An acidic lysosomal lumen (pH ~4.5) is essential for the degradative and signaling functions of this organelle, which serves as a central hub for cellular homeostasis. Lysosome pH (pHlys), however, is not static but dynamically regulated by the coordinated action of the V-ATPase, counterion fluxes, membrane composition, and nutrient-sensitive signaling networks.
This review integrates recent advances in the molecular mechanisms regulating pHlys with emerging insights on how dysregulated pHlys contributes to pathologies in neurodegenerative disorders, lysosomal storage diseases, and cancers with changes in lumenal proteolytic activity and macromolecular degradation.
We discuss how pHlys acts as both a sensor and effector in lysosome biology, shaping transcriptional responses, membrane trafficking, and stress adaptation. We also review tools to measure pHlys, ranging from fluorescent dyes to genetically encoded biosensors and nanomaterial-based probes, and evaluate their use in disease-modeling applications.
By highlighting pHlys as a nodal point in cellular functions, this review underscores the relevance of pHlys as a diagnostic marker and therapeutic target. Restoring pHlys in diseases offers translational potential to re-establish proteostasis and limit associated pathologies.
Mitochondrial dysfunction plays a central role in multiple neurodegenerative diseases, yet the temporal sequence of cellular events underlying neurodegeneration remains poorly defined. This study aimed to characterize the progression of neurodegeneration in a mouse model of fatal mitochondrial encephalopathy and to evaluate the therapeutic potential of oral N-acetylglucosamine supplementation.
A mouse model of primary coenzyme Q deficiency was used to examine neurodegeneration at presymptomatic, symptomatic and terminal stages. Neuronal integrity, glial activation, myelination and inflammatory responses were assessed using histological, molecular and ultrastructural approaches, together with behavioral analysis of motor coordination. N acetylglucosamine was administered orally from 1 month of age, and its effects on neuroinflammation, myelin integrity and motor performance were evaluated.
Astrocyte activation and neuronal loss were detected before the onset of clinical symptoms, whereas proinflammatory microglia appeared at later disease stages. Early myelin abnormalities were accompanied by an initial increase in oligodendrocyte precursor cells, suggesting a compensatory response to early myelin stress. Oral N-acetylglucosamine supplementation reduced glial activation and neuroinflammatory markers, likely through modulation of inflammatory signaling pathways. Although treatment did not fully reverse structural damage or restore myelin protein expression, it led to a significant improvement in motor coordination.
These findings define a temporal sequence of early glial activation, neuronal loss, and myelin alterations in mitochondrial encephalopathy. Targeting glial responses and neuroinflammation at early disease stages may mitigate neurodegenerative progression and improve functional outcomes, highlighting a physiologically relevant therapeutic window for mitochondrial disorders.
Controversy exists on which metabolites determine the exaggerated exercise pressor reflex (EPR) in peripheral artery disease (PAD). In decerebrated rats, we investigated the role played by lactate and hydrogen ions in a model of PAD, which was simulated by ligating the femoral artery for 72 h before the start of the experiment.
Production of lactate and hydrogen ions by the contracting hindlimb muscles was manipulated by knocking out the myophosphorylase gene (pygm). In both knockout (pygm−/−; n = 13; 6-females) and wild-type rats (pygm+/+; n = 14; 7-females), the EPR was evoked by statically contracting the triceps-surae muscles. Blood pressure, tension, and renal sympathetic nerve activity were measured. Responsiveness of the metabolic component of the EPR was evaluated by intra-arterial injections of lactic acid and diprotonated phosphate solutions. Responsiveness of the mechanical component of the EPR was evaluated by stretching the calcaneal tendon. In each rat, the pressor responses evoked from the freely perfused triceps-surae muscles were compared to those evoked from the contralateral ischemic triceps-surae muscles.
In pygm+/+ rats whose femoral artery was ligated, static contraction, lactic-acid injection and diprotonated phosphate injection evoked pressor responses that were 88%, 22%, and 58% greater than those evoked from muscles whose femoral arteries were freely perfused. In pygm−/− rats, ligation of the femoral artery for 72 h had no effect. In both groups, 72 h of femoral artery ligation exacerbated the pressor response to passive stretch.
Lactate and hydrogen-ions accumulation in contracting myocytes plays a key role in exaggerating the metabolic component of the EPR evoked from hindlimb muscles with chronically-ligated femoral arteries.
Alström syndrome 1 (ALMS1) is a protein linked to Alström syndrome, a rare genetic disorder characterized by obesity, insulin resistance, hyperinsulinemia, and hypertension. Genetic studies have further associated Alms1 with hypertension in human populations. However, the precise mechanisms by which ALMS1 regulates metabolic and cardiovascular function remain unclear.
