Biology subjects

Salin, B.

Publications and source records attributed to Salin, B..

8 recordsLinked to original sources

bioRxiv2026

A Female-Specific Microglial Redox Program Gates Susceptibility to Obesity

Chronic consumption of energy-dense, high-fat foods persistently exposes hypothalamic circuits that govern body weight to nutrient excess, progressively altering their activity and thereby promoting obesity. Microglia, the brain resident immune cells, sense circulating lipids, but how their intracellular metabolic programs adapt to chronic dietary excess, and how this contributes to obesity risk, is unclear. Here, we reveal a sex-dependent control of calorie overload by hypothalamic microglial cells. In females, but not males, microglia engage a protective metabolic program with increased antioxidant capacity and mitochondrial network remodeling, conferring resistance to early weight gain. Over time, activation of mTORC1 signaling in microglia disrupts mitochondrial functions and dismantles this transient resilience, culminating in weight gain. These findings identify microglial mTORC1 as a sex-specific switch between resilience and vulnerability to obesity and position microglial metabolism as a tractable target for sex-informed weight control.

neuroscience↗

bioRxiv2025

Cellular adaptation of mitochondrial metabolism and biogenesis in response to partial ATP synthase uncoupling

Cellular energy metabolism relies on tight regulation of mitochondrial biogenesis and turnover to maintain bioenergetic homeostasis. Understanding the signaling pathways that modulate mitochondrial content in response to changing energetic demands is therefore essential. This work examines how partial mitochondrial uncoupling reshapes mitochondrial content and metabolism in yeast and how such adaptations mirror features of pathological or age-associated states. Using a Saccharomyces cerevisiae ATP synthase mutant lacking the epsilon subunit ({Delta}{varepsilon}) and carrying a compensatory mutation that allows survival under uncoupling ({Delta}{varepsilon}+c-L57F), mitochondrial abundance, organization, and function were compared with those of wild-type and rescue strains (mutant re-expressing the epsilon subunit of the ATP synthase). Analyses included respiration assays, mitochondrial DNA quantification, {beta}-galactosidase reporters, fluorescence microscopy of the mitochondrial network, and 2D-DiGE proteomics. Uncoupling in the mutant led to a strong increase in mitochondrial mass per cell, higher respiratory capacity, elevated cytochrome levels, and increased mtDNA copy number, together with augmented transcriptional activity consistent with activation of HAP-dependent mitochondrial biogenesis. Despite a fragmented network, mitochondria retained typical ultrastructural features, while proteomic profiling indicated a shift toward ATP production via substrate-level phosphorylation. Overall, partial uncoupling promotes reversible mitochondrial biogenesis and metabolic remodeling that depend on a preserved proton-motive force, highlighting mitochondrial signaling as a key regulator of cellular energy homeostasis and offer new perspectives for studying metabolic disorders and mitochondrial pathologies. GRAPHICAL ABSTRACTS O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=179 SRC="FIGDIR/small/695256v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@19b1eceorg.highwire.dtl.DTLVardef@103a6ceorg.highwire.dtl.DTLVardef@bc48f6org.highwire.dtl.DTLVardef@15a191c_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMitochondrial uncoupling triggers a marked increase in mitochondrial biogenesis in yeast. C_LIO_LIUncoupling leads to fragmentation of the mitochondrial network, while preserving mitochondrial ultrastructure. C_LIO_LIUncoupling induces metabolic remodeling that favors ATP production through substrate-level phosphorylation. C_LIO_LIThese cellular adaptations are reversible upon re-establishment of mitochondrial coupling. C_LIO_LIThe proton motive force serves as a key signal sensed by the cell. C_LI

molecular biology↗

bioRxiv2024

Amyloid signaling in antiphage defense

Immune regulated cell death (RCD) is a defense strategy common to different domains of life involving purposeful sacrifice of infected cells. In animals and fungi, functional amyloids play a role in the control of RCD as molecular switches activating key cell death effectors, rather than causing direct toxicity as seen with pathological amyloids. Here, we describe a novel amyloid-based signal transduction mechanism in an antiphage defense system in Escherichia coli. This antiphage abortive infection (Abi) system is mediated by two proteins, Bab and Agp which share a common amyloid motif and are encoded by adjacent genes. Upon phage infection, Agp activates Bab through amyloid signaling, leading to cell death. We determined the structure of the Bab cell death execution domain, which is distantly related to pore-forming domains present in fungi, animals and plants. We show that Bab and the fungal HET-S amyloid-controlled cell death execution protein are functionally interchangeable in their respective roles in antiphage defense and allorecognition. These findings add antiphage defense to the functional repertoire of amyloids.

