The team, led by corresponding author Dinesh Upadhya of the Department of Anatomy, used human pluripotent stem cells, or PSCs, as their starting material. These cells were differentiated into neural stem cells and then into neurons, creating a controlled developmental trajectory that mirrors the earliest chapters of human brain formation. At each stage, the researchers isolated both whole-cell lipid extracts and purified mitochondrial fractions, verifying their purity with marker proteins such as ATP5A1 for mitochondria, GRP94 for the endoplasmic reticulum, and CD63 for other membranes. They then employed liquid chromatography coupled with tandem mass spectrometry, a sensitive lipidomics workflow, to quantify hundreds of individual lipid species across the glycerolipid and glycerophospholipid families.

The first broad observation was a gradual increase in relative lipid content as cells progressed from pluripotency toward neuronal identity, a trend seen in parallel at both the cellular and mitochondrial levels. Remarkably, the ratio of unsaturated to total lipids remained relatively stable across these transitions, suggesting that developing cells maintain a consistent degree of membrane fluidity even as they accumulate more lipid material. This constancy of unsaturation may reflect an underlying homeostatic program that protects membrane properties during the intense structural reorganization that accompanies neural differentiation.

Beneath this apparent calm, however, the cellular lipidome was anything but static. Relative levels of diacylglycerols, short-lived signaling lipids best known for activating protein kinase C pathways, rose steadily and significantly as PSCs became neural stem cells and then neurons. At the same time, relative levels of triacylglycerols, the cells’ storage fats, declined over the same trajectory. This reciprocal shift implies that developing neural cells actively break down their energy reserves and convert them into signaling-competent intermediates, possibly to fuel the demanding processes of proliferation, migration, and neurite extension that define neurodevelopment.

Among the glycerophospholipids, one change stood out with particular force: phosphatidylcholine, the most abundant phospholipid in most mammalian membranes, showed a drastic increase in relative abundance in mature neurons compared with pluripotent stem cells and neural stem cells. This enrichment likely supports the enormous expansion of membrane surface area required to build axons and dendrites, as well as the specialized electrical properties that neurons must acquire. In parallel, the ratio of phosphatidylcholine to phosphatidylethanolamine, two structural phospholipids whose balance influences membrane curvature and integrity, increased in both whole cells and mitochondria across the developmental sequence.

Yet when the researchers stepped back to compare the major lipid classes as a whole, a clear contrast emerged. The cellular lipid composition shifted significantly at every transition, while mitochondria maintained a relatively stable distribution of their principal lipids, including the glycerolipids and glycerophospholipids that form the inner and outer mitochondrial membranes. This stability makes functional sense: mitochondria depend on a tightly controlled lipid environment, particularly cardiolipin-rich inner membranes, to sustain oxidative phosphorylation, calcium handling, and the fission and fusion dynamics that developing cells rely on. Even as the cell around them reinvents itself, mitochondria appear to preserve their core lipid architecture.

Stability at the class level, however, did not mean molecular stagnation. More granular, species-level analyses of the mitochondrial lipidome revealed significant remodeling among individual lipid species, with differentially abundant molecular forms identified between PSCs, neural stem cells, and neurons through fold-change and univariate statistical comparisons. In other words, mitochondria fine-tune the precise fatty-acyl chains attached to their lipids while keeping the overall lipid class proportions constant, a strategy that could adjust membrane biophysics without disrupting core mitochondrial functions.

The study fills a genuine gap in developmental biology. Although mitochondria are known to be central players in neurodevelopment, powering the proliferation, differentiation, migration, and maturation of neural cells, the dynamics of their lipid composition during these critical windows had remained unexplored. Lipids are not passive structural fillers; they regulate membrane enzymes, transporters, signaling cascades, and the physical properties that determine whether membranes bend, fuse, or hold firm. Documenting their normal trajectory provides an essential reference point for understanding when development goes awry.

The clinical implications of this baseline dataset are considerable. Because many neurodevelopmental disorders, from autism spectrum conditions to intellectual disability syndromes, are now studied using patient-derived induced pluripotent stem cells, the lipid profiles established here offer a benchmark against which disease-associated lipid perturbations can be measured. If a patient’s neural lineage shows abnormal diacylglycerol accumulation, distorted phosphatidylcholine levels, or destabilized mitochondrial lipid proportions, researchers will now have the normal developmental template to compare against, potentially revealing metabolic vulnerabilities that underlie neurological disease.

