Disrupted Calcium Signaling, Fluid Secretion, and Mitochondrial Function in an Early Sjögren's Syndrome Mouse Model

核心概念

Early Sjögren's syndrome is characterized by dysregulated calcium signaling, reduced activation of the calcium-activated chloride channel TMEM16a, and compromised mitochondrial function, contributing to salivary gland hypofunction.

摘要

The study investigates the early cellular events in acinar cells during the initiation of Sjögren's syndrome (SS) using a mouse model induced by activation of the stimulator of interferon gene (STING) pathway.
Key highlights:

Activation of the STING pathway in mice leads to a significant reduction in saliva production from both the submandibular and parotid glands, mimicking the early stages of SS.
Despite the reduced fluid secretion, the magnitude of the calcium signals evoked by neural stimulation was paradoxically enhanced in the SS mouse model. However, the spatiotemporal characteristics of the calcium signals were disrupted, with a more global distribution of calcium throughout the cell rather than the typical apically confined signals.
The reduced fluid secretion was not due to changes in the expression or localization of the calcium-activated chloride channel TMEM16a. However, the activity of TMEM16a stimulated by muscarinic agonists was significantly decreased in the SS model.
Super-resolution microscopy revealed a disruption in the close spatial relationship between the apical endoplasmic reticulum IP3 receptors and the apical plasma membrane TMEM16a, which may contribute to the reduced TMEM16a activity.
The SS model also exhibited significant alterations in mitochondrial morphology, including reduced numbers, increased fragmentation, and decreased branching. Mitochondrial function was also compromised, with reduced membrane potential and oxygen consumption rates.
These findings suggest that early in the development of SS, dysregulated calcium signaling, reduced activation of the TMEM16a chloride channel, and compromised mitochondrial function contribute to the salivary gland hypofunction, potentially setting the stage for the progression of the disease.

統計資料

Saliva production was reduced from 130.1± 48.96 mg in vehicle-treated mice to 63.71± 30.41 mg in DMXAA-treated mice, a 48.97% reduction.
Saliva production in DMXAA-treated mice was 51.99% of that in vehicle-treated mice.
The peak calcium signal was significantly enhanced in DMXAA-treated mice compared to vehicle controls.
The distance between apical TMEM16a and IP3R3 increased from 84 ± 17 nm in controls to 155 ± 20 nm in the SS model.
Mitochondrial number was reduced by 22.16% ± 4.95 in the SS model compared to controls.
Mitochondrial basal respiration rate was reduced by 25% and maximal respiration rate was reduced by 47% ± 9.19 in the SS model.

引述

"Notably, however, in the disease model, the spatiotemporal characteristics of the Ca2+ signals were altered to result in global rather than largely apically confined Ca2+ rises observed physiologically."
"Notwithstanding the augmented Ca2+ signals, muscarinic stimulation resulted in reduced activation of TMEM16a, although there were no changes in channel abundance or absolute sensitivity to Ca2+."
"Disrupted mitochondrial morphology, a depolarized mitochondrial membrane potential, and reduced oxygen consumption rate were observed in DMXAA-treated animals compared to control animals."

從以下內容提煉的關鍵洞見

Dysregulated Ca2+ signaling, fluid secretion, and mitochondrial function in a mouse model of early Sjögren’s syndrome

by Huang,K.-T.,... 於 www.biorxiv.org 03-19-2024

https://www.biorxiv.org/content/10.1101/2024.03.19.585719v1

深入探究

How might the disrupted calcium signaling and mitochondrial dysfunction observed in this early stage of Sjögren's syndrome contribute to the progression of the disease over time

The disrupted calcium signaling and mitochondrial dysfunction observed in the early stage of Sjögren's syndrome could contribute to the progression of the disease over time through several mechanisms. Firstly, altered calcium signaling can impact the secretion of fluid by salivary glands, leading to dry mouth, a hallmark symptom of Sjögren's syndrome. Dysregulated calcium levels can disrupt the activation of ion channels involved in fluid secretion, such as TMEM16a, ultimately reducing saliva production. This reduction in saliva can further exacerbate oral health issues and increase the risk of infections in the oral cavity, which are common complications of Sjögren's syndrome. Additionally, calcium signaling is crucial for mitochondrial function, and disturbances in calcium homeostasis can lead to mitochondrial dysfunction. Impaired mitochondrial function can result in decreased energy production, oxidative stress, and altered cellular metabolism, all of which can contribute to the progression of Sjögren's syndrome. Furthermore, disrupted calcium signaling and mitochondrial dysfunction can trigger inflammatory responses and immune system dysregulation, which are key features of autoimmune diseases like Sjögren's syndrome. Chronic inflammation and immune system activation can further damage salivary glands and exacerbate the symptoms of the disease, leading to its progression over time.

What other cellular processes or pathways, beyond calcium signaling and mitochondrial function, could be impacted by the activation of the STING pathway and contribute to the development of Sjögren's syndrome

Beyond calcium signaling and mitochondrial function, the activation of the STING pathway in Sjögren's syndrome can impact various cellular processes and pathways that contribute to the development and progression of the disease. One such pathway is the type I interferon response, which is a hallmark of autoimmune diseases like Sjögren's syndrome. Activation of the STING pathway leads to the production of type I interferons, which can trigger inflammatory responses and immune cell infiltration in the salivary glands, contributing to glandular damage and dysfunction. Additionally, the STING pathway can modulate the expression of genes involved in immune regulation, apoptosis, and cell proliferation, all of which play a role in the pathogenesis of Sjögren's syndrome. Furthermore, STING activation can induce oxidative stress and DNA damage, leading to cellular dysfunction and tissue injury in the salivary glands. Overall, the activation of the STING pathway in Sjögren's syndrome can have broad effects on cellular processes beyond calcium signaling and mitochondrial function, contributing to the development and progression of the disease.

Could therapeutic strategies targeting the restoration of calcium signaling dynamics or mitochondrial function be effective in preventing or slowing the progression of Sjögren's syndrome

Therapeutic strategies targeting the restoration of calcium signaling dynamics or mitochondrial function could be effective in preventing or slowing the progression of Sjögren's syndrome. Restoring proper calcium signaling dynamics, such as maintaining the spatial and temporal characteristics of calcium signals in salivary gland cells, could help improve fluid secretion and alleviate dry mouth symptoms in patients with Sjögren's syndrome. This could involve modulating the activity of ion channels like TMEM16a or enhancing the communication between calcium release channels and effector proteins in the secretory machinery. Similarly, interventions aimed at improving mitochondrial function, such as promoting mitochondrial biogenesis, reducing oxidative stress, or enhancing ATP production, could help mitigate the cellular damage and metabolic alterations associated with Sjögren's syndrome. By targeting these key cellular processes, therapeutic strategies could potentially address the underlying mechanisms driving the progression of Sjögren's syndrome and improve the quality of life for affected individuals.