Core Insights - The research conducted by Fudan University reveals a novel role of Acetyl-CoA as a "metabolic messenger" that directly regulates mitochondrial autophagy, providing a new therapeutic target for overcoming resistance to KRAS inhibitors in pancreatic cancer [1][7]. Group 1: Research Findings - The study highlights that during nutrient scarcity, Acetyl-CoA bypasses the well-known AMPK and mTOR pathways, directly signaling to mitochondria through the protein NLRX1 [1][2]. - The research team utilized CRISPR/Cas9 technology to identify NLRX1 as a key protein involved in this newly discovered signaling pathway [3][4]. - The interaction between Acetyl-CoA and NLRX1 was confirmed through a "molecular fishing" experiment, demonstrating a direct binding relationship [4][5]. Group 2: Implications for Cancer Treatment - The findings indicate that in nutrient-rich conditions, high levels of Acetyl-CoA inhibit mitochondrial autophagy by locking NLRX1 in a dormant state, while nutrient deprivation releases this inhibition, promoting autophagy [6][7]. - The study also uncovers a mechanism by which cancer cells develop resistance to KRAS inhibitors by activating mitochondrial autophagy in response to decreased Acetyl-CoA levels, suggesting a potential new treatment strategy [7][8]. - Targeting the Acetyl-CoA-NLRX1 axis could enhance the effectiveness of KRAS inhibitors, offering new hope for cancer patients facing treatment resistance [7][8].

Core Insights - The research published by Fudan University reveals a novel signaling function of Acetyl-Coenzyme A (AcCoA) in regulating mitophagy through the receptor NLRX1, independent of classical pathways like AMPK and mTOR [3][14][16] - This discovery provides new potential targets and strategies for overcoming resistance to KRAS inhibitors in cancer treatment [3][14][16] Group 1: Mechanism of AcCoA in Mitophagy - AcCoA levels decrease during nutrient deprivation, such as short-term fasting, leading to the activation of mitophagy [5][6] - NLRX1 is identified as a key mediator that directly binds to AcCoA, regulating its signaling role in mitophagy [8][11] Group 2: Experimental Validation - In animal models, fasting resulted in a significant decrease in AcCoA levels in tissues, correlating with increased mitophagy [11] - Supplementing with acetate or knocking out NLRX1 gene can block the fasting-induced mitophagy, indicating the critical role of AcCoA and NLRX1 in this process [11][12] Group 3: Implications for Cancer Treatment - The study indicates that KRAS inhibitors downregulate ACLY expression, reducing AcCoA levels and triggering NLRX1-dependent mitophagy, which may contribute to cancer cell resistance [14] - Short-term fasting may have dual effects in cancer treatment, potentially enhancing immune response while also promoting resistance through mitophagy [14][16] Group 4: Future Directions - Targeting the AcCoA-NLRX1 signaling axis may enhance cancer treatment efficacy and could have implications in various metabolic and neurodegenerative diseases [16]

Core Viewpoint - Urolithin A (UA) is a compound produced from foods rich in ellagitannins, such as pomegranates and raspberries, that activates mitophagy and improves mitochondrial health, showing potential in combating age-related immune decline and inflammation [3][4][7]. Group 1: Research Findings - A study published in Immunity demonstrated that UA can promote the expansion of T memory stem cells (Tscm), providing a rejuvenated immune system that can suppress cancer growth [3]. - A randomized, double-blind, placebo-controlled trial indicated that short-term oral administration of UA (1000 mg daily for 4 weeks) can regulate the composition and function of immune cells, supporting its potential against age-related immune decline [4][7]. - The trial involved 50 healthy middle-aged participants, with results showing that UA increased peripheral initial CD8+ T cells and improved their fatty acid oxidation capacity by 14.72 percentage points [7][8]. Group 2: Immune Cell Changes - UA treatment resulted in changes to the phenotype of CD8+ T cells, indicating a metabolic reprogramming of human immune cells [9][10]. - Enhanced mitochondrial biogenesis and an increase in peripheral blood CD56dim CD16bright NK cells were observed, along with improved TNF secretion and monocyte phagocytosis [11]. - Exploratory single-cell RNA sequencing revealed that UA drives transcriptional changes in immune cell populations, regulating pathways related to inflammation and metabolism [11][12]. Group 3: Overall Implications - Overall, the findings suggest that short-term supplementation of UA can modulate the composition and function of human immune cells, supporting its potential to counteract age-related immune decline and inflammatory aging [13].

Core Viewpoint - The research highlights the role of dietary flavonoid quercetin and its microbial metabolite DOPAC in enhancing CD8⁺ T cell anti-tumor immunity, suggesting DOPAC as a potential candidate for cancer immunotherapy [2][8]. Group 1: Mechanism of Action - Quercetin, when metabolized by gut microbiota, produces DOPAC, which enhances CD8⁺ T cell anti-tumor immunity through NRF2-mediated mitophagy [3][4]. - DOPAC binds directly to KEAP1 protein, disrupting its interaction with NRF2, thereby preventing KEAP1-mediated NRF2 degradation [4]. - Increased NRF2 activity leads to enhanced transcription of BNIP3, promoting mitophagy and improving the adaptability of CD8⁺ T cells in the tumor microenvironment [4][6]. Group 2: Synergistic Effects - DOPAC exhibits a synergistic effect with immune checkpoint blockade (ICB) therapy, further inhibiting tumor growth [5][6]. Group 3: Implications for Cancer Treatment - The findings underscore the importance of dietary nutrients and their microbial metabolites in regulating anti-tumor immune responses, positioning DOPAC as a promising candidate for cancer immunotherapy [8].

Core Insights - The article discusses the significant role of mitochondria in mammalian development and introduces a new method for enforced mitophagy that allows for the reduction or complete removal of mitochondria, revealing their influence on pluripotency and embryonic development [3][15]. Group 1: Research Findings - The study published by Professor Wu Jun's team at the University of Texas Southwestern Medical Center demonstrates that enforced mitophagy can lead to a reduction in mitochondrial quantity, which subsequently delays pre-implantation embryonic development in mice [3][11]. - The research indicates that pluripotent stem cells (PSCs) lacking mitochondria can survive for 3-5 days in vitro but cease to divide, suggesting that these cells can compensate for the absence of mitochondria by taking over energy production and other functions typically performed by mitochondria [8][13]. - The study also reveals that the enforced mitophagy method can be applied across different species and cell types, potentially opening new avenues for research and treatment of mitochondrial diseases [8][15]. Group 2: Methodology - The enforced mitophagy technique involves expressing the PRKN protein in cells, which promotes the degradation of dysfunctional mitochondria, followed by treatment with mitochondrial uncouplers to stimulate extensive mitophagy [6][8]. - The research team successfully generated PSCs devoid of mitochondria and assessed the gene expression changes, finding that 788 genes became less active while 1696 genes became more active, indicating a shift in cellular function [8][13]. - The study further explores the fusion of human PSCs with those from non-human primates, revealing that these hybrid cells selectively retain human mitochondrial DNA, demonstrating the interchangeability of mitochondrial support for pluripotency across species [9][13]. Group 3: Implications - The findings suggest that a significant reduction in mitochondrial content can hinder embryonic development, with a 65% loss leading to implantation failure and a 33% loss resulting in developmental delays [11][13]. - The research provides a powerful tool for investigating the roles of mitochondria in cellular functions, organ development, aging, and evolutionary biology, potentially impacting future therapeutic strategies for mitochondrial diseases [15].