Biology subjects

Ehninger, D.

Publications and source records attributed to Ehninger, D..

6 recordsLinked to original sources

bioRxiv2026

Nup153 regulates neuronal responsiveness through HDAC1-mediated epigenetic modulation

Neural activity-dependent gene regulation is central to the development of neural networks and neuronal plasticity. Induction of activity-dependent gene programs is equally important as repression of these programs, and both need to be balanced carefully. However, little is known about how repressive mechanisms modulate neuronal responsiveness across the genome before stimulation. Here, we identify nucleoporin-dependent regulation of neuronal responsiveness, in which Nup153 represses neuronal genes including activity-regulated genes (ARGs), in the basal state. By characterizing the genome-wide landscape of chromatin accessibility, histone modifications and Nup153 chromatin binding, we show that Nup153 bidirectionally regulates chromatin states through both basal activity-dependent and -independent mechanisms and influences associated genes. Mechanistically, Nup153 associates with HDAC1 to modulate histone acetylation and chromatin accessibility at target regulatory regions. Our data suggests Nup153 organizes chromatin states that regulate neuronal gene programs involved in maintaining neuronal responsiveness. TeaserNup153 primes neuronal responsiveness through multi-layered epigenetic regulation.

neuroscience↗

bioRxiv2025

Manipulation of the Extracellular Vesicle Biogenesis Pathway in Paternal Somatic Cells Contributes to the Phenotypic Fate of the Next Generation

Human and animal studies have shown that risk factors for certain diseases are linked to our fathers physiological and psychological condition. So far, mainly in vitro evidence indicates extracellular vesicles (EVs) as one of the potential mediators of these paternal effects. In a full in vivo model system, we demonstrate that targeting the EV biogenesis pathway within somatic cells of the male Drosophila melanogaster reproductive tract induces sex-specific phenotypic changes in the progeny. These findings highlight the critical role of the EV pathway in paternal somatic cells in shaping the phenotypic destiny of the next generation and underscore the necessity for further investigations into the mechanisms of somatic to germline information transfer.

physiology↗

bioRxiv2024

Interaction with AK2A links AIFM1 to cellular energy metabolism

Apoptosis inducing factor 1 (AIFM1) is a flavoprotein essential for mitochondrial function and biogenesis. Its interaction with MIA40, the central component of the mitochondrial disulfide relay, accounts for some, but not all effects of AIFM1 loss. Our high-confidence AIFM1 interactome revealed novel interaction partners of AIFM1. For one of these interactors, adenylate kinase 2 (AK2), an essential enzyme maintaining cellular adenine nucleotide pools, AIFM1 binding specifically stabilized the isoform AK2A via interaction with its C-terminus. High resolution cryo-EM and biochemical analyses showed that both, MIA40 and AK2A bind AIFM1s C-terminal {beta}-strand, enhancing NADH oxidoreductase activity by locking an active, dimer conformation and, in the case of MIA40, affecting the cofactor binding site. The AIFM1-AK2A interaction is crucial during respiratory conditions. We further identified ADP/ATP translocases and the ATP synthase as AIFM1 interactors, emphasizing its important regulatory role as a central, organizing platform in energy metabolism.

