Biology subjects

Omholt, S. W.

Publications and source records attributed to Omholt, S. W..

6 recordsLinked to original sources

bioRxiv2026

A DNA mass conservation mechanism underpins cellular mtDNA number regulation

The nucleoid, which houses mtDNA within the mitochondrial matrix, is a phase-separation-driven biomolecular condensate capable of carrying out a broad spectrum of complex functions, including DNA replication, transcription, and repair. Here, we show by data-driven computational modelling that the concept of a tightly regulated intranucleoid de-oxynucleoside triphoshate (dNTP) pool explains the observation that the number of mtDNA base pairs per cell is conserved in human hybrid cell lines regardless of the size of the introduced mitochondrial genome. This concept is then used to address the enigmatic observation that the synthesis rate of the short DNA strand called 7S DNA, which is part of the triple-stranded displacement loop (D-loop) found in the main noncoding region of mtDNA, increases dramatically during the cell cycle. Collectively, our quantitative analyses suggest that the mammalian mtDNA replisome uses a strictly controlled intranucleoid dNTP pool based predominantly on the synthesis and degradation of 7S DNA. One potential evolutionary explanation for this mechanism is that it offers an energetic advantage by enabling greater reliance on the salvage pathway for mtDNA replication.

molecular biology↗

bioRxiv2025

High reelin expression can explain why the entorhinal cortex is a cradle for Alzheimer's disease

The entorhinal cortex (EC) plays a crucial role in memory functions. Long before the clinical symptoms of Alzheimers disease (AD) emerge, it has already undergone significant degeneration, making it a primary site for the onset of the disease. The reasons for this remain elusive. It was recently shown that in layer II neurons of the anterolateral entorhinal cortex (alECLII neurons), which are especially prone to display a very early increase in intracellular amounts of amyloid-{beta} peptide (A{beta}) and hyperphosphorylated tau protein (p-tau), the large glycoprotein reelin binds to A{beta}, suggesting that reelin functions as a sink for intracellular A{beta}. The expression of reelin is extraordinarily high in alECLII neurons compared to most other cortical neurons. Here, we show by computational modeling that, in a senescent physiology predisposing to frequent inflammation-driven A{beta}42 production bursts, the intracellular amount of A{beta}42-reelin complexes can accumulate to extraordinarily high levels in alECLII neurons compared to the vast majority of cortical neurons. This explains experimental data showing that intracellular accumulations of A{beta}42 positive material ranged from 20 to 80% of the total cytoplasmic volume in EC neurons from patients with sporadic AD. We also show that this extreme intracellular aggregation can cause the accumulation of detrimental hyperphosphorylated tau fragments. Thus, when exposed to recurrent AD-promoting stress, the exceptionally high expression of reelin in alECLII neurons appears to be instrumental in their early demise relative to other cortical neurons.

neuroscience↗

bioRxiv2023

Intraneuronal binding of amyloid beta with reelin -implications for the onset of Alzheimer's disease

It was recently shown that in anteriolateral entorhinal cortex layer II neurons (ECLII neurons) in McGill-R-Thy1-APP homozygous transgenic rats (a model commonly used to study Alzheimers disease (AD)), the glycoprotein reelin and intracellular amyloid-{beta} (A{beta}) engage in a direct protein-protein interaction. Numerous studies of the human brain supported by experimental results from rodent and cell models point to a role for intracellular oligomeric A{beta} in the onset of AD. If reelin functions as a sink for intracellular A{beta} and if the binding to reelin makes A{beta} physiologically inert, it implies that reelin may prevent the neuron from being exposed to the detrimental effects typically associated with oligomeric A{beta}. Considering that reelin expression is extraordinarily high in the major subset of ECLII neurons compared to most other cortical neurons, such a protective role appears very difficult to reconcile with the fact that ECLII is clearly a major cradle for the onset of AD in humans. Here we show that this conundrum may be resolved if ECLII neurons have a much higher maximum production capacity of A{beta} than neurons expressing low levels of reelin. We provide a rationale for why this difference has evolved, and argue that the higher maximum production capacity of A{beta} in ECLII neurons may in a senescent A{beta}-inducing physiology predispose these neurons to initiate AD development. Author summaryAmyloid-{beta} is a small peptide that is widely recognized as one of the main culprits involved in the development of Alzheimers disease. It was recently shown that in the major subset of neurons in entorhinal cortex layer II, which expresses high levels of the protein reelin, amyloid-{beta} and reelin bind to each other. These neurons, which are strongly involved in memory formation, are among the first to die in subjects with Alzheimers disease. If intracellular amyloid-{beta}, which is clearly involved in the onset of the disease, becomes physiologically inert when it binds to reelin, it implies that reelin can prevent the neuron from being exposed to the detrimental effects of increased levels of amyloid-{beta}. Considering that reelin expression is extraordinarily high in ECLII neurons compared to most other cortical neurons, such a protective role appears very difficult to reconcile with the fact that ECLII constitute the predominant cortical site for initiation of Alzheimers disease. Here, we show that this paradox may be resolved if ECLII neurons have a much higher maximum amyloid-{beta} production capacity than neurons expressing low levels of reelin. We provide reasons why this difference has evolved and argue that it, in a senescent physiology, predisposes ECLII neurons to initiate the development of Alzheimers disease.

