Objective: To explore the potential pathogenic genes and variants of spontaneous abortion by exome sequencing (ES). Methods: From September to December 2024, 20 spontaneous abortion samples with no chromosomal abnormalities detected by chromosomal microarray analysis (CMA) in the Women's Hospital of Nanjing Medical University were selected for familial ES detection. According to the American College of Medical Genetics and Genomics (ACMG) guidelines (2015 edition), the pathogenicity of the sequencing results was interpreted, and the possible pathogenic or pathogenic gene variants were verified by Sanger sequencing. Results: Of the 20 patients with spontaneous abortion, 2 were found to have genetic variants that might be related to spontaneous abortion: KYNU gene c.766G>T(p.Gly256Ter) and c.235C>T(p.Gln79Ter) compound heterozygous variants, which were likely pathogenic (paternal) and pathogenic (maternal), respectively, and were associated with xanthurenic aciduria and vertebral-heart, kidney, limb deficiency syndrome type 2 (VCRL2). DNM1L gene c.185C>T(p.Pro62Leu), a likely pathogenic variant, was a de novo variant, which was associated with mitochondrial and peroxisome fission-deficient encephalopathy. Conclusions: ES technology could facilitate the genetic diagnosis of spontaneous abortion, and provide theoretical basis and guidance for subsequent genetic counseling and subsequent pregnancies. 目的： 应用外显子测序（ES）技术检测自然流产患者流产物的基因变异情况，寻找自然流产的潜在致病性基因及变异。 方法： 选取2024年9月至12月因自然流产于南京医科大学附属妇产医院就诊的20例染色体微阵列分析（CMA）检测未见染色体异常的流产物样本行家系ES检测，根据美国医学遗传学与基因组学学会（ACMG）指南（2015版）对测序结果进行致病性判读，对可能致病性或致病性基因变异位点行Sanger测序验证。 结果： 20例自然流产患者的流产物中，共发现2例存在可能与自然流产相关的基因变异：KYNU基因c.766G>T（p.Gly256Ter）和c.235C>T（p.Gln79Ter）复合杂合变异，分别为可能致病性变异（父源）和致病性变异（母源），与黄尿酸尿症和椎骨、心脏、肾脏和肢体缺陷综合征2型（VCRL2）相关；DNM1L基因c.185C>T（p.Pro62Leu），为可能致病性变异，新发变异，与线粒体和过氧化物酶体裂变缺陷相关性脑病有关。 结论： ES技术可助力自然流产的遗传学诊断，为后续遗传咨询及再次生育提供理论依据和指导。.

Impaired mitophagy results in the accumulation of defective mitochondria that are unable to be cleared effectively in Alzheimer's disease (AD). Aloe-emodin (AE), a key component of the traditional Chinese medicine Rhubarb, exhibits neuroprotective effects against Alzheimer's disease, though the underlying mechanism remains unclear. Studying aloe-emodin's role in enhancing mitophagy is vital for improving cognitive function and reducing neuronal damage in Alzheimer's disease. The APP/PS1 double transgenic mice were adopted as models for AD to assess the effects of aloe-emodin upon cognitive function and its neuroprotective impact on hippocampal neurons. Additionally, we investigated the regulatory mechanisms of proteins within the aforementioned pathway, and the morphological characteristics of mitophagy-related proteins. An AD hippocampal neuron model was developed using Aβ25-35 to evaluate the mitochondrial function, the protein expression of such a pathway and the mitophagy. This approach aims to elucidate the effects and underlying mechanisms of aloe-emodin in relation to AD. AE activates mitophagy in neurons, improves cognitive dysfunction, reduces hippocampal damage, and alleviates AD symptoms in model mice. AE activates the expression of AMPK, PGC-1α and SIRT3. Increased expression of SIRT3 in mitochondria promotes mitophagy and regulates the function of mitochondrial proteins. When mitochondrial autophagy is enhanced, the expression of Beclin1, LC3, P62, Parkin, and PINK1-related proteins changes. Further in vitro experiments showed that AE can enhance mitochondrial function in Alzheimer's disease cell models. The mitochondrial membrane potential, GSH, ROS and Ca2+ levels gradually recover, alleviating the pathological manifestations of AD. Knocking down SIRT3 leads to increased mitochondrial damage and a reduction in mitophagy in HT22 cells. Experimental results show that AE can activate mitophagy through AMPK/PGC-1α/SIRT3 pathway, alleviate cognitive dysfunction in AD, and reduce damage to hippocampal neurons.

