Executioner caspases restrict mitochondrial RNA-driven Type I IFN induction during chemotherapy-induced apoptosis

Abstract

During apoptosis, mitochondrial outer membrane permeabilization (MOMP) enables certain mitochondrial matrix macromolecules to escape into the cytosol. However, the fate of mitochondrial RNA (mtRNA) during apoptosis is unknown. Here, we demonstrate that MOMP results in the cytoplasmic release of mtRNA and that executioner caspases-3 and -7 (casp3/7) prevent cytoplasmic mtRNA from triggering inflammatory signaling. In the setting of genetic or pharmacological casp3/7 inhibition, apoptotic insults result in mtRNA activation of the MDA5/MAVS/IRF3 pathway to drive Type I interferon (IFN) signaling. This pathway is sufficient to activate tumor-intrinsic Type I IFN signaling in immunologically cold cancer models that lack an intact cGAS/STING signaling pathway, promote CD8+ T-cell-dependent anti-tumor immunity, and overcome anti-PD1 refractoriness in vivo. Thus, a key function of casp3/7 is to inhibit inflammation caused by the cytoplasmic release of mtRNA, and pharmacological modulation of this pathway increases the immunogenicity of chemotherapy-induced apoptosis.

Surface-Charge-Driven Ferroptosis and Mitochondrial Dysfunction Is Involved in Toxicity Diversity in the Marine Bivalve Exposed to Nanoplastics

“…NPs are known to influence immune responses in diverse organisms, and this is particularly relevant for clams, which primarily rely on innate, nonlymphoid immune functions such as phagocytosis to mitigate stress. ,− This aspect was confirmed by both GO and KEGG analyses (Data Set S3). DEGs, as evident in the presented data, were chiefly engaged in processes like protein digestion and autophagy, with those related to mitochondrial functionsuch as ATP generation and mitochondrial respiratory chainbeing significantly enriched in the p-NP group (Figure d,e), highlighting a connection to mitochondrial and associated complications like energy production anomalies and cell death. , …”

“…Notably, clams exposed to p-NPs showed heightened apoptosis. , Similarly, high-dose n-NPs also induced apoptosis, albeit to a lesser extent compared with p-NP exposure. The mitochondrial route, often activated under stress conditions, is a primary initiator of apoptosis. ,, The study found that p-NPs intensified ROS production in R. philippinarum, activating this mitochondrial route.…”

“…Conversely, proteins related to purine metabolism (important for cell signaling) and ECM–receptor interaction (known regulators of autophagy) are implicated in clams’ ability to cope with n-NP stress. , Furthermore, our proteomic analysis unveiled that the p-NPs enhanced ferroptosis, marked by iron-dependent lipid peroxidation (Figure d). This form of cell death is associated with inflammation-related processes and may result from mitochondrial dysfunction. , While ferroptosis and mitochondrial dysfunction are not directly correlated, mitochondrial dysfunction can lead to cellular conditions that favor ferroptosis. , The proteomics-based protein–protein interaction (PPI) network highlighted glycogen phosphorylase protein as critical in the metabolic processes induced by p-NPs (Figure f). In the n-NP group, proteins with the highest centrality were the upstream in-frame stop codon and glyceraldehyde-3-phosphate dehydrogenase, indicating their pivotal role in maintaining system balance in n-NP-treated bivalves (Figure g and Figure S6c, and Data Set S6).…”

“…Prolonged imbalances in intracellular redox can trigger cell death processes like ferroptosis, which are closely linked to mitochondrial dysfunction. , Cells treated with p-NPs (≥5.4 × 10 10 particles/mL) displayed distinct alterations in mitochondrial ultrastructure, including mitochondrial shrinkage, increased membrane density, and fractured or missing mitochondrial cristae (Figure a). These changes in mitochondrion can have a significant impact on various cellular processes, including cell signaling and energy metabolism. ,, Additionally, we assessed mitochondrial membrane potential (MMP), a crucial parameter reflecting ferroptosis and mitochondrial health. , In control cells, the JC-1 dye predominantly exhibited polymerization (indicated by red dots). However, in cells treated with p-NPs, the green fluorescence intensity increased (Figure b,c and Figure S7j), indicating a decline in MMP. , Moreover, the ADP/ATP ratio in cells cocultured with p-NPs was significantly elevated (Figure d).…”

“…The mitochondrial route, often activated under stress conditions, is a primary initiator of apoptosis. 7,31,36 for external substance interaction, displayed toxic impacts of NPs. Specifically, clams exposed to a high dose of NPs exhibited clear gut and ciliary damage, manifesting as harm to the epithelial cells, mucous, and mucosal layers.…”