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Mitochondria fuel most animal cells with ATP, ensuring proper energetic metabolism of organs. Early and extensive mitochondrial dysfunction often leads to severe disorders through multiorgan failure. Hacd2 gene encodes an enzyme involved in very long chain fatty acid (C ≥ 18) synthesis, yet its roles in vivo remain poorly understood. Since mitochondria function relies on specific properties of their membranes conferred by a particular phospholipid composition, we investigated if Hacd2 gene participates to mitochondrial integrity. We generated two mouse models, the first one leading to a partial knockdown of Hacd2 expression and the second one, to a complete knockout of Hacd2 expression. We performed an in-depth analysis of the associated phenotypes, from whole organism to molecular scale. Thanks to these models, we show that Hacd2 displays an early and broad expression, and that its deficiency in mice is lethal. Specifically, partial knockdown of Hacd2 expression leads to death within one to four weeks after birth, from a sudden growth arrest followed by cachexia and lethargy. The total knockout of Hacd2 is even more severe, characterized by embryonic lethality around E9.5 following developmental arrest and pronounced cardiovascular malformations. In-depth mechanistic analysis revealed that Hacd2 deficiency causes altered mitochondrial efficiency and ultrastructure, as well as accumulation of oxidized cardiolipin. Altogether, these data indicate that the Hacd2 gene is essential for energetic metabolism during embryonic and postnatal development, acting through the control of proper mitochondrial organization and function. • Hacd2 is a new mitochondrial disease-associated gene in mouse • Hacd2 is necessary to preserve cardiolipin integrity • Its deficiency in mice leads to embryonic or early postnatal death • Alterations of mitochondria function and structure drive a multiorgan failure [ABSTRACT FROM AUTHOR]

Summary: Molecular motors are fundamental to neuronal morphogenesis and function. However, the extent to which molecular motors are involved in higher brain functions remains largely unknown. In this study, we show that mice deficient in the kinesin family motor protein KIF13A (Kif13a −/− mice) exhibit elevated anxiety-related behavioral phenotypes, probably because of a reduction in 5HT1A receptor (5HT1AR) transport. The cell-surface expression level of the 5HT1AR was reduced in KIF13A-knockdown neuroblastoma cells and Kif13a −/− hippocampal neurons. Biochemical analysis showed that the forkhead-associated (FHA) domain of KIF13A and an intracellular loop of the 5HT1AR are the interface between the motor and cargo vesicles. A minimotor consisting of the motor and FHA domains is able to transport 5HT1AR-carrying organelles in in vitro reconstitution assays. Collectively, our results suggest a role for this molecular motor in anxiety control. [ABSTRACT FROM AUTHOR]

Epidermal growth factor (EGF) is a common mitogenic factor that stimulates the proliferation of different types of cells, especially fibroblasts and epithelial cells. EGF activates the EGF receptor (EGFR/ErbB), which initiates, in turn, intracellular signaling. EGFR family is also expressed in neurons of the hippocampus, cerebellum, and cerebral cortex in addition to other regions of the central nervous system (CNS). EGF enhances the differentiation, maturation and survival of a variety of neurons. Transgenic mice lacking the EGFR developed neurodegenerative disease and die within the first month of birth. EGF acts not only on mitotic cells but also on postmitotic neurons, and many studies have indicated that EGF has neuromodulatory effect on various types of neurons in the CNS. This review highlights some of the major recent findings pertinent to the EGF and ErbB family with special references to elucidating their roles in the regulation of neurogenesis, signal transduction and trafficking and degradation. [Copyright &y& Elsevier]

Nuclear pore complex (NPC) is a gating nanomachine with a central selective barrier composed mainly of Nups, which contain intrinsically disordered (non-structured) regions (IDRs) with phenylalanine-glycine (FG) motifs (FG-NUPs). The NPC central FG network dynamics is poorly understood, as FG-NUPs liquid-liquid phase separation (LLPS) have evaded structural characterization. Moreover, the working mechanism of single FG-NUP-biofilaments residing at the central lumen is unknown. In general, flexible biofilaments are expected to be tangled and knotted during their motion and interaction. However, filament knotting visualization in real-time and space has yet to be visualized at the nanoscale. Here, we report a spatiotemporally tracking method for FG-NUP organization with nanoscale resolution, unveiling FG-NUP conformation in NPCs of colorectal cells and organoids at timescales of ~150 ms using high-speed atomic force microscopy (HS-AFM). Tracking of FG-NUP single filaments revealed that single filaments have a heterogeneous thickness in normal and cancer models which in turn affected the filament rotation and motion. Notably, FG-NUPs are overexpressed in various cancers. Using the FG-NUP inhibitor, trans -1,2-cyclohexanediol, we found that central plug size was significantly reduced and incompletely reversible back to filamentous structures in aggressive colon cancer cells and organoids. These data showed a model of FG-NUPs reversible self-assembly devolving into the central plug partial biogenesis. Taken together, HS-AFM enabled the tracking and manipulation of single filaments of native FG-NUPs which has remained evasive for decades. Schematic illustration of manipulation and tracking of native nuclear nano-pores from mammalian cancer cells and 3D organoids. Live tracking of single nano-filament conformations inside the nuclear pore presented as a diagnosis for the colorectal cancer. Image 1 [ABSTRACT FROM AUTHOR]