The work also raises intriguing questions for future research. What mechanisms anchor the mitochondrial lipidome in place during development, and how do mitochondria communicate their lipid needs to the endoplasmic reticulum, the major site of phospholipid synthesis? Do specific lipid species emerging during the stem-cell-to-neuron transition serve as developmental signals in their own right? As lipidomics technology becomes faster and more accessible, the mitochondrial lipid landscape of the developing human brain, long an invisible dimension of neurobiology, is finally coming into focus, one fatty acid chain at a time.

Subject of Research: Lipidomic changes in cells and mitochondria during early human neurodevelopment

Article Title: Mitochondrial lipidome exhibits relatively higher stability than cell lipidome during early neurodevelopment

Article References: Hegde, S., Chandran, D., Tripathy, D. K., Ramesh, A. I., Prabhu, K., & Upadhya, D. (2026). Mitochondrial lipidome exhibits relatively higher stability than cell lipidome during early neurodevelopment. BMC Biology. https://doi.org/10.1186/s12915-026-02726-0

Image Credits: AI Generated

DOI: 10.1186/s12915-026-02726-0

Keywords: mitochondria, lipidomics, neurodevelopment, neural stem cells, pluripotent stem cells, phosphatidylcholine, diacylglycerols, triacylglycerols, neurons, BMC Biology, Mitochondrial, lipidome

PCOS is one of the most common endocrine disorders affecting women of reproductive age, characterized by irregular ovulation, clinical or biochemical signs of elevated androgens, and the presence of polycystic ovarian morphology. A hallmark of the condition is an excess of small, arrested follicles that fail to reach developmental maturity, a phenomenon known as follicular arrest. Anti-Müllerian hormone, or AMH, is often elevated in PCOS patients because of the abundance of small growing follicles, and it has become a valuable biomarker for diagnosis and disease severity. Yet the cellular reasons why these follicles stall remain incompletely understood. Because granulosa cells supply the developing follicle with energy, growth factors, and vascular signals, they represent a logical place to look for the roots of this arrest.

To investigate, the team isolated granulosa cells from women undergoing in vitro fertilization at a single center, applying the Rotterdam criteria to diagnose PCOS. The final cohort consisted of a control group of twelve women whose serum AMH levels fell within the normal range of 2 to 5 nanograms per milliliter, and a PCOS group of eleven women who met the Rotterdam criteria and displayed elevated AMH above 5 nanograms per milliliter. To control for the possibility that differences might simply reflect follicle size rather than disease, the researchers further subdivided cells from both groups according to follicular diameter, comparing cells from large follicles exceeding 14 millimeters with those from small follicles under 14 millimeters. All cells were cultured under standardized laboratory conditions, allowing the team to compare morphology, proliferation, mitochondrial activity, and secretory function directly.

The results were consistent across several independent lines of measurement. Under the microscope, PCOS-derived granulosa cells displayed abnormal morphology and an enlarged cell size compared with cells from healthy controls. When their capacity to divide was assessed, the PCOS cells proliferated significantly more slowly. This impaired growth is particularly consequential because granulosa cell proliferation drives follicle expansion during development; cells that cannot multiply properly cannot support a follicle’s progression toward ovulation. The finding suggests that the follicular arrest characteristic of PCOS may begin within the somatic compartment of the follicle rather than being solely an oocyte problem.

Deeper analysis revealed where the cellular failure likely originates: the mitochondria. These organelles serve as the cell’s power plants, generating adenosine triphosphate, or ATP, the chemical currency that fuels virtually every energy-demanding process, including cell division, protein synthesis, and secretion. The researchers found that both mitochondrial function and intracellular ATP levels were significantly reduced in PCOS granulosa cells. This energy deficit provides a coherent explanation for the observed proliferation defect, as cells with insufficient ATP cannot sustain the biosynthetic workload required to replicate. Mitochondrial dysfunction in granulosa cells has been suspected in PCOS before, but linking it quantitatively to both proliferative failure and secretory impairment in the same cohort strengthens the case that it is a central defect rather than an incidental finding.

Perhaps the most novel component of the study concerns angiogenesis, the formation of new blood vessels, which is essential for follicle development. A growing follicle depends on a rich vascular network to receive oxygen, nutrients, and hormones from the bloodstream. Granulosa cells contribute to building this network indirectly through paracrine signaling, releasing factors that stimulate nearby endothelial cells to organize into vessel structures. To test this function, the team collected conditioned media, essentially the liquid culture environment in which the granulosa cells had been growing, and applied it to human umbilical vein endothelial cells in a tube formation assay, a standard laboratory test of angiogenic capacity. The conditioned media from PCOS granulosa cells significantly impaired the ability of endothelial cells to form tubes, demonstrating that the angiogenic support normally provided by these ovarian cells was diminished in the disease state.

