, Huntington’s disease (HD), and non-alcoholic fatty liver disease. The protein node prioritization analysis identified subunits of the complex I of the mitochondrial respiratory chain (MRC) as the nodes with the main regulatory effect within the entire interaction network. Additional high-ranked nodes were succinate dehydrogenase subunit B (SDHB), complex II, and ATP5F1, complex V of MRC. The analysis supports existence of the NADH/NAD+ driven regulatory feedback loop between SIRT3, complex I (MRC), and acetyl-CoA synthetases, and existence of the nuclear substrates of SIRT3. Unexplored functions of SIRT3 substrates such as LMNA and LMNB; HIF-1a, p53, DNA-PK, and PARK7 are highlighted for further scientific advances. SIRT3 acts as a repressor of BACE1 through the SIRT3-LKB1-AMPK-CREB-PGC1A-PPARG-BACE1 (SIRT3-BACE1), which functions are fitted the best by the Circadian Clock pathway. It forms a new working hypothesis as the therapeutical target for AD treatment. Other important pathways linked to SIRT3 activity are highlighted for therapeutical interventions.
KEY WORDS: SIRT3, NAD+-dependent protein deacetylase, protein interaction network, pathway enrichment analysis, aging, respiratory electron transport chain, mitochondria, age-related disease