Biology subjects

Schjenken, J. E.

Publications and source records attributed to Schjenken, J. E..

5 recordsLinked to original sources

bioRxiv2025

The genetic origin of fetal growth restriction and mitochondrial complex I dysregulation

BackgroundMitochondria are organelles required for bioenergetic homeostasis, providing energy in the form of ATP to support cellular function, growth, and proliferation. Mitochondria synthesise ATP using the electron transport chain (ETC) to produce an electrochemical gradient that facilitates the conversion of ADP to ATP by ATP synthase. Mitochondrial function is governed by an intricate bidirectional relationship between the mitochondrial genome encoding 1-2% of proteins and the nuclear genome which encodes 98-99% of mitochondrial proteins. Pregnancy creates a unique environment whereby the mitochondrial genome of the placenta is maternally inherited, while the nuclear genome is comprised of both maternal and paternal contributions. Thus, mitochondrial structure and function are largely dependent on the adaptability of mitochondria to conform to the new mixed nuclear genome. In pregnancy, fetal growth restriction (FGR) is characterised by poor placental development, underlying trophoblast insufficiencies, and is associated with mitochondrial dysfunction within the placenta, although the mechanisms which underpin these changes remain unclear. This study investigated if mitochondrial dysfunction in FGR is programmed by genetic incompatibility arising from single nucleotide polymorphisms (SNPs). Methods and findingsWe performed a targeted meta-analysis of over 100 genome wide association studies within the early growth genetics (EGG) consortium, assessing 289 genes encoding mitochondrial function across the ETC and ATP synthase. This study identified 37 SNPs across 32 genes associated with low birthweight. Sanger sequencing was performed to validate the presence of 10 SNPs of interest located within the nuclear genome in a cohort of fetal growth restricted placentas. Of the 10 SNPs assessed we confirmed the presence of 6 in FGR, and identified an additional previously unidentified SNP, and detected 3 nucleotide deletions across numerous components of the electron transport chain. This analysis identified 5 mutations within genes that encode complex I. Subsequent analysis of the gene and proteins that correspond to complex I mutations was performed using PCR, proteomics, and western blotting. Notably, we identified significant downregulation of NDUFA6 at the gene and protein level in FGR, lower protein levels of NDUFS3 and NDUFS6, and confirmed the largest log2 fold change identified in NDUFS6 by western blot. Subsequent investigation of mitochondrial respiratory capacity identified decreased ATP-linked respiration in FGR using Seahorse XF Analysis. ConclusionOur results identify that there is an inheritable contribution of SNPs within the maternal and paternal nuclear genome in fetal growth restriction. These SNPs alter gene expression and protein abundance of mitochondrial complex I components, impacting structural assembly and subsequent bioenergetic function within the placenta. Collectively these findings suggest that SNPs that affect mitochondrial assembly and function are associated with low birthweight and fetal growth restriction.

developmental biology↗

bioRxiv2025

Electron tomography reveals mitochondrial network and cristae remodelling during cell differentiation in the human placenta

Mitochondria adapt their structure through fusion and fission, yet how their morphology and cristae architecture alter as cells differentiate remains unclear. The human placenta is an ideal model for studying mitochondrial diversity within a single tissue. As epithelial trophoblast cells of the placenta differentiate, their accompanying mitochondria morphologically and functionally transform. We used array tomography to characterise mitochondrial volume and network complexity. Cryo-electron tomography revealed two distinct subpopulations of mitochondria within progenitor cytotrophoblasts, and a singular, homogeneous population in the differentiated syncytiotrophoblast. We showcased the 3D topology of individual cristae through a standardised metric of "curvedness". Proteomic analysis of isolated mitochondria identified reduced dynamics proteins and cristae organisation complexes, accompanied by subunit variations within the electron transport chain, ATP synthase, and altered supercomplex abundance. This study highlights the advantages of combining multimodal imaging with mechanistic insights, to elucidate the process of mitochondrial morphology and cristae architecture remodelling as cells differentiate.

cell biology↗

bioRxiv2024

Sub-chronic elevation in ambient temperature drives alterations to the sperm epigenome and accelerates early embryonic development in mice

