Biology subjects

Duchen, M.

Publications and source records attributed to Duchen, M..

6 recordsLinked to original sources

bioRxiv2026

Chromatin- and actin-mediated mitochondrial streaming leads to patterning of mitochondrial distribution in oocytes

Mitochondria are highly dynamic organelles, and their spatiotemporal organization is strictly regulated. While it has long been recognized that mitochondria in ovulated oocytes are concentrated in the spindle hemisphere, the mechanism remains unknown. Through live cell imaging and modelling, we have discovered three features of mitochondrial dynamics in the ooplasm: (i) actin-driven cortical mitochondrial streaming is delimited to the boundary of the polarized spindle hemisphere; (ii) distinct from bulk cytoplasmic streaming, mitochondrial streaming occurs bilaterally and perpendicular to the long axis of the MII spindle and, (iii) mitochondria movement from the cytoplasm to the polarized cortex is via MYO19-mediated chromatin-associated channel around the spindle midzone. This directionality in mitochondrial streaming patterns the ooplasm of the spindle cortex, creating mitochondria-rich and mitochondria-poor regions. These features explain the establishment of the polar gradient of mitochondria in MII oocytes and may provide new insight into the spatiotemporal organization of mitochondria in cells.

cell biology↗

bioRxiv2025

Chaperone AIP Couples mTORC1 Activation and Catabolic Metabolism During Neonatal Development

To grow and divide cells must tightly coordinate anabolic programs with the availability of nutrients and growth factors. This balance is especially critical during postnatal development, when biosynthetic and energetic demands are high, and nutrient supply and neonates have to adapt to periods of fasting. These conditions place acute stress on the proteostasis network, making autophagy essential for nutrient recycling. We found that the chaperone aryl hydrocarbon receptor-interacting protein (AIP) supports both arms of this metabolic balance: promoting anabolic PI3K-AKT signaling for mTORC1 activation and enabling catabolic processes such as proteasomal degradation and autophagy. Loss of AIP causes a severe neonatal metabolic disorder, where affected infants fail to thrive postnatally. Our findings establish AIP as a central regulator of neonatal metabolic adaptation and cellular homeostasis. One Sentence SummaryAIP integrates nutrient sensing and protein recycling to sustain neonatal survival.

developmental biology↗

bioRxiv2024

A humanized neuronal model system reveals key roles for manganese in neuronal endocytosis, calcium flux and mitochondrial bioenergetics

Manganese (Mn) is an essential trace metal that is necessary for life. Its duality as both a crucial micronutrient and potential neurotoxicant necessitates tight control of intracellular and extracellular Mn levels. Dysregulation of Mn is implicated in a broad range of human diseases, from neurodevelopmental sequelae related to Mn levels in drinking water, to acquired forms of manganism, rare inherited Mn transportopathies and more common disorders such as Parkinsons and Alzheimers disease. Despite the clear association between Mn dysregulation and neurodevelopmental or neurodegenerative diseases, the underlying cellular mechanisms that govern neuropathology remain poorly understood. We established an induced pluripotent stem cells-derived midbrain neuronal system from SLC39A14, SLC39A8, and SLC30A10 patients to better understand the neuronal sequelae of Mn dysregulation. By integrating transcriptomic and functional approaches, we show that Mn dyshomeostasis leads to dysregulation of key cellular pathways that are crucial to normal neuronal function, including defects in mitochondrial bioenergetics, calcium signalling, endocytosis, and glycosylation, as well as cellular stress and early neurodegeneration. Our humanized model has enhanced understanding of the role of Mn in the human brain, and the consequences of both acquired and genetic disorders associated with Mn dysregulation. Better understanding of these underlying pathophysiological processes will identify potential targets for future therapeutic intervention.

