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Abstract Mitochondria are central to endothelial cell activation and angiogenesis, with the RNA polymerase mitochondrial (POLRMT) serving as a key protein in regulating mitochondrial transcription and oxidative phosphorylation. In our study, we examined the impact of POLRMT on angiogenesis and found that its silencing or knockout (KO) in human umbilical vein endothelial cells (HUVECs) and other endothelial cells resulted in robust anti-angiogenic effects, impeding cell proliferation, migration, and capillary tube formation. Depletion of POLRMT led to impaired mitochondrial function, characterized by mitochondrial depolarization, oxidative stress, lipid oxidation, DNA damage, and reduced ATP production, along with significant apoptosis activation. Conversely, overexpressing POLRMT promoted angiogenic activity in the endothelial cells. In vivo experiments demonstrated that endothelial knockdown of POLRMT, by intravitreous injection of endothelial specific POLRMT shRNA adeno-associated virus, inhibited retinal angiogenesis. In addition, inhibiting POLRMT with a first-in-class inhibitor IMT1 exerted significant anti-angiogenic impact in vitro and in vivo. Significantly elevated expression of POLRMT was observed in the retinal tissues of streptozotocin-induced diabetic retinopathy (DR) mice. POLRMT endothelial knockdown inhibited pathological retinal angiogenesis and mitigated retinal ganglion cell (RGC) degeneration in DR mice. At last, POLRMT expression exhibited a substantial increase in the retinal proliferative membrane tissues of human DR patients. These findings collectively establish the indispensable role of POLRMT in angiogenesis, both in vitro and in vivo.

Abstract Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.

Abstract Background We aimed to analyze the characteristics of the body composition of children and adolescents aged 3–17 in Suzhou, China. Methods A cross-sectional study between January 2020 and June 2022 using bioelectrical impedance was conducted to determine the fat mass (FM), fat-free mass (FFM), skeletal muscle mass, and protein and mineral contents of 24,845 children aged 3–17 who attended the Department of Child and Adolescent Healthcare, Children’s Hospital of Soochow University, China. Measurement data was presented in tables as mean ± SD, and groups were compared using the independent samples t-test. Results FM and fat-free mass increased with age in both boys and girls. The fat-free mass of girls aged 14–15 decreased after reaching a peak, and that of boys in the same age group was higher than that of the girls (p

Abstract The mitochondrial integrity and function in endothelial cells are essential for angiogenesis. TIMM44 (translocase of inner mitochondrial membrane 44) is essential for integrity and function of mitochondria. Here we explored the potential function and the possible mechanisms of TIMM44 in angiogenesis. In HUVECs, human retinal microvascular endothelial cells and hCMEC/D3 brain endothelial cells, silence of TIMM44 by targeted shRNA largely inhibited cell proliferation, migration and in vitro capillary tube formation. TIMM44 silencing disrupted mitochondrial functions in endothelial cells, causing mitochondrial protein input arrest, ATP reduction, ROS production, and mitochondrial depolarization, and leading to apoptosis activation. TIMM44 knockout, by Cas9-sgRNA strategy, also disrupted mitochondrial functions and inhibited endothelial cell proliferation, migration and in vitro capillary tube formation. Moreover, treatment with MB-10 (“MitoBloCK-10”), a TIMM44 blocker, similarly induced mitochondrial dysfunction and suppressed angiogenic activity in endothelial cells. Contrarily, ectopic overexpression of TIMM44 increased ATP contents and augmented endothelial cell proliferation, migration and in vitro capillary tube formation. In adult mouse retinas, endothelial knockdown of TIMM44, by intravitreous injection of endothelial specific TIMM44 shRNA adenovirus, inhibited retinal angiogenesis, causing vascular leakage, acellular capillary growth, and retinal ganglion cells degeneration. Significant oxidative stress was detected in TIMM44-silenced retinal tissues. Moreover, intravitreous injection of MB-10 similarly induced oxidative injury and inhibited retinal angiogenesis in vivo. Together, the mitochondrial protein TIMM44 is important for angiogenesis in vitro and in vivo, representing as a novel and promising therapeutic target of diseases with abnormal angiogenesis.

Abstract Background Short stature is defined as height below 2 standard deviations of the population with the same age, gender. This study is aimed to assess the characteristics of body composition in preschool children with short stature. Methods Anthropometric measurements and body composition were assessed in 68 preschool children aged 3 to 6 years old with short stature and 68 normal controls matched on age and gender. Height, weight and body composition (total body water, protein, minerals, body fat mass, fat-free mass, soft lean mass, skeletal muscle mass, and bone mineral contents) in the two groups were measured and compared. Results The total body water, protein, minerals, body fat mass, fat-free mass, soft lean mass, skeletal muscle mass, and bone mineral contents were lower in preschool children with short stature than controls (P

Despite the global abundance of studies on children’s lead (Pb) exposure, the magnitude of Pb exposure among children across China remains unclear, especially for rural areas. In 2000, Pb was removed from petrol, marking a change in the sources of Pb exposure in China. To better understand children’s Pb exposure and inform potential approaches to exposure reduction, we conducted a national blood Pb survey of 31,373 children (0–84 months old) from May 2013 to March 2015, using a multi-stage and multi-strata sampling method. Blood lead levels (BLLs) were tested using graphite furnace atomic absorption spectrometry with a detection limit of 1 µg/L. The results show that Chinese children had a contemporary geometric mean (GM) BLL of 26.7 μg/L, with 8.6% of BLLs exceeding 50 µg/L. Boys had higher BLLs (GM 27.2 μg/L) compared to girls (GM: 25.9 μg/L) (p