Developmental mitochondrial complex I activity determines lifespanStefanatos, Rhoda; Robertson, Fiona; Castejon-Vega, Beatriz; Yu, Yizhou; Uribe, Alejandro Huerta; Myers, Kevin; Kataura, Tetsushi; Korolchuk, Viktor I; Maddocks, Oliver D K; Martins, L Miguel; Sanz, Alberto
doi: 10.1038/s44319-025-00416-6pmid: 40097814
Aberrant mitochondrial function has been associated with an increasingly large number of human disease states. Observations from in vivo models where mitochondrial function is altered suggest that maladaptations to mitochondrial dysfunction may underpin disease pathology. We hypothesized that the severity of this maladaptation could be shaped by the plasticity of the system when mitochondrial dysfunction manifests. To investigate this, we have used inducible fly models of mitochondrial complex I (CI) dysfunction to reduce mitochondrial function at two stages of the fly lifecycle, from early development and adult eclosion. Here, we show that in early life (developmental) mitochondrial dysfunction results in severe reductions in survival and stress resistance in adulthood, while flies where mitochondrial function is perturbed from adulthood, are long-lived and stress resistant despite having up to a 75% reduction in CI activity. After excluding developmental defects as a cause, we went on to molecularly characterize these two populations of mitochondrially compromised flies, short- and long-lived. We find that our short-lived flies have unique transcriptomic, proteomic and metabolomic responses, which overlap significantly in discrete models of CI dysfunction. Our data demonstrate that early mitochondrial dysfunction via CI depletion elicits a maladaptive response, which severely reduces survival, while CI depletion from adulthood is insufficient to reduce survival and stress resistance.
Molecular architecture of glideosome and nuclear F-actin in Plasmodium falciparumPražák, Vojtěch; Vasishtan, Daven; Grünewald, Kay; Douglas, Ross G; Ferreira, Josie L
doi: 10.1038/s44319-025-00415-7pmid: 40128412
Actin-based motility is required for the transmission of malaria sporozoites. While this has been shown biochemically, filamentous actin has remained elusive and has not been directly visualised inside the parasite. Using focused ion beam milling and electron cryo-tomography, we studied dynamic actin filaments in unperturbed Plasmodium falciparum cells for the first time. This allowed us to dissect the assembly, path and fate of actin filaments during parasite gliding and determine a complete 3D model of F-actin within sporozoites. We observe micrometre long actin filaments, much longer than expected from in vitro studies. After their assembly at the parasite’s apical end, actin filaments continue to grow as they are transported down the cell as part of the glideosome machinery, and are disassembled at the basal end in a rate-limiting step. Large pores in the IMC, constrained to the basal end, may facilitate actin exchange between the pellicular space and cytosol for recycling and maintenance of directional flow. The data also reveal striking actin bundles in the nucleus. Implications for motility and transmission are discussed.
Borrelia burgdorferi lacking all cp32 prophage plasmids retains full infectivity in miceHillman, Chad; Theriault, Hannah; Dmitriev, Anton; Hansra, Satyender; Rosa, Patricia A; Wachter, Jenny
doi: 10.1038/s44319-025-00378-9pmid: 40108404
The causative agent of Lyme disease, Borrelia burgdorferi, contains a unique, segmented genome comprising multiple linear and circular plasmids. To date, the genomes of over 63 sequenced Lyme disease Borrelia carry one or more 32 kbp circular plasmids (cp32) or cp32-like elements. The cp32 plasmids are endogenous prophages and encode, among other elements, a family of surface exposed lipoproteins termed OspEF-related proteins. These lipoproteins are synthesized during mammalian infection and are considered important components of the spirochete’s adaptive response to the vertebrate host. Here, we detail the construction and infectivity of the first described B. burgdorferi strain lacking all cp32 plasmids. Despite their universal presence, our findings indicate that B. burgdorferi does not require any cp32 plasmids to complete the experimental mouse-tick-mouse infectious cycle and a total lack of cp32s does not impair spirochete infectivity.