neuroscience↗

bioRxiv2024

A co-transcriptional mechanism for tightly controlling RNA homeostasis in yeast

Transcription termination by the Nrd1-Nab3-Sen1 (NNS) complex is key in repressing pervasive transcription in Saccharomyces cerevisiae. Counterintuitively, during starvation, multiple mRNAs that are upregulated are also increasingly bound and prematurely terminated and degraded via NNS. Here we demonstrate that this NNS-mediated attenuation is important for controlling the expression and protein concentration of an evolutionarily conserved mitochondrial transporter, Pic2. Strikingly, we find that even a modest increase in Pic2 protein levels caused by defective NNS regulation has major phenotypical consequences, increasing cell volume and intracellular stress, prolonging cell cycle and decreasing growth rate. Disrupting Nab3 binding to PIC2 globally redistributed Nrd1 binding, changing the levels of other NNS-regulated transcripts. We propose that imbalances in the availability of the subunits constituting the NNS complex underlie the cell volume and cycle anomalies. Collectively our results illustrate that even subtle changes in how RNA-binding proteins interact with a single RNA substrate can cause global defects and they emphasise the crucial role of the NNS complex in preserving microbial fitness during stress. HighlightsO_LINNS regulates the expression and protein concentration of a stress-response protein-coding gene (PIC2), improving cell fitness and adaptability to environmental challenges. C_LIO_LICreating an imbalance in RNA binding of Nab3 and Nrd1 for PIC2 mRNA disturbs the homeostasis of co-regulated transcripts. C_LIO_LIEven a modest defect in NNS regulation of PIC2 elicits severe defects in cell growth, increases cell size and intracellular stress, and prolongs the cell cycle. C_LI

molecular biology↗

bioRxiv2024

Biallelic Loss of Molecular Chaperone Molecule AIP Results in a Novel Severe Multisystem Disease Defined by Defective Proteostasis

Children born with deleterious biallelic variants of the chaperone aryl hydrocarbon receptor interacting protein (AIP) have a novel pediatric metabolic disease presenting a severe, complex clinical phenotype characterized by failure to develop following birth. Analysis of Aip knockout mouse embryonic fibroblasts and patient-derived dermal fibroblasts revealed that AIP was required to support proteostasis; including proteasome activity, induction of autophagy and lysosome function. aip knockout zebrafish, recapitulated the phenotype of the children; dying at an early stage of development when autophagy is required to adapt to periods of starvation. Our results demonstrate that AIP plays a crucial role in initiating autophagy and maintaining proteostasis in vitro and in vivo. One Sentence SummaryHomozygous loss of the chaperone AIP results in a novel pediatric disease exhibiting multiple features of a lysosomal storage disease.

molecular biology↗

bioRxiv2020

Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency

Neuronal excitation imposes a high demand of ATP in neurons. Most of the ATP derives primarily from pyruvate-mediated oxidative phosphorylation, a process that relies on import of pyruvate into mitochondria occuring exclusively via the mitochondrial pyruvate carrier (MPC). To investigate whether deficient oxidative phosphorylation impacts neuron excitability, we generated a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the mitochondrial pyruvate carrier, specifically in adult glutamatergic neurons. We found that, despite decreased levels of oxidative phosphorylation in these excitatory neurons, mice were normal at rest. Paradoxically, in response to mild inhibition of GABA mediated synaptic activity, they rapidly developed severe seizures and died, whereas under similar conditions the behaviour of control mice remained unchanged. We show that neurons with a deficient MPC are intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduces M-type potassium channel activity. Provision of ketone bodies restores energy status, calcium homeostasis and M-channel activity and attenuates seizures in animals fed a ketogenic diet. Our results provide an explanation for the paradoxical seizures that frequently accompany a large number of neuropathologies, including cerebral ischemia and diverse mitochondriopathies, in which neurons experience an energy deficit. One Sentence SummaryDecreased OXPHOS and Ca2+-mediated neuronal hyperexcitability lead to seizure in a mouse model of mitochondrial pyruvate import deficiency.

neuroscience↗