ミトコンドリア病

Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which neutrophils, especially the pro-inflammatory low-density neutrophil (LDN) subset, play a central pathogenic role. Yet, the molecular mechanisms that link neutrophil ferroptosis, degranulation, and interferon amplification remain incompletely understood. Through integrative bioinformatics and validation in clinical samples, we identified acyl-CoA synthetase long-chain family member 1 (ACSL1) as a pivotal regulator in SLE. ACSL1 expression was consistently elevated in patient-derived neutrophils, with the highest levels observed in LDNs. Elevated ACSL1 strongly correlated with signatures of ferroptosis, mitochondrial dysfunction, neutrophil degranulation, and type I interferon responses. Single-cell RNA sequencing further revealed ACSL1 enrichment along the trajectory of neutrophil differentiation toward a transcriptional state consistent with pathogenic LDNs, suggesting a potential role in shaping their inflammatory phenotype that warrants further experimental validation. Importantly, molecular docking identified several small-molecule compounds, including the FDA-approved drug fenofibrate, with strong predicted binding to ACSL1. Together, these findings establish ACSL1 as a novel dual regulator orchestrating ferroptosis and degranulation in LDNs, thereby bridging mitochondrial dysfunction with aberrant immune activation in SLE. Targeting ACSL1 may represent a feasible approach to restrain neutrophil-driven inflammation with reduced risk of broad immunosuppression, highlighting its potential as a precision therapeutic target in systemic lupus erythematosus and related autoimmune conditions.

Mitochondria-associated endoplasmic reticulum membranes (MAMs), functional domains within endoplasmic reticulum (ER)-mitochondria contact sites, provide spatial domains through which ER-derived Ca²⁺ signals are coupled to mitochondrial metabolism, redox balance, and stress adaptation. In asthma, this concept is relevant because many disease-associated stimuli, including allergens, cytokines, oxidative stress, infection-related signals, and mechanical stress, disturb both ER and mitochondrial homeostasis. However, MAMs should not be used as a general label for all ER stress or mitochondrial dysfunction. Their unique value lies in explaining how selected stress signals are organized at sites of ER-mitochondria communication. This review critically evaluates whether MAM-related mechanisms contribute to asthma pathogenesis and where the current evidence remains indirect. The strongest asthma-relevant support is found in monocyte/macrophage-centered inflammatory responses, in which ER-mitochondria Ca²⁺ transfer, mitochondrial stress, and inflammasome activation may be functionally connected. In airway epithelial cells and airway smooth muscle cells (ASMCs), available studies more consistently support mitochondrial dysfunction, Ca²⁺ dysregulation, oxidative stress, barrier injury, cell death, and remodeling-related responses, but direct evidence that these changes are initiated by defined MAM remodeling remains limited. We therefore distinguish MAM-specific mechanisms from MAM-adjacent ER or mitochondrial stress responses across different asthma-relevant cell types. By organizing the literature around ER-to-mitochondria Ca²⁺ transfer, contact-site remodeling, mitochondrial stress signaling, and cell type-specific inflammatory or remodeling outcomes, this review highlights both the potential importance and the current limitations of MAM biology in asthma. Future studies should combine structural assessment of ER-mitochondria contacts with functional readouts of Ca²⁺ transfer, mitochondrial redox state, mitophagy, inflammasome activation, and disease-relevant cellular phenotypes. Such work will be essential to determine whether MAMs are causal regulators of asthma pathology or stress-responsive interfaces associated with broader organelle dysfunction.

