Homologs of the Saccharomyces cerevisiae Sir2 protein, sirtuins, promote longevity in many organisms. Studies of the sirtuin SIRT3 have so far been limited to cell culture systems. Here, we investigate the localization and function of SIRT3 in vivo. We show that endogenous mouse SIRT3 is a soluble mitochondrial protein. To address the function and relevance of SIRT3 in the regulation of energy metabolism, we generated and phenotypically characterized SIRT3 knockout mice. SIRT3-deficient animals exhibit striking mitochondrial protein hyperacetylation, suggesting that SIRT3 is a major mitochondrial deacetylase. In contrast, no mitochondrial hyperacetylation was detectable in mice lacking the two other mitochondrial sirtuins, SIRT4 and SIRT5. Surprisingly, despite this biochemical phenotype, SIRT3-deficient mice are metabolically unremarkable under basal conditions and show normal adaptive thermogenesis, a process previously suggested to involve SIRT3. Overall, our results extend the recent finding of lysine acetylation of mitochondrial proteins and demonstrate that SIRT3 has evolved to control reversible lysine acetylation in this organelle.Conserved from bacteria to humans, the sirtuin family of NAD ϩ -dependent protein deacetylase/mono-ADP-ribosyltransferase enzymes controls a variety of cellular processes such as aging, metabolism, and gene silencing (18,24). It has been proposed that sirtuins mediate the longevity-promoting effects of calorie restriction (CR) in yeast, worms, flies, and mice (4,17,22,24). Seven mammalian sirtuins (SIRT1 to -7) are known (11,12,18,24). At least three sirtuins (SIRT3, SIRT4, and SIRT5) localize to mitochondria, suggesting the existence of sirtuin substrates in that organelle (19,26,28,(31)(32)(33). Several lines of evidence link SIRT3 to metabolism: SIRT3 is down-regulated in muscle from diabetic animals (37) and upregulated in white and brown adipose tissue in response to CR (33). Overexpression of SIRT3 in cells affects expression of genes involved in mitochondrial function (33). SIRT3 regulates the acetylation level and activity of acetyl-coenzyme A synthetase 2, a protein that may play a role in energy production in mammals under starvation conditions (20,31). SIRT4 is an ADP-ribosyltransferase that has been implicated in regulating amino acid-stimulated insulin secretion in mice via modification of glutamate dehydrogenase (GDH) (19). No functions have been reported for SIRT5.
SUMMARY The dynamic and reversible N6-methyladenosine (m6A) RNA modification installed and erased by N6-methyltransferases and demethylases regulates gene expression and cell fate. We show that the m6A demethylase ALKBH5 is highly expressed in glioblastoma stem-like cells (GSCs). Silencing ALKBH5 suppresses the proliferation of patient-derived GSCs. Integrated transcriptome and m6A-seq analyses revealed altered expression of certain ALKBH5 target genes, including the transcription factor FOXM1. ALKBH5 demethylates FOXM1 nascent transcripts, leading to enhanced FOXM1 expression. Further, a long noncoding RNA antisense to FOXM1 (FOXM1-AS) promotes the interaction of ALKBH5 with FOXM1 nascent transcripts. Depleting ALKBH5 and FOXM1-AS disrupted GSC tumorigenesis through the FOXM1 axis. Our work uncovers a critical function for ALKBH5 and provides insight into critical roles of m6A methylation in glioblastoma.
Tumour suppressor SIRT3 deacetylates and activates manganese superoxide dismutase to scavenge ROSMitochondria manganese superoxide dismutase (SOD2) is a major antioxidant enzyme associated with several diseases. This study shows that SOD2 is inhibited by acetylation and activated by SIRT3-mediated deacetylation in response to reactive oxygen species (ROS).
Rationale: Over 50% of heart failure patients have preserved, rather than reduced ejection fraction (HFpEF vs. HFrEF). Complexity of its pathophysiology and the lack of animal models hamper the development of effective therapy for HFpEF. Objective: This study was designed to investigate the metabolic mechanisms of HFpEF and test therapeutic interventions using a novel animal model.Methods and Results: By combining the age, long-term high-fat diet and desoxycorticosterone pivalate challenge in a mouse model we were able to recapture the myriad features of HFpEF. In these mice, mitochondrial hyperacetylation exacerbated while increasing ketone body availability rescued the phenotypes. The HFpEF mice exhibited overproduction of interleukin (IL)-1β/IL-18, and tissue fibrosis due to increased assembly of NLPR3 inflammasome on hyperacetylated mitochondria. Increasing β-hydroxybutyrate (β-OHB) level attenuated NLPR3 inflammasome formation and antagonized proinflammatory cytokines-triggered mitochondrial dysfunction and fibrosis. Moreover, β-OHB downregulated the acetyl-CoA pool and mitochondrial acetylation, partially via activation of citrate synthase and inhibition of fatty acid uptake. Conclusions: Therefore, we identify the interplay of mitochondrial hyperacetylation and inflammation as a key driver in HFpEF pathogenesis which can be ameliorated by promoting β-OHB abundance.
Purpose: We assessed whether perioperative circulating tumor DNA (ctDNA) could be a biomarker for early detection of molecular residual disease (MRD) and prediction of postoperative relapse in resected non–small cell lung cancer (NSCLC). Experimental Design: Based on our prospective, multicenter cohort on dynamic monitoring of ctDNA in lung cancer surgery patients (LUNGCA), we enrolled 950 plasma samples obtained at three perioperative time points (before surgery, 3 days and 1 month after surgery) of 330 stage I–III NSCLC patients (LUNGCA-1), as a part of the LUNGCA cohort. Using a customized 769-gene panel, somatic mutations in tumor tissues and plasma samples were identified with next-generation sequencing and utilized for ctDNA-based MRD analysis. Results: Preoperative ctDNA positivity was associated with lower recurrence-free survival (RFS; HR = 4.2; P < 0.001). The presence of MRD (ctDNA positivity at postoperative 3 days and/or 1 month) was a strong predictor for disease relapse (HR = 11.1; P < 0.001). ctDNA-based MRD had a higher relative contribution to RFS prediction than all clinicopathologic variables such as the TNM stage. Furthermore, MRD-positive patients who received adjuvant therapies had improved RFS over those not receiving adjuvant therapy (HR = 0.3; P = 0.008), whereas MRD-negative patients receiving adjuvant therapies had lower RFS than their counterparts without adjuvant therapy (HR = 3.1; P < 0.001). After adjusting for clinicopathologic variables, whether receiving adjuvant therapies remained an independent factor for RFS in the MRD-positive population (P = 0.002) but not in the MRD-negative population (P = 0.283). Conclusions: Perioperative ctDNA analysis is effective in early detection of MRD and relapse risk stratification of NSCLC, and hence could benefit NSCLC patient management.
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