Forecasted increases in the prevalence and severity of extreme weather events accompanying changes in climatic behavior pose potential risk to the reproductive capacity of humans and animals of ecological and agricultural significance. While several studies have revealed that heat stress induced by challenges such as testicular insulation can elicit a marked negative effect on the male reproductive system, and particularly the production of spermatozoa, less is known about the immediate impact on male reproductive function following sub-chronic whole-body exposure to elevated ambient temperature. To address this knowledge gap, we exposed unrestrained male mice to heat stress conditions that emulate a heat wave (daily cycle of 8_h at 35{degrees}C followed by 16 h at 25{degrees}C) for a period of seven days. Neither the testes or epididymides of heat exposed male mice exhibited evidence of gross histological change, and similarly, spermatozoa of exposed males retained their functionality and ability to support embryonic development. However, the embryos generated from heat exposed spermatozoa experienced pronounced changes in gene expression linked to acceleration of early embryo development, aberrant blastocyst hatching and increased fetal weight. Such changes were causally associated with an altered sperm small non-coding RNA (sncRNA) profile, such that these developmental phenotypes were recapitulated by microinjection of wild-type embryos sired by control spermatozoa with RNAs extracted from heat exposed spermatozoa. Such data highlight that even a relatively modest excursion in ambient temperature can affect male reproductive function and identify the sperm sncRNA profile as a particular point of vulnerability to this imposed environmental stress. Significance StatementThe fidelity of sperm production underpins successful reproduction yet is highly vulnerable to various forms of environmental challenge, including heat stress. Despite this knowledge, we lack a complete understanding of the immediate impact on male reproduction of whole-body exposure to elevated ambient temperatures such as those encountered during a heatwave. By experimentally emulating heatwave conditions, we demonstrate that the spermatozoa of exposed male mice accumulate changes in their small RNA profile that are causally linked to pronounced changes in embryonic gene expression, accelerated pre-implantation development, aberrant blastocyst hatching, and increased fetal weight. Such data highlight that even a relatively modest alteration in ambient temperature can affect male reproductive function, demonstrating the acute sensitivity of sperm small RNAs to environmental stress.

cell biology↗

bioRxiv2024

A single cell atlas of the mouse seminal vesicle

During mammalian reproduction, sperm are delivered to the female reproductive tract bathed in a complex medium known as seminal fluid, which plays key roles in signaling to the female reproductive tract and in nourishing sperm for their onwards journey. Along with minor contributions from the prostate and the epididymis, the majority of seminal fluid is produced by a somewhat understudied organ known as the seminal vesicle. Here, we report the first single-cell RNA-seq atlas of the mouse seminal vesicle, generated using tissues obtained from 23 mice of varying ages, exposed to a range of dietary challenges. We define the transcriptome of the secretory cells in this tissue, identifying a relatively homogeneous population of the epithelial cells which are responsible for producing the majority of seminal fluid. We also define the immune cell populations - including large populations of macrophages, dendritic cells, T cells, and NKT cells - which have the potential to play roles in producing various immune mediators present in seminal plasma. Together, our data provide a resource for understanding the composition of an understudied reproductive tissue with potential implications for paternal control of offspring development and metabolism.

genomics↗

bioRxiv2022

Blockade of redox second messengers inhibits JAK/STAT and MEK/ERK signaling sensitizing FLT3-mutant acute myeloid leukemia to targeted therapies

FLT3-mutations are diagnosed in 25-30% of patients with acute myeloid leukemia (AML) and are associated with a poor prognosis. AML is associated with the overproduction of reactive oxygen species (ROS), which drives genomic instability through the oxidation of DNA bases, promoting clonal evolution, treatment resistance and poor outcomes. ROS are also important second messengers, triggering cysteine oxidation in redox sensitive signaling proteins, however, the specific pathways influenced by ROS in AML remain enigmatic. Here we have surveyed the posttranslational architecture of primary AML patient samples and assessed oncogenic second messenger signaling. Signaling proteins responsible for growth and proliferation were differentially oxidized and phosphorylated between patient subtypes either harboring recuring mutation in FLT3 compared to patients expressing the wildtype-FLT3 receptor, particularly those mapping to the Src family kinases (SFKs). Patients harboring FLT3-mutations also showed increased oxidative posttranslational modifications in the GTPase Rac activated-NADPH oxidase-2 (NOX2) complex to drive autocratic ROS production. Pharmacological and molecular inhibition of NOX2 was cytotoxic specifically to FLT3-mutant AMLs, and reduced phosphorylation of the critical hematopoietic transcription factor STAT5 and MAPK/ERK to synergistically increase sensitivity to FLT3-inhibitors. NOX2 inhibition also reduced phosphorylation and cysteine oxidation of FLT3 in patient derived xenograft mouse models in vivo, highlighting an important link between oxidative stress and oncogenic signaling. Together, these data raise the promising possibility of targeting NOX2 in combination with FLT3-inhibitors to improve treatment of FLT3-mutant AML. One Sentence SummaryFLT3-precision therapies have entered the clinic for AML however, their durability is limited. Here we identify the Rac-NOX2 complex as the major driver of redox second messenger signaling in FLT3-mutant AML. Molecular and pharmacological inhibition of NOX2 decreased FLT3, STAT5 and MEK/ERK signaling to delay leukemia progression, and synergistically combined with FLT3 inhibitors.

cancer biology↗