According to the World Health Organization (WHO), approximately 6% of COVID-19 cases develop serious long-term sequelae referred to as post-COVID-19 condition (PCC). Immunological disturbances such as persistent activation of immune cells and reduced cytotoxicity by natural killer (NK) cells are reported as key aspects in PCC. Recently, electrophysiological studies by our group demonstrated impairment of transient receptor potential melastatin 3 (TRPM3) ion channels in NK cells from PCC patients. The significant reduction in TRPM3 channel function and reduced functional activity by NK cells warrants further investigation. Hence, using live cell calcium (Ca2+) imaging ex vivo, we examined the downstream impact of TRPM3 ion channel dysfunction on intracellular and mitochondrial Ca2+ mobilization in NK cells from N = 8 PCC patients, age and sex matched to N = 8 PCC healthy controls (HC). Our findings provide new evidence of altered passive and TRPM3-mediated Ca2+ influx, significantly impacting cytoplasmic and mitochondrial Ca2+ mobilization in PCC. Passive cytosolic Ca2+ influx amplitude (p < 0.0001) was significantly reduced in PCC; however, passive mitochondrial Ca2+ mobilization (p < 0.0001) was significantly increased. Importantly, cytoplasmic and mitochondrial response rates (slope, p < 0.001) to pregnenolone sulphate stimulation were significantly reduced in PCC. Consequently, TRPM3-dependent cytosolic (p < 0.001) and mitochondrial (p < 0.0005) Ca2+ mobilization were significantly reduced in PCC compared with HC. Altered ion channel Ca2+ signalling can severely impact both the immune system and bioenergetic processes, potentially leading to broader systemic dysregulations underpinning the pathomechanism of the PCC condition, and warrants further investigations.

The tight regulation of bidirectional solute flux between the systemic circulation and neural tissue by the blood-brain barrier (BBB) remains a principal obstacle to effective pharmacotherapy of the central nervous system. In this study, we evaluate the biocompatibility and biodistribution of a novel third-generation PEGylated carbosilane dendrimer (G3Si PEG6000) and its siRNA dendriplex with an APOE4-directed siRNA relevant to late-onset Alzheimer's disease using a tiered, upstream strategy that progresses from BBB-relevant monocultures to a capillary-weighted BBB model and in vivo/ex vivo biodistribution in mice, in accordance with current recommendations for nanomaterial testing. In endothelial cells, pericytes, and astrocytes, mitochondrial/redox profiling (MTT, DCF-ROS, and JC-1 ΔΨm) defined tolerated exposure ranges. Complexation with siRNA consistently attenuated apparent cytotoxicity across cell types, yet both free and complexed formulations elicited modest ROS and dose-dependent ΔΨm depolarization, indicating persistent mitochondrial stress. In the BBB model, responses were concentration- and formulation-dependent: 10 µM free dendrimers produced sustained impedance and nuclear confluence loss with sheet-like detachment, whereas the 0.1-2.5 µM free dendrimer and the dendriplex induced transient, recoverable perturbations or increases in impedance and proliferation. In vivo, whole-body IVIS imaging demonstrated prolonged systemic exposure for the dendriplex and an ex vivo kidney-dominant, liver-secondary distribution; no robust dendriplex signal was detected in brain fluorescence by planar NIR-I IVIS under the applied acquisition conditions. Collectively, these data indicate that siRNA complexation broadens the functional window at the BBB model with partially recoverable barrier effects and improved systemic exposure, while not substantially reducing mitochondrial or oxidative stress responses. The results provide a mechanistically informed basis for dose optimization and efficacy testing of this dendrimer-siRNA platform in CNS indications and for advancing this platform in further investigations targeting Alzheimer's disease.

Serious non-AIDS events (SNAEs), including non-AIDS malignancies, cardiovascular disease, and hepatic complications, remain major causes of mortality in treated HIV infection. These outcomes are driven by persistent immune activation, systemic inflammation, and metabolic dysfunction despite effective viral suppression with antiretroviral therapy (ART). To investigate mechanisms underlying SNAE pathogenesis, we performed a cross-site multi-omic analysis integrating plasma proteins, plasma metabolites, and mucosal microbiomes in 82 ART-treated people with HIV (PWH) and 10 people without HIV from the United States and Mexico. Geography was the dominant source of variation, particularly across lipid classes. However, individuals at high risk for SNAEs, defined by low CD4+ T cell counts and low CD4/CD8 ratios, shared a consistent signature of systemic inflammation, mitochondrial dysfunction, and microbial dysbiosis, including elevated plasma IL-6 and ω-oxidation products (adipic and suberic acids) and depletion of short-chain fatty acid-producing commensals in the gut mucosa, including Akkermansia muciniphila, Bacteroides uniformis, and Ruminococcus. A. muciniphila abundance correlated with lower IL-6 levels, fewer HIV RNA-producing cells in lymph nodes, and higher CD4/CD8 ratios. These findings identify a shared inflammatory and metabolic phenotype in PWH and implicate A. muciniphila as a potential microbiome-based target to mitigate immune activation and SNAE risk in treated HIV.