Lytton-Jean, A. | bioRxiv Science

bioRxiv2026

Mitochondrial amino acid export preserves mitochondrial volume at the egg-to-embryo transition

In animals, the transition from egg to embryo marks a rapid shift in cellular physiology, yet how mitochondria adapt to support this conversion remains poorly understood. We performed a targeted RNAi screen of conserved, nuclear-encoded mitochondrial proteins in Drosophila melanogaster to identify maternal effects. We identified distinct phenotypic classes affecting mitochondrial distribution or morphology in early embryos. We focused on Sideroflexin-1/3 (Sfxn1-3), a conserved mitochondrial inner membrane transporter, because it uniquely affects embryonic mitochondrial morphology. Maternal loss of Sfxn1-3 causes striking mitochondrial enlargement in embryos but not in oocytes, placing the trigger at the egg-to-embryo transition. Combining mitochondrial immunopurification with LC/MS-based metabolomic profiling, we show that amino acids are markedly enriched in Sfxn1-3-deficient mitochondria in both oocytes and embryos. This accumulation developmentally uncouples the metabolic and morphological phenotypes. By selectively disrupting discrete steps of egg activation, including translational activation, cell cycle re-entry, and fertilization, we demonstrate that mitochondrial swelling is independent of each, prompted instead by egg hydration. Beyond its reported role in proliferating cells as a serine importer, our data support a role for germline Sfxn1-3 in regulating inner mitochondrial membrane permeability to osmotically active amino acids. This activity is crucial for preserving organelle volume during the osmotic challenge of oocyte hydration. When this export fails, amino acid accumulation amplifies osmotic stress and drives rapid mitochondrial swelling. Together, these findings identify mitochondrial inner membrane permeability to amino acids as a key regulatory step that couples pre-established metabolite compartmentalization to osmotic adaptation at egg activation, and reveal how mitochondrial metabolic integrity and volume control are coordinated at this critical developmental transition.

developmental biology↗

bioRxiv2024

Constant surface area-to-volume ratio during cell growth as a design principle in mammalian cells

All cells are subject to geometric constraints, including the surface area-to-volume (SA/V) ratio, which can limit nutrient uptake, maximum cell size, and cell shape changes. Like the SA/V ratio of a sphere, it is generally assumed that the SA/V ratio of cells decreases as cell size increases. However, the structural complexity of the plasma membrane makes studies of the surface area challenging in cells that lack a cell wall. Here, we investigate near-spherical mammalian cells using single-cell measurements of cell mass and plasma membrane proteins and lipids, which allows us to examine the cell size scaling of cell surface components as a proxy for the SA/V ratio. Surprisingly, in various proliferating cell lines, cell surface components scale proportionally with cell size, indicating a nearly constant SA/V ratio as cells grow larger. This behavior is largely independent of the cell cycle stage and is also observed in quiescent cells, including primary human monocytes. Moreover, the constant SA/V ratio persists when cell size increases excessively during polyploidization. This is enabled by increased plasma membrane folding in larger cells, as verified by electron microscopy. We also observe that specific cell surface proteins and cholesterol can deviate from the proportional size scaling. Overall, maintaining a constant SA/V ratio ensures sufficient plasma membrane area for critical functions such as cell division, nutrient uptake, growth, and deformation across a wide range of cell sizes.

cell biology↗