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In Alzheimer's disease (AD), dysfunctional mitochondrial metabolism is associated with synaptic loss, the major pathological correlate of cognitive decline. Mechanistic insight for this relationship, however, is still lacking. Here, comparing isogenic wild-type and AD mutant human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neurons (hiN), evidence is found for compromised mitochondrial energy in AD using the Seahorse platform to analyze glycolysis and oxidative phosphorylation (OXPHOS). Isotope-labeled metabolic flux experiments revealed a major block in activity in the tricarboxylic acid (TCA) cycle at the α-ketoglutarate dehydrogenase (αKGDH)/succinyl coenzyme-A synthetase step, metabolizing α-ketoglutarate to succinate. Associated with this block, aberrant protein S-nitrosylation of αKGDH subunits inhibited their enzyme function. This aberrant S-nitrosylation is documented not only in AD-hiN but also in postmortem human AD brains versus controls, as assessed by two separate unbiased mass spectrometry platforms using both SNOTRAP identification of S-nitrosothiols and chemoselective-enrichment of S-nitrosoproteins. Treatment with dimethyl succinate, a cell-permeable derivative of a TCA substrate downstream to the block, resulted in partial rescue of mitochondrial bioenergetic function as well as reversal of synapse loss in AD-hiN. These findings have therapeutic implications that rescue of mitochondrial energy metabolism can ameliorate synaptic loss in hiPSC-based models of AD.

A causal relationship between mitochondrial metabolic dysfunction and neurodegeneration has been implicated in synucleinopathies, including Parkinson disease (PD) and Lewy body dementia (LBD), but underlying mechanisms are not fully understood. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons with mutation in the gene encoding α-synuclein (αSyn), we report the presence of aberrantly S-nitrosylated proteins, including tricarboxylic acid (TCA) cycle enzymes, resulting in activity inhibition assessed by carbon-labeled metabolic flux experiments. This inhibition principally affects α-ketoglutarate dehydrogenase/succinyl coenzyme-A synthetase, metabolizing α-ketoglutarate to succinate. Notably, human LBD brain manifests a similar pattern of aberrantly S-nitrosylated TCA enzymes, indicating the pathophysiological relevance of these results. Inhibition of mitochondrial energy metabolism in neurons is known to compromise dendritic length and synaptic integrity, eventually leading to neuronal cell death. Our evidence indicates that aberrant S-nitrosylation of TCA cycle enzymes contributes to this bioenergetic failure.

Background Opportunistic salpingectomy (OS) can be used as a primary prevention of ovarian cancer (OC) , but OS may cause impairment of ovarian function due to the homologous blood supply system shared by ovaries and fallopian tubes, thereby increasing the risk of ovarian aging and early menopause. Objective To evaluate the short-term effects of OS on ovarian reserve based on GRADE evidence grading system. Methods In September 2022, CNKI, Wanfang, VIP, PubMed, Web of Science, and Scopus were searched for literature assessing the short-term effects of OS on ovarian reserve from inception to 10 September 2022. Two investigators independently screened the literature and extracted the data. The Jadad scale was used to evaluate the quality of literature, Stata 17.0 software was used for data processing and meta-analysis, and GRADEpro 3.2 software was used to assess the evidence quality for the results of meta-analysis. Results A total of 9 randomized controlled trials (RCT) were included, involving 482 patients, including 238 cases in the OS group and 244 in the non-OS group. The results of the Jadad risk assessment scale showed that the included RCTs were all of high quality literature. The results of meta-analysis showed that the differences in changes of anti-mullerian hormone (AMH) (WMD=-0.07, 95%CI=-0.28-0.13, P=0.13) , follicle-stimulating hormone (FSH) (WMD=-0.03, 95%CI=-1.65-1.59, P=0.24) , luteinizing hormone (LH) (WMD=-0.39, 95%CI=-1.62-0.83, P=0.08) and estradiol (E2) (WMD=3.08, 95%CI=-4.26-10.43, P=0.35) before and after surgery between the OS and non-OS groups were not significant (P>0.05) . The results of the meta-analysis by GRADEpro software showed high quality evidence for AMH, moderate quality evidence for FSH, and low quality evidence for E2 and LH. Conclusion There is no significant difference in ovarian reserve indicators between the non-menopausal women who receive OS for benign disease in the short term and those who did not receive OS. It is reasonable for premenopausal women who have completed childbearing to prevent OC by OS, but this conclusion remains to be validated by a longer follow-up and more rigorous RCTs with a larger sample size.

Protein S-nitros(yl)ation (SNO) is a posttranslational modification involved in diverse processes in health and disease and can contribute to synaptic damage in Alzheimer's disease (AD). To identify SNO proteins in AD brains, we used triaryl phosphine (SNOTRAP) combined with mass spectrometry (MS). We detected 1449 SNO proteins with 2809 SNO sites, representing a wide range of S-nitrosylated proteins in 40 postmortem AD and non-AD human brains from patients of both sexes. Integrative protein ranking revealed the top 10 increased SNO proteins, including complement component 3 (C3), p62 (SQSTM1), and phospholipase D3. Increased levels of S-nitrosylated C3 were present in female over male AD brains. Mechanistically, we show that formation of SNO-C3 is dependent on falling β-estradiol levels, leading to increased synaptic phagocytosis and thus synapse loss and consequent cognitive decline. Collectively, we demonstrate robust alterations in the S-nitrosoproteome that contribute to AD pathogenesis in a sex-dependent manner.