Increasing maternal age associates with lower placental CPT1B mRNA expression and acylcarnitines, particularly in overweight women.

Older pregnant women have increased risks of complications including gestational diabetes and stillbirth. Carnitine palmitoyl transferase (CPT) expression declines with age in several tissues and is linked with poorer metabolic health. Mitochondrial CPTs catalyze acylcarnitine synthesis, which facilitates fatty acid oxidization as fuel. We hypothesized that the placenta, containing maternally-inherited mitochondria, shows an age-related CPT decline that lowers placental acylcarnitine synthesis, increasing vulnerability to pregnancy complications. We assessed CPT1A, CPT1B, CPT1C and CPT2 mRNA expression by qPCR in 77 placentas and quantified 10 medium and long-chain acylcarnitines by LC-MS/MS in a subset of 50 placentas. Older maternal age associated with lower expression of placental CPT1B, but not CPT1A, CPT1C or CPT2. CPT1B expression positively associated with eight acylcarnitines and CPT1C with three acylcarnitines, CPT1A negatively associated with nine acylcarnitines, while CPT2 did not associate with any acylcarnitine. Older maternal age associated with reductions in five acylcarnitines, only in those with BMI≥ 25 kg/m2, and not after adjusting for CPT1B expression. Our findings suggest that CPT1B is the main transferase for placental long-chain acylcarnitine synthesis, and age-related CPT1B decline may underlie decreased placental metabolic flexibility, potentially contributing to pregnancy complications in older women, particularly if they are overweight.

A phase I/II randomized, double-blinded, placebo-controlled trial of a self-amplifying Covid-19 mRNA vaccine.

Coronavirus disease-19 (Covid-19) pandemic have demonstrated the importantance of vaccines in disease prevention. Self-amplifying mRNA vaccines could be another option for disease prevention if demonstrated to be safe and immunogenic. Phase 1 of this randomized, double-blinded, placebo-controlled trial (N = 42) assessed the safety, tolerability, and immunogenicity in healthy young and older adults of ascending levels of one-dose ARCT-021, a self-amplifying mRNA vaccine against Covid-19. Phase 2 (N = 64) tested two-doses of ARCT-021 given 28 days apart. During phase 1, ARCT-021 was well tolerated up to one 7.5 µg dose and two 5.0 µg doses. Local solicited AEs, namely injection-site pain and tenderness were more common in ARCT-021vaccinated, while systemic solicited AEs, mainly fatigue, headache and myalgia were reported in 62.8% and 46.4% of ARCT-021 and placebo recipients, respectively. Seroconversion rate for anti-S IgG was 100% in all cohorts, except for the 1 µg one-dose in younger adults and the 7.5 µg one-dose in older adults. Anti-S IgG and neutralizing antibody titers showed a general increase with increasing dose, and overlapped with titers in Covid-19 convalescent patients. T-cell responses were also observed in response to stimulation with S-protein peptides. Taken collectively, ARCT-021 is immunogenic and has favorable safety profile for further development.

Sex-Dependent Regulation of Placental Oleic Acid and Palmitic Acid Metabolism by Maternal Glycemia and Associations with Birthweight.

Pregnancy complications such as maternal hyperglycemia increase perinatal mortality and morbidity, but risks are higher in males than in females. We hypothesized that fetal sex-dependent differences in placental palmitic-acid (PA) and oleic-acid (OA) metabolism influence such risks. Placental explants (n = 22) were incubated with isotope-labeled fatty acids (13C-PA or 13C-OA) for 24 or 48 h and the production of forty-seven 13C-PA lipids and thirty-seven 13C-OA lipids quantified by LCMS. Linear regression was used to investigate associations between maternal glycemia, BMI and fetal sex with 13C lipids, and between 13C lipids and birthweight centile. Placental explants from females showed greater incorporation of 13C-OA and 13C-PA into almost all lipids compared to males. Fetal sex also influenced relationships with maternal glycemia, with many 13C-OA and 13C-PA acylcarnitines, 13C-PA-diacylglycerols and 13C-PA phospholipids positively associated with glycemia in females but not in males. In contrast, several 13C-OA triacylglycerols and 13C-OA phospholipids were negatively associated with glycemia in males but not in females. Birthweight centile in females was positively associated with six 13C-PA and three 13C-OA lipids (mainly acylcarnitines) and was negatively associated with eight 13C-OA lipids, while males showed few associations. Fetal sex thus influences placental lipid metabolism and could be a key modulator of the impact of maternal metabolic health on perinatal outcomes, potentially contributing toward sex-specific adaptions in which females prioritize survival.

