Biology subjects

Morrison (Rehm), M.

Publications and source records attributed to Morrison (Rehm), M..

4 recordsLinked to original sources

bioRxiv2026

A Na⁺-PINK1 signaling axis couples mitochondrial fission to structural remodeling during synaptic depression

Mitochondrial density in dendrites adapts to the number of synaptic inputs to adequately sustain local ATP and Ca2+ buffering for neuronal signaling. During long-term depression (LTD), synapse elimination is accompanied by activation of caspase-3 through sublethal mitochondria-derived apoptotic signals, driving neurotransmitter receptor internalization and spine shrinking. However, the upstream signals that link synaptic activity to mitochondrial remodeling remain unknown. Here we show that Na+ influx through NMDA receptors depolarizes mitochondria during chemically induced LTD. This triggers stabilization and activation of the PINK1 kinase in a translation-dependent manner, leading to asynchronous mitochondrial fission. Na+ influx and PINK1 are required for cLTD-induced fission, and blocking either Na+ influx or PINK1 prevents caspase-3 activation and spine shrinking in cultured neurons. Together, these findings identify a Na+-PINK1 signaling axis that couples NMDA receptor activity to mitochondrial fission and caspase-3-dependent synapse elimination during LTD, with implications for the homeostatic regulation of synaptic density.

neuroscience↗

bioRxiv2025

Stochasticity contributes to explaining minority and majority MOMP during apoptosis

Apoptosis dysfunction is linked to diseases like cancer and neurodegenerative disorders. A key event during apoptosis is mitochondrial outer membrane permeabilization (MOMP), which typically proceeds in a rapid all-or-none fashion. If MOMP occurs only in a subset of mitochondria (minority MOMP), it can be sublethal and contribute to tumorigenesis and cancer progression. Similarly, individual mitochondria escaping widespread MOMP (majority MOMP) can allow cancer cells to recover if apoptosis execution fails. How such heterogeneities in mitochondrial MOMP responsiveness arise within cells is incompletely understood. In particular, whether stochasticity in subcellular protein distributions and interactions across cytosol and mitochondria can realistically contribute to mitochondrial MOMP heterogeneity has not yet been studied. To assess this, we sequentially built and experimentally parameterized a particle-based, cell-sized model including cytosolic and mitochondrial compartments, and that featured a reduced interactome of MCL-1, BAK and tBID. High-performance computing enabled cell-scale simulations of protein distributions and interactions to understand how and under which conditions stochasticity could contribute to heterogeneity in MOMP susceptibility. Our results show that stochastic effects strongly predispose sub-pools of fragmented mitochondria to MOMP under low apoptotic stress. At higher apoptotic stress, fractions of small mitochondria were more likely to escape MOMP than large mitochondria. Retrospective quantification of mitochondrial sizes in experimental scenarios of minority and majority MOMP confirmed these findings. We therefore conclude that stochasticity substantially contributes to enabling small or fragmented mitochondria to undergo MOMP in minority MOMP scenarios and to escape MOMP in majority MOMP scenarios.

cell biology↗

bioRxiv2021

An atlas of inter- and intra-tumor heterogeneityof apoptosis competency in colorectal cancertissue at single cell resolution

Cancer cells ability to inhibit apoptosis is key to malignant transformation and limits response to therapy. Here, we performed multiplexed immunofluorescence analysis on tissue microarrays with 373 cores from 168 patients, segmentation of 2.4 million individual cells and quantification of 20 cell lineage and apoptosis proteins. Ordinary differential equation-based modelling of apoptosis sensitivity at single cell resolution was conducted and an atlas of inter- and intra-tumor heterogeneity in apoptosis susceptibility generated. We identified an enrichment for BCL2 in immune, and BAK, SMAC and XIAP in cancer cells. ODE-based modelling at single cell resolution identified an enhanced sensitivity of cancer cells to mitochondrial permeabilization and executioner caspase activation compared to immune and stromal cells, with significant inter- and intra-tumor heterogeneity. However, we did not find increased spatial heterogeneity of apoptosis signaling in cancer cells, suggesting that such heterogeneity is an intrinsic, non-genomic property not increased by the process of malignant transformation.

cancer biology↗

bioRxiv2021

Cell-to-cell heterogeneities during extrinsic apoptosis arise from cell cycle progression and transmitotic apoptosis resistance

Extrinsic apoptosis relies on TNF-family receptor activation by immune cells or receptor-activating biologics. Here, we monitored cell cycle progression at minutes resolution to relate apoptosis kinetics and cell-to-cell heterogeneities in death decisions to cell cycle phases. Interestingly, we found that cells in S phase delay TRAIL receptor-induced death in favour for mitosis, thereby passing on an apoptosis-primed state to their offspring. This translates into two distinct fates, apoptosis execution post mitosis or cell survival from inefficient apoptosis. Transmitotic resistance is linked to Mcl-1 upregulation from mid S phase onwards, which allows cells to pass through mitosis with activated caspase-8, and with cells escaping apoptosis after mitosis sustaining sublethal DNA damage. Antagonizing Mcl-1 by BH3-mimetics suppresses cell cycle-dependent delays in apoptosis, prevents apoptosis-resistant progression through mitosis and averts unwanted survival from apoptosis induction. Cell cycle progression therefore modulates signal transduction during extrinsic apoptosis, with Mcl-1 governing decision making between death, proliferation and survival from inefficient apoptosis induction. Cell cycle progression thus is a crucial process from which cell-to-cell heterogeneities in fates and treatment outcomes emerge in isogenic cell populations during extrinsic apoptosis signalling.

cell biology↗