Mitochondrial dysfunction is a central driver of neonatal hypoxic-ischaemic encephalopathy (HIE), yet the specific vulnerabilities of mitochondrial fusion machinery in the neonatal brain remain poorly defined. Here, we investigate Optic Atrophy (OPA)1 as a critical determinant of mitochondrial resilience during hypoxia-ischaemia (HI). Human developmental transcriptomics showed stable perinatal expression of mitochondrial dynamics genes, supporting their […]

-Lipoic acid (LA) is widely included in mitochondrial cocktails recommended to patients with primary mitochondrial disorders, yet its mechanism of action remains unclear. Here, we define the intracellular availability and functional utilization of LA in mammalian cells. We show that LA exists in two functionally distinct cellular pools: a low-abundance free pool and a protein-bound […]

Malonate is often described as an endogenous inhibitor of complex II of the electron transport chain. However, the cellular source of malonate is unclear, and current knowledge concerning its metabolism is limited to the action of a single enzyme, Acyl-CoA Synthetase Family Member 3 (ACSF3), which converts malonate to malonyl-CoA in the mitochondrial matrix. One […]

Mitochondria are essential for cellular energy production and are particularly critical for brain development and function. Neurons rely predominantly on oxidative phosphorylation for energy production, rendering the brain highly vulnerable to mitochondrial dysfunction. Consequently, impaired mitochondrial function contributes to a broad spectrum of neurological and systemic disorders, making mitochondria attractive therapeutic targets. Despite this importance, […]

Plant viruses have evolved diverse strategies to facilitate their movement and survival within the host. Among them, geminiviruses co-opt host cellular machinery to replicate and disseminate. Traditionally, viral propagation has been associated with intercellular symplastic trafficking mediated by plasmodesmata and viral movement proteins. However, recent evidence demonstrated that the plant RNA virus turnip mosaic virus […]

CRISPR screens with single-cell RNA-seq readouts provide a powerful tool for characterizing the functions of noncoding elements and genes. However, designing these experiments to balance statistical power and cost is challenging, given the large number of design parameters. The only available tool for this purpose is a simulation-based power calculator, but it is computationally costly […]

CRISPR-Cas9 perturbation screens coupled with single-cell multi-omic profiling enable dissection of gene regulatory mechanisms, yet existing analyses largely quantify total perturbation effects and offer limited insight into the molecular intermediates that transmit these effects. We introduce CMAPS (Causal Mediation Analysis for Perturbation Screens), a semiparametric framework for robust mediation analysis that accommodates unmeasured mediator-outcome confounding […]

Hailey-Hailey disease (HHD) is a genetic skin blistering disorder lacking approved treatments despite linkage to ATP2C1 variants 25 years ago. Since knockout mice did not replicate HHD, we ablated ATP2C1 in human keratinocytes or chemically inhibited its encoded Golgi calcium pump SPCA1. In organotypic epidermis, SPCA1 deficiency or inhibition reproduced HHD pathology, disrupting desmosomal cadherins […]

Fatty acid biosynthesis is a central metabolic process required for membrane formation, organelle maintenance, and cellular proliferation, yet its broader relationship with stress responses and cellular aging remains incompletely understood. Here, we combined human and yeast interactome analyses with transcriptomic profiling and chronological lifespan assays to investigate the systems-level organization of fatty acid metabolic pathways […]

Accurate in vivo prediction of neuropathology is critical for advancing diagnosis and treatment of Alzheimer’s disease and related dementias (ADRDs). As many individuals with ADRDs have mixed pathologies (beta-amyloid, pathologic tau, cerebrovascular disease, vascular brain injury, pathologic TDP-43, hippocampal sclerosis, Lewy bodies), there is interest in determining how accurately we can infer these pathologic changes […]

Parasitism is one of the most widespread trophic strategies in nature, though its diversity and ecological distribution in marine ecosystems remain poorly characterized. Apicomplexa are a major clade of obligate parasites best known for medically important taxa, yet their diversity and distribution in the ocean is still largely unresolved. Here, we used metabarcoding data from […]

Native mass spectrometry (nMS) is well established for measuring protein masses and stoichiometries using nano-electrospray ionization (nESI), yet salt adduction and source activation energies can limit routine measurements. In this study, we benchmark submicron quartz nanopipette nESI emitters (<50 nm internal diameter) across three mass spectrometry platforms (quadrupole-time-of-flight, quadrupole-Orbitrap, and tribrid-Orbitrap platforms) and a wide […]