Discovering and targeting mitochondrial loss in NOTCH1-related aortic aneurysm
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Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
The dual role of PGAM5 in inflammation
In recent years, the focus on human inflammation in research has increased, with aging-related inflammation widely recognized as a defining characteristic of aging. Inflammation is strongly correlated with mitochondrial dysfunction. Phosphoglycerate mutase family member 5 (PGAM5) is a novel modulator of mitochondrial homeostasis in response to mechanical stimulation. Here we review the structure and sublocalization of PGAM5, introduce its importance in programmed cell death and summarize its crucial roles in the development and progression of inflammatory diseases such as pneumonia, hepatitis, neuroinflammation and aging. Notably, PGAM5 has dual effects on controlling inflammation: distinct PGAM5-mediated mitochondrial functions exhibit cellular heterogeneity, leading to its dual functions in inflammation control. We therefore highlight the double-edged sword nature of PGAM5 as a potential critical regulator and innovative therapeutic target in inflammation. Finally, the challenges and future directions of the use of PGAM5, which has dual properties, as a target molecule in the clinic are discussed. This review provides crucial insights to guide the development of intelligent therapeutic strategies targeting PGAM5-specific regulation to treat intractable inflammatory conditions, as well as the potential extension of its broader application to other diseases to achieve more precise and effective treatment outcomes.
SLC5A3 depletion promotes apoptosis by inducing mitochondrial dysfunction and mitophagy in gemcitabine-resistant pancreatic cancer cells
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor prognosis, largely due to the rapid development of chemoresistance in patients. Mitochondrial dynamics play a crucial role in cancer cell survival. Currently, the specific mechanisms underlying gemcitabine resistance in PDAC remain unknown. In this study, we identified the sodium/myo-inositol co-transporter solute carrier family 5 member 3 (SLC5A3) as a key modulator promoting chemoresistance in PDAC. SLC5A3 levels were significantly upregulated in gemcitabine-resistant PDAC cells, enhancing their cell survival by stabilizing the mitochondrial functions and inhibiting apoptosis. Mitochondrial analysis showed that SLC5A3 inhibition disrupted the mitochondrial dynamics, leading to increased reactive oxygen species production, mitochondrial fission, and impaired oxidative phosphorylation. Moreover, SLC5A3 inhibition activated the PTEN-induced kinase 1/Parkin-mediated mitophagy pathway, resulting in the excessive removal of damaged and healthy mitochondria, thereby depleting the mitochondrial reserves and sensitizing the cells to apoptosis. In vivo studies revealed that targeting SLC5A3 enhanced the efficacy of gemcitabine and significantly reduced the tumor growth. Collectively, these results suggest SLC5A3-mediated mitochondrial regulation as a promising therapeutic strategy to overcome gemcitabine resistance in PDAC.
Mitochondrial priming and response to BH3 mimetics in “one-two punch” senogenic-senolytic strategies
A one-two punch sequential regimen of senescence-inducing agents followed by senolytic drugs has emerged as a novel therapeutic strategy in cancer. Unfortunately, cancer cells undergoing therapy-induced senescence (TIS) vary widely in their sensitivity to senotherapeutics, and companion diagnostics to predict the response of TIS cancer cells to a specific senolytic drug are lacking. Here, we hypothesized that the ability of the BH3 profiling assay to functionally measure the mitochondrial priming state—the proximity to the apoptotic threshold—and the dependencies on pro-survival BCL-2 family proteins can be exploited to inform the sensitivity of TIS cancer cells to BH3-mimetics. Replicative, mitotic, oxidative, and genotoxic forms of TIS were induced in p16-null/p53-proficient, BAX-deficient, and BRCA1-mutant cancer cells using mechanistically distinct TIS-inducing cancer therapeutics, including palbociclib, alisertib, doxorubicin, bleomycin, and olaparib. When the overall state of mitochondrial priming and competence was determined using activator peptides, the expected increase in overall mitochondrial priming was an exception rather than a generalizable feature across TIS phenotypes. A higher level of overall priming paralleled a higher sensitivity of competent TIS cancer cells to BCL-2/BCL-xL- and BCL-xL-targeted inhibitors when comparing TIS phenotypes among themselves. Unexpectedly, however, TIS cancer cells remained equally or even less overally primed than their proliferative counterparts. When sensitizing peptides were used to map dependencies on anti-apoptotic BCL-2 family proteins, competent TIS cancer cells appeared to share a dependency on BCL-xL. Furthermore, regardless of senescence-inducing therapeutic, stable/transient senescence acquisition, or genetic context, all TIS phenotypes shared a variable but significant senolytic response to the BCL-xL-selective BH3 mimetic A1331852. These findings may help to rethink the traditional assumption of the primed apoptotic landscape of TIS cancer cells. BCL-xL is a conserved anti-apoptotic effector of the TIS BCL2/BH3 interactome that can be exploited to maximize the efficacy of “one-two punch” senogenic-senolytic strategies.
AAV library screening identifies novel vector for efficient transduction of human aorta
Targeted gene delivery to vascular smooth muscle cells (VSMCs) could prevent or improve a variety of diseases affecting the vasculature and particularly the aorta. Thus, we aimed to develop a delivery vector that efficiently targets VSMCs. We selected engineered adeno-associated virus (AAV) capsids from a random AAV capsid library and tested the top enriched motifs in parallel screening through individual barcoding. This approach allowed us to distinguish capsids that only transduce cells based on genomic DNA (gDNA) from those also mediating transgene expression based on transcribed cDNA reads. After three rounds of selection on primary murine VSMCs (mVSMCs), we identified a novel targeting motif (RFTEKPA) that significantly improved transduction and gene expression efficiency over AAV9-wild type (WT) and increased expression in mVSMCs by 70% compared to the previously identified SLRSPPS peptide. Further analysis showed that the novel motif also improved expression in human aortic smooth muscle cells (HAoSMCs) and human aortic tissue ex vivo up to threefold compared to SLRSPPS and approximately 70-fold to AAV9-WT. This high cross-species transduction efficiency makes the novel capsid motif a potential candidate for future clinical application in vascular diseases.
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