microbiology↗

bioRxiv2023

Identification of a novel and ancestral machinery involved in mitochondrial membrane branching in Trypanosoma brucei

Unlike most other eukaryotes, where mitochondria continuously fuse and divide, the mitochondrion of trypanosome cells forms a single and continuously interconnected network that divides only during cytokinesis. However, the machinery governing mitochondrial remodeling and interconnection of trypanosome mitochondrion remain largely unknown. We functionally characterize a novel dynamin-superfamily protein (DSP) from T. brucei (TbMfnL) which shares close similarity with a family of homologs present in various eukaryotic and prokaryotic phyla, but not in opisthokonts like mammals and budding yeast. The sequence and domain organization of TbMfnL is distinct and it is phylogenetically very distant from the yeast and mammalian dynamin-related proteins involved in mitochondrial fusion/fission dynamincs, such as Opa1 and Mfn. TbMfnL localizes to the inner mitochondrial membrane facing the matrix, and upon overexpression, induces a strong increase in the interconnection and branching of mitochondrial filaments in a GTPase-dependent manner. TbMfnL is a component of a novel membrane remodeling machinery with an unprecedented matrix-side localization that is able to modulate the degree of intermitochondrial connections.

microbiology↗

bioRxiv2020

Astroglial calcium transfer from endoplasmic reticulum to mitochondria determines synaptic integration

Intracellular calcium signaling underlies the astroglial control of synaptic transmission and plasticity. Mitochondria-endoplasmic reticulum contacts (MERCs) are key determinants of calcium dynamics, but their functional impact on astroglial regulation of brain information processing is currently unexplored. We found that the activation of astrocyte mitochondrial-associated CB1 receptors (mtCB1) determines MERCs-dependent intracellular calcium signaling and synaptic integration. The stimulation of mtCB1 receptors promotes calcium transfer from the endoplasmic reticulum to mitochondria through specific mechanisms regulating the activity of the mitochondrial calcium uniporter (MCU) channel. Physiologically, mtCB1-dependent mitochondrial calcium uptake determines the precise dynamics of cytosolic calcium events in astrocytes upon endocannabinoid mobilization. Accordingly, electrophysiological recordings in hippocampal slices showed that genetic exclusion of mtCB1 receptors or specific astroglial MCU inhibition blocks lateral synaptic potentiation, a key example of astrocyte-dependent integration of distant synapses activity. Altogether, these data reveal an unforeseen link between astroglial MERCs and the regulation of brain network functions.