Oxygen Glucose Deprivation Induced Prosurvival Autophagy Is Insufficient to Rescue Endothelial Function.

Endothelial dysfunction, referring to a disturbance in the vascular homeostasis, has been implicated in many disease conditions including ischemic/reperfusion injury and atherosclerosis. Endothelial mitochondria have been increasingly recognized as a regulator of calcium homeostasis which has implications in the execution of diverse cellular events and energy production. The mitochondrial calcium uniporter complex through which calcium enters the mitochondria is composed of several proteins, including the pore-forming subunit MCU and its regulators MCUR1, MICU1, and MICU2. Mitochondrial calcium overload leads to opening of MPTP (mitochondrial permeability transition pore) and results in apoptotic cell death. Whereas, blockage of calcium entry into the mitochondria results in reduced ATP production thereby activates AMPK-mediated pro-survival autophagy. Here, we investigated the expression of mitochondrial calcium uniporter complex components (MCU, MCUR1, MICU1, and MICU2), induction of autophagy and apoptotic cell death in endothelial cells in response to oxygen-glucose deprivation. Human pulmonary microvascular endothelial cells (HPMVECs) were subjected to oxygen-glucose deprivation (OGD) at 3-h timepoints up to 12 h. Interestingly, except MCUR1 which was significantly downregulated, all other components of the uniporter (MCU, MICU1, and MICU2) remained unchanged. MCUR1 downregulation has been shown to activate AMPK mediated pro-survival autophagy. Similarly, MCUR1 downregulation in response to OGD resulted in AMPK phosphorylation and LC3 processing indicating the activation of pro-survival autophagy. Despite the activation of autophagy, OGD induced Caspase-mediated apoptotic cell death. Blockade of autophagy did not reduce OGD-induced apoptotic cell death whereas serum starvation conferred enough cellular and functional protection. In conclusion, the autophagic flux induced by MCUR1 downregulation in response to OGD is insufficient in protecting endothelial cells from undergoing apoptotic cell death and requires enhancement of autophagic flux by additional means such as serum starvation.

Mitochondrial Dysfunction in Age-Related Metabolic Disorders.

Aging is a natural biological process in living organisms characterized by receding bioenergetics. Mitochondria are crucial for cellular bioenergetics and thus an important contributor to age-related energetics deterioration. In addition, mitochondria play a major role in calcium signaling, redox homeostasis, and thermogenesis making this organelle a major cellular component that dictates the fate of a cell. To maintain its quantity and quality, mitochondria undergo multiple processes such as fission, fusion, and mitophagy to eliminate or replace damaged mitochondria. While this bioenergetics machinery is properly protected, the functional decline associated with age and age-related metabolic diseases is mostly a result of failure in such protective mechanisms. In addition, metabolic by-products like reactive oxygen species also aid in this destructive pathway. Mitochondrial dysfunction has always been thought to be associated with diseases. Moreover, studies in recent years have pointed out that aging contributes to the decay of mitochondrial health by promoting imbalances in key mitochondrial-regulated pathways. Hence, it is crucial to understand the nexus of mitochondrial dysfunction in age-related diseases. This review focuses on various aspects of basic mitochondrial biology and its status in aging and age-related metabolic diseases.