neuroscience↗

bioRxiv2023

Bnip3 expression is strongly associated with reelin-positive entorhinal cortex layer II neurons

In layer II of the entorhinal cortex, the principal neurons that project to the dentate gyrus and the CA3/2 hippocampal fields express the large glycoprotein reelin (Re+ ECLII-neurons). In rodents, neurons located at the dorsal extreme of the entorhinal cortex that thus border the rhinal fissure, express the highest levels, and the expression gradually decreases at levels successively further away from the rhinal fissure. Here we test two predictions following from the hypothesis that reelin expression is strongly correlated with neuronal metabolic rate. Since mitochondrial turnover rate serves as a proxy for energy expenditure, we predicted that the expression of the canonical promitophagic BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (Bnip3) would be upregulated in Re+ ECLII-neurons, and that the degree of upregulation would strongly correlate with the expression level of reelin in these neurons. We confirm both predictions, which implies that the energy requirement of Re+ ECLII-neurons is generally high, and that there is a systematic decrease in metabolic rate in these neurons as one moves successively away from the rhinal fissure. We tentatively suggest that the reasons for the high energy requirement of these neurons are their high rate of synaptic transmission and the high frequency by which they remold their synaptic contacts. This implies that the systematic variation in energy requirement of the neurons manifesting the observed reelin gradient ties in with the level of spatial and temporal detail by which they encode information about the external environment.

neuroscience↗

bioRxiv2020

Control of mitochondrial superoxide production includes programmed mtDNA deletion and restoration

Deletion of mitochondrial DNA in eukaryotes is mainly attributed to rare accidental events associated with mitochondrial replication or repair of double-strand breaks. We report the discovery that yeast cells arrest harmful intramitochondrial superoxide production by shutting down respiration through genetically controlled deletion of mitochondrial oxidative phosphorylation genes. We show that the regulatory circuitry underlying this editing critically involves the antioxidant enzyme superoxide dismutase 2 and two-way mitochondrial-nuclear communication. While mitochondrial DNA homeostasis is rapidly restored after cessation of a short-term superoxide stress, long-term stress causes maladaptive persistence of the deletion process, leading to complete annihilation of the cellular pool of intact mitochondrial genomes and irrevocable loss of respiratory ability. Our results may therefore be of etiological as well as therapeutic importance with regard to age-related mitochondrial impairment and disease. One-Sentence SummaryGenetically controlled editing of mitochondrial DNA is an integral part of the yeasts defenses against oxidative damage.

cell biology↗

bioRxiv2016

Functional Analysis of All Salmonid Genomes (FAASG): an international initiative supporting future salmonid research, conservation and aquaculture

We describe an emerging initiative - the Functional Analysis of All Salmonid Genomes (FAASG), which will leverage the extensive trait diversity that has evolved since a whole genome duplication event in the salmonid ancestor, to develop an integrative understanding of the functional genomic basis of phenotypic variation. The outcomes of FAASG will have diverse applications, ranging from improved understanding of genome evolution, through to improving the efficiency and sustainability of aquaculture production, supporting the future of fundamental and applied research in an iconic fish lineage of major societal importance.

genomics↗