Abstract
SIRT3, the primary mitochondrial deacetylase, plays a significant role in enhancing the function of mitochondrial proteins. Downregulation of SIRT3 is a key component of metabolic syndrome, a precondition for obesity, diabetes and cardiovascular diseases. In this study, we examined the effects of brain mitochondrial protein hyperacetylation in western diet-fed Sirt3−/− mice, a model for metabolic syndrome. Brain mitochondrial proteins were hyperacetylated, following western diet feeding and Sirt3 deletion. To identity these hyperacetylated proteins, we performed a comprehensive acetylome analysis by label-free tandem mass spectrometry. Gene ontology pathway analysis revealed Sirt3 deletion-mediated downregulation of enzymes in several metabolic pathways, including fatty acid oxidation and tricarboxylic acid cycle. Mitochondrial respiration was impaired at multiple states, along with lower levels of mitochondrial fission proteins Mfn1 and Mfn2. Cleavage of procaspase-1 suggested inflammasome formation. Assembly of inflammasomes with caspase-1 and NLRP3 was detected as shown by proximity ligation assay. Markers of neuroinflammation including microgliosis and elevated brain IL-1β expression were also observed. Importantly, these findings were further exacerbated in Sirt3−/− mice when fed a calorie-rich western diet. The observations of this study suggest that SIRT3 deficiency-induced brain mitochondrial dysfunction and neuroinflammation in metabolic syndrome may play a role in late-life cognitive decline.
Highlights
Sirtuins are a family of seven proteins with NAD+-dependent deacetylase activity
Acceleration of metabolic syndrome (MetS) in western diet-fed Sirt3−/− mice
In Sirt3−/− mice, insulin resistance was evident with standard diet itself as shown by 2.1-fold higher plasma insulin levels whereas in western diet-fed Sirt3−/− mice, insulin levels were 4.3-fold higher (Fig. 1b)
Summary
Sirtuins are a family of seven proteins with NAD+-dependent deacetylase activity. These conserved proteins play important roles in the regulation of metabolism, inflammation and longevity[1,2]. Acetylome analysis of liver mitochondria from Sirt3−/− mice has revealed SIRT3-mediated acetylation on multiple proteins, often at multiple sites, across several metabolic pathways including fatty acid oxidation, ketogenesis, amino acid catabolism, and tricarboxylic acid (TCA) cycle, as well as other key regulatory proteins in mitochondria[14] Another acetyl proteomic study showed that calorie restriction-mediated deacetylation of liver mitochondrial proteins is regulated by SIRT315. We hypothesize that SIRT3 deficiency-mediated mitochondrial dysfunction leads to inflammasome formation in the brain of MetS and thereby setting the stage for chronic CNS inflammation, one of the causes of cognitive decline. The objective of this study was to identify the downregulated SIRT3 targets in the brain, evaluate mitochondrial dysfunction and determine if it leads to inflammasome formation in western diet-fed, Sirt3−/− mice, a model of MetS
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