The effect was not uniform across follicle sizes. Granulosa cells harvested from larger follicles showed a more pronounced impairment in angiogenic support than those from smaller follicles, an observation that could help explain why larger follicles in PCOS ovaries so often fail to progress to ovulation despite reaching substantial size. At the molecular level, the researchers examined the expression of angiogenesis-related cytokines and found that three key pro-angiogenic chemokines, CXCL6, IL8, and MCP1, were consistently downregulated in PCOS granulosa cells. Interestingly, vascular endothelial growth factor A, or VEGF-A, the most famous angiogenic factor, showed a less consistent pattern, suggesting that the angiogenic deficit in PCOS is not simply a matter of reduced VEGF but rather a broader disruption of the chemokine-mediated signaling network that coordinates blood vessel formation.

Taken together, the findings sketch a coherent mechanistic framework for how PCOS disrupts follicle development. Mitochondrial dysfunction reduces ATP availability, which in turn limits cellular proliferation and dampens the secretion of angiogenic chemokines. Reduced angiogenic signaling compromises the vascular supply to developing follicles, depriving both the granulosa cells and the oocyte of the metabolic support needed for maturation. The authors describe this as a functional interplay between metabolic dysfunction and disrupted chemokine-mediated angiogenic signaling, a chain of causation that connects the metabolic phenotype of PCOS to its reproductive consequences. Because the chemokines CXCL6, IL8, and MCP1 emerged as consistently downregulated factors, they represent plausible targets for interventions aimed at restoring follicular vascular support in affected women.

The study carries practical implications for fertility medicine. Many women with PCOS require assisted reproductive technology to conceive, and the quality of the follicular environment is a determinant of oocyte competence and embryo development. If the granulosa cell dysfunction identified here proves to be modifiable, strategies to improve mitochondrial function or replenish angiogenic chemokine signaling could theoretically enhance follicle quality in PCOS patients undergoing IVF. Such approaches remain speculative, and the study is a relatively small observational analysis conducted at a single center, so the findings will need replication in larger and more diverse cohorts before they translate into clinical protocols. The authors note that the work provides potential targets for improving reproductive outcomes rather than an immediate treatment.

Beyond its clinical relevance, the study contributes to a growing appreciation of the ovary as a metabolically demanding organ in which cellular energy status and developmental signaling are tightly intertwined. The follicle is often studied primarily through its hormonal and genetic regulation, but this research underscores that the physical infrastructure of follicle growth, from mitochondrial ATP production to the surrounding vasculature, may be equally decisive. For the millions of women living with PCOS worldwide, a condition that remains among the leading causes of anovulatory infertility, understanding that their follicles may be starved of both energy and vascular support offers a new dimension to the search for causes and cures. As research continues to map the molecular pathways linking mitochondrial health, chemokine signaling, and folliculogenesis, the granulosa cell may well emerge as a key gateway through which future therapies for PCOS are delivered.

The study was conducted under ethical oversight at Cathay General Hospital in Taipei, with approval from the hospital’s Ethics Committee and written informed consent obtained from all participants, in accordance with the Declaration of Helsinki. The work received financial support from the National Science and Technology Council of Taiwan and from Cathay General Hospital, and the authors declared no competing interests.

Readers should note that the article was published as an accepted manuscript in open access form, released early to provide faster access to peer-reviewed research. This version is citable and carries a permanent DOI, though it remains subject to editorial revisions before the final Version of Record replaces it. The research is categorized under topics including endocrine reproductive disorders, fertility, and gonadal disorders, reflecting its position at the intersection of reproductive endocrinology and cellular metabolism research.

Subject of Research: Mitochondrial dysfunction in granulosa cells is associated with impaired proliferation and angiogenic support in women with polycystic ovarian syndrome and elevated AMH

Article Title: Mitochondrial dysfunction in granulosa cells is associated with impaired proliferation and angiogenic support in women with polycystic ovarian syndrome and elevated AMH

Article References: Hong, K.-J., Lin, J.-J., & Lai, T.-H. (2026). Mitochondrial dysfunction in granulosa cells is associated with impaired proliferation and angiogenic support in women with polycystic ovarian syndrome and elevated AMH. Journal of Ovarian Research. https://doi.org/10.1186/s13048-026-02264-x

Image Credits: AI Generated

DOI: 10.1186/s13048-026-02264-x

Keywords: Mitochondrial, dysfunction, granulosa, cells, associated, impaired, proliferation, angiogenic, support, women, polycystic, ovarian