biochemistry↗

bioRxiv2023

TMEM65-dependent Ca2+ extrusion safeguards mitochondrial homeostasis

The bidirectional transport of Ca2+ into and out of mitochondria is a conserved biological process controlling multiple events, including metabolism, signaling, and cell fate. In the presence of membrane potential driving mitochondrial Ca2+ accumulation, transient changes of [Ca2+]mt in response to cytosolic [Ca2+] variations are ensured by a molecular machinery for Ca2+ influx and efflux embedded in the inner mitochondrial membrane (IMM). While it is well established that influx relies on the Mitochondrial Calcium Uniporter (MCU), efflux was expected to be molecularly diversified, given the occurrence of functionally different exchange pathways with either Na+ or H+1. Accordingly, dedicated transporters ensure proper Ca2+ homeostasis and tightly regulated mitochondrial bioenergetics, but the process is not yet fully elucidated. We here demonstrate that TMEM65, a protein with an unknown biological function, is a fundamental component of the Ca2+ efflux machinery of mitochondria. As the MCU, TMEM65 has a broad tissue expression and localizes to the IMM. Its overexpression dramatically enhances Na+- and Li+-dependent mitochondrial Ca2+ extrusion, which is abrogated by the pharmacological inhibitor CGP-37157. Conversely, its downregulation chronically elevates resting mitochondrial Ca2+ levels and inhibits efficient Ca2+ efflux upon cellular activation, culminating in mitochondrial calcium overload and causing organelle dysfunction. Since TMEM65 has been associated with a severe human mitochondrial disease2, we deleted the TMEM65 homologues in Caenorhabditis elegans (CeTMEM65). While the two CeTMEM65 orthologs are dispensable for the survival at permissive growing conditions, their loss undermines embryonic developments when eggs are exposed to mild temperature-stress. In this regard, we find that CeTMEM65 (null) alleles cause necrotic lesions that are suppressed by inhibiting the mitochondrial calcium uniporter MCU-1. Overall, these results unambiguously assign a primary role in mitochondrial Ca2+ homeostasis to the orphan protein TMEM65. More importantly, our findings describe a novel molecular component that may be relevant in pathological settings in which excessive mitochondrial Ca2+ accumulation critically contribute to degenerative pathways.

biochemistry↗

bioRxiv2020

Comparative profiling of N-respirasomes predicts aberrant mitochondrial bioenergetics at single-cell resolution

AO_SCPLOWBSTRACTC_SCPLOWMitochondria sustain the energy demand of the cell. The composition and functional state of the mitochondrial oxidative phosphorylation system are informative indicators of organelle homeostasis and bioenergetic capacity. Here we describe a highly sensitive and reproducible method for single-cell visualization and quantification of mitochondrial respiratory supercomplexes as a novel means of measuring mitochondrial respiratory chain integrity. We apply a proximity ligation assay (PLA) and perform comparative studies of mitochondrial CI, CIII and CIV-containing supercomplexes (or N-respirasomes) in fixed human and mouse brain tissues, tumorigenic cells, iPSCs and iPSC-derived NPCs and neurons. Our optimized approach enables a quantitative in-situ assessment of even subtle mitochondrial lesions associated with aberrant respiration. By combining quantitative proteomics with single cell imaging analysis, we also report the mechanistic contribution of the MICOS complex subunit CHCHD3 in regulating N-respirasomes. Overall, our PLA-based profiling of N-respirasomes establishes a sensitive and complementary technique for detecting cell-type specific mitochondrial perturbations in fixed materials.

cell biology↗

bioRxiv2018

Memory trace superimposition impairs recall in a mouse model of AD

Learning and memory processes depend on the hippocampus and are impaired in Alzheimers disease (AD). Active neuronal ensembles form an engram by encoding information during learning. Their reactivation is required for memory recall. However, it remains unresolved whether the engram in CA1 principal neurons is impaired under AD-like conditions. We used two-photon in vivo imaging to visualize the expression of the immediate early gene c-fos within CA1 neurons during contextual fear conditioning and retrieval. Surprisingly, we identified engrams in wild-type mice and in the mouse model of AD indicating intact memory formation. However, under AD-like conditions engrams were superimposed by a high number of newly recruited fosGFP+ neurons during memory recall. This superimposition resembled the network configuration of wild-type mice exposed to a novel context. Artificial superimposition of the memory trace during recall in wild-type mice was sufficient to induce memory impairment. Thus, we propose superimposition of the CA1 memory trace as a mechanism for memory impairment in a mouse model of AD.\n\nHighlightsO_LIDecreased fosGFP expression in direct vicinity to amyloid-{beta} plaques\nC_LIO_LIIntact engram in CA1 of APP/PS1 mice\nC_LIO_LIImpurity of the retrieval network in CA1 is sufficient to impair memory recall\nC_LI\n\nPoll et al. present a novel mechanism for memory impairment in a mouse model of AD. The potential memory trace was found intact in the CA1 region of the hippocampus. However, excessive neuronal activity during retrieval, was superimposing the memory trace in a mouse model of AD.

neuroscience↗