Abstract Migrasomes are migration-dependent extracellular organelles that form on retraction fibers of migrating cells. Although they can enter the extracellular space, their biogenesis and membrane organization are distinct from those of conventional extracellular vesicle subtypes. They are involved in intercellular signaling, clearance of cellular material, and maintenance of mitochondrial homeostasis. Emerging evidence suggests their involvement in the development of kidney diseases, such as podocyte injury, membranous nephropathy, diabetic kidney disease (DKD), and renal cell carcinoma (RCC). Podocyte-derived migrasomes in urine have shown potential as non-invasive biomarkers for early detection of kidney injury, with levels correlating with PLA2R antigen expression in membranous nephropathy. In DKD, migrasomes may help mitigate oxidative stress by removing damaged mitochondria. In clear cell renal cell carcinoma, they appear to influence the tumor microenvironment, affecting disease progression and prognosis. However, research on migrasomes in kidney diseases is still in its early stages. Challenges, including an incomplete understanding of their mechanisms and a lack of standardized detection methods, limit clinical application. This review outlines recent advances in understanding migrasomes and explores their potential for early diagnosis, disease monitoring, and prognosis evaluation in kidney diseases, while discussing existing barriers to guide future research efforts.
Abstract Autophagy is the cell’s recycling system; it removes unwanted or dysfunctional cellular material, thereby preventing damage. Importantly, it is a key pro-survival pathway during periods of stress, for instance, during nutrient scarcity. As it can support nutrition during starvation, it is not surprising that autophagy is controlled by nutrient availability. As a result, diet-based strategies to modify autophagy have attracted considerable scientific and public interest, although what is presented to the public is often not supported by a solid scientific foundation. Evidence from animal models is compelling: several of these interventions robustly activate autophagy and are linked to improved lifespan and healthspan. Data from humans, however, are much more limited. Many human studies rely on measurement of steady-state levels of autophagy genes or proteins, metrics that do not independently establish pathway activity. Far fewer have measured autophagic ‘flux’, the more rigorous readout of turnover, and where they have, findings are often negative or inconclusive. Here, we review the human research on popular nutritional interventions purported to change autophagy—including prolonged fasting, intermittent fasting, calorie restriction, and altered macronutrient intake—and contrast these findings with the preclinical evidence that has shaped public expectations. We highlight key gaps in the literature, particularly the scarcity of flux-based measurements and the reliance on blood as a proxy for autophagy in other, less accessible tissues. Refining how we monitor autophagy in humans should be a key priority for the field and is ultimately needed to establish whether and how diet modulates human autophagy.
Abstract Plasma membrane rupture (PMR) is a terminal event in many forms of lytic cell death, yet was long regarded as a passive consequence of osmotic swelling and mechanical membrane failure. The identification of ninjurin-1 (NINJ1) as a key mediator of PMR fundamentally changed this view by establishing that membrane permeabilisation and terminal membrane rupture are mechanistically distinct processes. Across different cell death modalities, NINJ1 promotes the transition from membrane damage to catastrophic cellular disintegration. Structural studies have revealed how NINJ1 is restrained by autoinhibition in healthy cells and assembles into higher-order membrane-remodelling complexes following activation. However, how NINJ1 is activated and how its assemblies cooperate with the physical state of the dying cell to produce membrane rupture remain incompletely understood. NINJ1-dependent PMR also determines the release of intracellular contents, linking cell death to inflammation, host defence, tissue homeostasis and disease. Emerging evidence suggests that NINJ1 integrates molecular, metabolic and biophysical signals and can function beyond canonical cell-death pathways. Here, we discuss the molecular mechanisms governing NINJ1-mediated PMR, how diverse cell death pathways converge on this process, and how terminal membrane rupture shapes inflammatory responses, host defence and tissue pathology. We further consider unresolved mechanisms of NINJ1 activation and the therapeutic potential of uncoupling cell death from inflammatory membrane rupture.
Abstract A substantial portion of the proteome consists of intrinsically disordered regions (IDRs) that do not fold into well-defined structures. IDRs often comprise low-complexity domains (LCDs), whose repetitive, compositionally biased sequences drive multivalent interactions that can lead to liquid–liquid phase separation, forming biomolecular assemblies. These LCD-mediated assemblies play an important role in transcriptional control, and productive output depends not on their mere presence but on how strongly and selectively LCDs interact. The present review integrates the optimal-interaction, or ‘Goldilocks,’ principle with RNA polymerase II phosphorylation and RNA-mediated feedback into a unified mechanistic framework spanning the transcription cycle. We connect dysregulation of LCD-mediated multivalent interactions to pathological transcription in cancer, neurodegeneration, and developmental disorders, whether through oncogenic LCD fusions, disease-associated post-translational modifications, or mutations altering phase-separation propensity. We further summarize experimental approaches for studying LCD function, discuss current methodological limitations, and highlight directions for future research.
Inflammatory caspases play essential roles in regulating IL-1 cytokine processing and secretion, as well as in inducing pyroptosis as part of the innate immune response to pathogens and other noxious stimuli. While the activation of caspase-1 is controlled by dedicated pattern recognition receptors, human caspase-4 and caspase-5, and murine caspase-11 function themselves as direct sensors for lipopolysaccharide (LPS), the immunostimulatory component of the Gram-negative bacterial outer membrane. These caspases bind LPS through their N-terminal caspase recruitment domain (CARD), which triggers their oligomerization and activation. Recent studies have provided new insights into the molecular basis of LPS recognition by the caspase-4/11 CARD, including its interactions with LPS and other lipid ligands, the evolutionary origins of inflammatory caspases, the structural organization of LPS-caspase complexes, and the regulatory mechanisms that govern CARD-ligand association. In this review, we summarize these advances and discuss their implications for inflammatory caspase activation and innate immune signaling.