Sertm2 is a conserved micropeptide that promotes GDNF-mediated motor neuron subtype specificationHsu, Fang-Yu; Yen, Ya-Ping; Fan, Hung-Chi; Chang, Mien; Chen, Jun-An
doi: 10.1038/s44319-025-00400-0pmid: 40108406
Small open-reading frame-encoded micropeptides within long noncoding RNAs (lncRNAs) are often overlooked due to their small size and low abundance. However, emerging evidence links these micropeptides to various biological pathways, though their roles in neural development and neurodegeneration remain unclear. Here, we investigate the function of murine micropeptide Sertm2, encoded by the lncRNA A730046J19Rik, during spinal motor neuron (MN) development. Sertm2 is predicted to be a conserved transmembrane protein found in both mouse and human, with subcellular analysis revealing that it is enriched in the cytoplasm and neurites. By generating C terminally Flag-tagged Sertm2 and expressing it from the A730046J19Rik locus, we demonstrate that the Sertm2 micropeptide localizes in spinal MNs in mice. The GDNF signaling-induced Etv4+ motor pool is impaired in Sertm2 knockout mice, which display motor nerve arborization defects that culminate in impaired motor coordination and muscle weakness. Similarly, human SERTM2 knockout iPSC-derived MNs also display reduced ETV4+ motor pools, highlighting that Sertm2 is a novel, evolutionarily conserved micropeptide essential for maintaining GDNF-induced MN subtype identity.
SERTM2: a neuroactive player in the world of micropeptidesLisi, Michela; Santini, Tiziana; D’Andrea, Tiziano; Salvatori, Beatrice; Setti, Adriano; Paiardini, Alessandro; Nutarelli, Sofia; Nicoletti, Carmine; Pellegrini, Flaminia; Fucile, Sergio; Bozzoni, Irene; Martone, Julie
doi: 10.1038/s44319-025-00404-wpmid: 40108405
In this study, we analyze the long noncoding RNA, lncMN3, that is predominantly expressed in motor neurons and shows potential coding capabilities. Utilizing custom antibodies, we demonstrate the production of a lncMN3-derived type I transmembrane micropeptide, SERTM2. Patch-clamp experiments performed on both wild-type and SERTM2 knockout motor neurons, differentiated in vitro from mouse embryonic stem cells, show a difference in the resting membrane potential and overall decreased excitability upon SERTM2 depletion. In vivo studies indicate that the absence of the peptide impairs treadmill test performance. At the mechanistic level, we identify a two-pore domain potassium channel, TASK1, known to be a major determinant of the resting membrane potential in motor neurons, as a SERTM2 interactor. Our study characterizes one of the first lncRNA-derived micropeptides involved in neuronal physiology.
Transdifferentiation of plasmatocytes to crystal cells in the lymph gland of Drosophila melanogasterMarcetteau, Julien; Duarte, Patrícia; Leitão, Alexandre B; Sucena, Élio
doi: 10.1038/s44319-025-00366-zpmid: 40075235
Under homeostatic conditions, haematopoiesis in Drosophila larvae occurs in the lymph gland and sessile haemocyte clusters to produce two functionally and morphologically different cells: plasmatocytes and crystal cells. It is well-established that in the lymph gland both cell types stem from a binary decision of the medullary prohaemocyte precursors. However, in sessile clusters and dorsal vessel, crystal cells have been shown to originate from the transdifferentiation of plasmatocytes in a Notch/Serrate-dependent manner. We show that transdifferentiation occurs also in the lymph gland. In vivo phagocytosis assays confirm that cortical plasmatocytes are functionally differentiated phagocytic cells. We uncover a double-positive population in the cortical zone that lineage-tracing and long-term live imaging experiments show will differentiate into crystal cells. The reduction of Notch levels within the lymph gland plasmatocyte population reduces crystal cell number. This extension of a transdifferentiation mechanism reinforces the growing role of haematopoietic plasticity in maintaining homeostasis in Drosophila and vertebrate systems. Future work should test the regulation and relative contribution of these two processes under different immunological and/or metabolic conditions.