Both fluorine (F) and aluminium (Al) exhibit neurotoxic effects. Fluorine and aluminium (FA) coexist in naturally and artificially polluted environments and potentially affect human cognitive functions. However, the mechanism through which FA exposure impairs spatial learning and memory of the second-generation offspring (F2) rats remains unknown. Mitochondria are critical for brain function and are responsible for energy production. Excessive mitochondrial fission can cause dysfunction and neuron damage. In this study, SD rats were exposed to FA, while NG108-15 cells were pretransfected with peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) siRNA or the silent information regulator1 (SIRT1) siRNA or treated with mitochondrial division inhibitor-1 (Mdivi-1), and then exposed to FA. FA exposure led to histopathological and mitochondrial structural abnormalities in the cerebral cortex; reduced GAP-43 and Ng protein expression; induced mitochondrial dysfunction; increased dynamin-related protein1 (Drp1), fission protein1 (Fis1) and mitochondrial fission factor (MFF) expression; and inhibited expression of proteins involved in the p-Drp1 (Ser637) and SIRT1/PGC-1α pathways in neurons. In vitro experiments revealed that silencing PGC-1α or SIRT1 exacerbated the FA-induced mitochondrial fission. However, treatment with Mdivi-1 suppressed mitochondrial fission and alleviated mitochondrial dysfunction caused by FA. These findings reveal that the SIRT1/PGC-1α pathway plays a role in regulating mitochondrial fission and is involved in FA-induced neurotoxicity, highlighting the protective effects of Mdivi-1 against FA-induced neurotoxicity.

The dysfunction in learning and memory observed in Alzheimer's disease (AD) is strongly associated with impaired neurogenesis in the hippocampal region. As research on adult neurogenesis advances, it becomes increasingly crucial to identify potential targets for interventions aimed at enhancing endogenous neurogenesis and promoting functional recovery in AD patients. Our previous studies have demonstrated the potential of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) in mitigating the pathological abnormalities associated with AD. Serving as a ubiquitous metabolic regulator, PGC-1α is highly expressed in energy-demanding tissues, such as the hippocampus. However, the precise role and underlying mechanisms by which PGC-1α regulates neurogenesis within the AD-affected hippocampus remain to be fully elucidated. In this study, we induced PGC-1α overexpression by microinfusing AAV-Pgc-1α into the dentate gyrus (DG) of the hippocampus in APP/PS1 mice. Our findings indicate that PGC-1α effectively alleviates AD-related pathological abnormalities and behavioral dysfunction, including deficits in short-term habituation and spatial reference memory impairment. PGC-1α induces the activation of quiescent radial-glia like neural stem cells (NSCs) in the hippocampal DG region, giving rise to intermediate progenitor cells and neuroblasts that ultimately differentiate into mature neurons. By regulating mitochondrial dynamics-specifically promoting fusion while inhibiting fission-PGC-1α facilitates the expansion of precursor cell populations. Collectively, these findings highlight the significance of PGC-1α in maintaining NSC self-renewal, promoting neuronal lineage progression, and contributing to endogenous neurogenesis in AD. Elevating PGC-1α levels, either pharmacologically or through alternative approaches, may represent a promising therapeutic strategy for treating AD.

Mitochondria and peroxisomes are dynamic signaling organelles that constantly undergo fission, driven by the large GTPase dynamin-related protein 1 (DRP1; encoded by DNM1L). Patients with de novo heterozygous missense mutations in DNM1L present with encephalopathy due to defective mitochondrial and peroxisomal fission (EMPF1) - a devastating neurodevelopmental disease with no effective treatment. To interrogate the mechanisms by which DRP1 mutations cause cellular dysfunction, we used human-derived fibroblasts from patients who present with EMPF1. In addition to elongated mitochondrial morphology and lack of fission, patient cells display lower coupling efficiency, increased proton leak and upregulation of glycolysis. Mitochondrial hyperfusion also results in aberrant cristae structure and hyperpolarized mitochondrial membrane potential. Peroxisomes show a severely elongated morphology in patient cells, which is associated with reduced respiration when cells are reliant on fatty acid oxidation. Metabolomic analyses revealed impaired methionine cycle and synthesis of pyrimidine nucleotides. Our study provides insight into the role of mitochondrial dynamics in cristae maintenance and the metabolic capacity of the cell, as well as the disease mechanism underlying EMPF1.