neuroscience↗

bioRxiv2020

Prion cross-seeding between fungal and mammalian amyloid signaling motifs

In filamentous fungi, NLR-based signalosomes activate downstream membrane-targeting cell-death inducing proteins by a mechanism of amyloid templating. In the species Podospora anserina, two such signalosomes, NWD2/HET-S and FNT1/HELLF have been described. An analogous system, involving a distinct amyloid signaling motif termed PP was also identified in the genome of the species Chaetomium globosum and studied using heterologous expression in Podospora anserina. The PP-motif bears resemblance to the RHIM and RHIM-like motifs controlling necroptosis in mammals and innate immunity in flies. We identified here, a third NLR signalosome in Podospora anserina comprising a PP-motif and organized as a two-gene cluster encoding a NLR and a HELL-domain cell-death execution protein termed HELLP. We show that the PP-motif region of HELLP forms a prion we term [{pi}] and that [{pi}] prions trigger the cell-death inducing activity of full length HELLP. We detect no prion cross-seeding between HET-S, HELLF and HELLP amyloid motifs. In addition, we find that akin to PP-motifs, RHIM motifs from human RIP1 and RIP3 kinases are able to form prions in Podospora, and that [{pi}] and [Rhim] prions partially cross-seed. Our study shows that Podospora anserina displays three independent cell-death inducing amyloid signalosomes. Based on the described functional similarity between RHIM and PP, it appears likely that these amyloid motifs constitute evolutionary related cell-death signaling modules. ImportanceAmyloids are {beta}-sheet-rich protein polymers that can be pathological or display a variety of biological roles. In filamentous fungi, specific immune receptors activate programmed cell-death execution proteins through a process of amyloid templating akin to prion propagation. Among these fungal amyloid signaling sequences, the PP-motif stands out because it shows similarity to RHIM, an amyloid sequence controlling necroptotic cell-death in mammals. We characterized an amyloid signaling system comprising a PP-motif in the model species Podospora anserina thus bringing to three the number of independent amyloid signaling cell death pathways described in that species. We then show that human RHIM motifs not only propagate as prions in P. anserina but also partially cross-seed with fungal PP-prions. These results indicate that in addition to show sequence similarity, PP and RHIM-motif are at least partially functionally related, supporting a model of long-term evolutionary conservation of amyloid signaling mechanisms from fungi to mammals.

microbiology↗

bioRxiv2020

TMEM70 promotes ATP synthase assembly within cristae via transient interactions with subunit c

Mitochondrial ATP-synthesis is catalyzed by a F1Fo-ATP synthase, an enzyme of dual genetic origin enriched at the edge of cristae where it plays a key role in their structure/stability. The enzymes biogenesis remains poorly understood, both from a mechanistic and a compartmentalization point of view. The present study provides novel molecular insights into this process through investigations on a human protein called TMEM70 with an unclear role in the assembly of ATP synthase. A recent study has revealed the existence of physical interactions between TMEM70 and the subunit c (Su.c), a protein present in 8 identical copies forming a transmembrane oligomeric ring (c-ring) within the ATP synthase proton translocating domain (FO). Herein we analyzed the ATP-synthase assembly in cells lacking TMEM70, mitochondrial DNA or F1 subunits and observe a reciprocal dependence of TMEM70 and Su.c levels, regardless of the status of other ATP synthase subunits or of mitochondrial bioenergetics. Immunoprecipitation and two-dimensional blue-native/SDS-PAGE reveal that TMEM70 forms large oligomers composed of 8 TMEM70 dimers and that TMEM70 oligomers interact with Su.c not yet incorporated into ATP synthase complexes. Moreover, discrete TMEM70-Su.c complexes with increasing Su.c contents can be detected, suggesting a role for TMEM70 oligomers in the gradual assembly of the c-ring. Furthermore, we demonstrate using expansion super-resolution microscopy the specific localization of TMEM70 at the inner cristae membrane, distinct from the MICOS component MIC60. Taken together, our results show that TMEM70 oligomers provide a scaffold for c-ring assembly and that mammalian ATP synthase is assembled within inner cristae membranes.

cell biology↗

bioRxiv2020

Identification of NLR-associated amyloid signaling motifs in filamentous bacteria

NLRs (Nod-like receptors) are intracellular receptors regulating immunity, symbiosis, non-self recognition and programmed cell death in animals, plants and fungi. Several fungal NLRs employ amyloid signaling motifs to activate downstream cell-death inducing proteins. Herein, we identify in Archaea and Bacteria, short sequence motifs that occur in the same genomic context as fungal amyloid signaling motifs. We identify 10 families of bacterial amyloid signaling sequences (we term BASS), one of which (BASS3) is related to mammalian RHIM and fungal PP amyloid motifs. We find that BASS motifs occur specifically in bacteria forming multicellular structures (mainly in Actinobacteria and Cyanobacteria). We analyze experimentally a subset of these motifs and find that they behave as prion forming domains when expressed in a fungal model. All tested bacterial motifs also formed fibrils in vitro. We analyze by solid-state NMR and X-ray diffraction, the amyloid state of a protein from Streptomyces coelicolor bearing the most common BASS1 motif and find that it forms highly ordered non-polymorphic amyloid fibrils. This work expands the paradigm of amyloid signaling to prokaryotes and underlies its relation to multicellularity.

microbiology↗