In this study, we investigate metabolic and cardiovascular functions regulated by ALMS1.
To investigate this, we developed and characterized an Alms1 knockout (KO) rat model, which spontaneously develops metabolic syndrome and hypertension.
Our findings reveal that Alms1 KO rats exhibit age-dependent metabolic dysfunction, with hypertension and increased body weight becoming evident by 10–12 weeks of age. Obesity, hyperinsulinemia, and vascular dysfunction emerge later, at 14–16 weeks, suggesting progressive metabolic deterioration. Notably, Alms1 KO rats develop hyperleptinemia as early as 7 weeks, prior to the onset of obesity, implicating ALMS1 in early leptin regulation and metabolic signaling. Moreover, female Alms1 KO rats develop severe metabolic syndrome with hypertension, like males, demonstrating a lack of the typical female cardiovascular protection. Echocardiographic analysis shows progressive cardiac dysfunction, including left ventricular (LV) dilation, increased wall thickness, and impaired contractility. Despite these structural changes, the LV mass/BW ratio remains unchanged, suggesting a shift toward maladaptive eccentric remodeling rather than hypertrophy.
Collectively, these findings establish the Alms1 KO rat as a robust preclinical model of metabolic syndrome. This model closely mimics human disease and provides a powerful tool for studying the mechanisms of metabolic and cardiovascular dysfunction as well as for testing potential therapeutic interventions.
The current understanding of the underlying pathogenesis of depression is still limited. Silent information regulator 1 (SIRT1) has been shown to mediate the development of depression. However, the underlying mechanisms are not well understood.
SIRT1flox/flox mice were used to observe the effect of selective knockdown of SIRT1 in glutamatergic or GABAergic neurons of the central amygdala (CeA) on depression-like behaviors. Western blot and immunofluorescence staining were used to determine the protein levels. Optogenetic technology was used to manipulate neuronal excitability. Whole cell patch-clamp recordings and c-Fos immunofluorescence staining were used to detect the excitability of different types of neurons.
Our study demonstrated that selective knockdown of SIRT1 in CeA glutamatergic neurons induced depression-like behaviors and increased the excitability of glutamatergic neurons in mice. Optogenetic inhibition of glutamatergic neurons in CeA significantly ameliorated the depression-like behaviors induced by downregulation of SIRT1 in CeA glutamatergic neurons. In addition, selective knockdown of SIRT1 in CeA GABAergic neurons could also induce depression-like behaviors, accompanied by decreased excitability of GABAergic neurons and increased excitability of glutamatergic neurons. Optogenetic activation of GABAergic neurons in CeA significantly alleviated the depression-like behaviors induced by downregulation of SIRT1 in CeA GABAergic neurons.
Our findings indicate that cell-type-specific loss of SIRT1 may mediate the development of depression-like behaviors in mice by divergent changes in the excitability of CeA glutamatergic and GABAergic neurons. These data demonstrate a new mechanism for the development of depression and provide a potential therapeutic target for depression.
The glomerulus is a specialized microvascular unit that filters plasma through the coordinated function of podocytes and parietal epithelial cells (PECs). From this perspective, the glomerulus functions like a living hydrogeological filtration system. This review aims to integrate mechanobiology and hydrogeology, reframing podocytes and PECs as active regulators in a pressure-driven network, with Piezo1 central to glomerular homeostasis, adaptation, and pathology.
This review integrates existing literature on glomerular biology, mechanosensitive signaling, and epithelial cell function, focusing on podocytes, PECs, and mechanosensitive structures such as the Piezo1 channel.
Podocytes form interdigitating foot processes connected by the slit diaphragm, forming both a selective barrier against protein loss and a mechanosensory interface. Through mechanosensitive structures, such as the Piezo1 channel, podocytes detect variations in hydrostatic pressure and transduce these cues into intracellular signaling that regulates permeability and preserves structural integrity. Sustained mechanical stress, however, can compromise podocyte function and viability. PECs line Bowman capsule, forming an impermeable boundary surrounding the filtration core. Once considered passive, PECs exhibit dynamic properties: some retain progenitor-like potential, contributing to repair, whereas others promote fibrosis in disease conditions. In this analogy, blood flow replaces groundwater while the multilayered filtration barrier mirrors stratified geological formations. Podocytes function as biological piezometers—sensing pressure and modulating filtration—while PECs resemble aquicludes, defining impermeable boundaries that can constrain or reshape the system under mechanical or inflammatory challenges.
By integrating mechanobiology and hydrogeology, this review reframes the glomerulus as a living, pressure-driven filtration system in which podocytes and PECs act as active regulators rather than passive structural elements, with Piezo1 playing a central role in glomerular homeostasis, adaptation, and pathology.
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：