bims-mitdyn 2024-09-15 papers

Nat Cell Biol. 2024 Sep 11.

Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells.

Huafeng Zhang, Jincheng Liu, Wu Yuan, Qian Zhang, Xiao Luo, Yonggang Li, Yue'e Peng, Jingyu Feng, Xiaoyu Liu, Jie Chen, Yabo Zhou, Jiadi Lv, Nannan Zhou, Jingwei Ma, Ke Tang, Bo Huang.

Ammonia is thought to be a cytotoxin and its increase in the blood impairs cell function. However, whether and how this toxin triggers cell death under pathophysiological conditions remains unclear. Here we show that ammonia induces a distinct form of cell death in effector T cells. We found that rapidly proliferating T cells use glutaminolysis to release ammonia in the mitochondria, which is then translocated to and stored in the lysosomes. Excessive ammonia accumulation increases lysosomal pH and results in the termination of lysosomal ammonia storage and ammonia reflux into mitochondria, leading to mitochondrial damage and cell death, which is characterized by lysosomal alkalization, mitochondrial swelling and impaired autophagic flux. Inhibition of glutaminolysis or blocking lysosomal alkalization prevents ammonia-induced T cell death and improves T cell-based antitumour immunotherapy. These findings identify a distinct form of cell death that differs from previously known mechanisms.

DOI: https://doi.org/10.1038/s41556-024-01503-x

EMBO J. 2024 Sep 11.

Systematic mapping of mitochondrial calcium uniporter channel (MCUC)-mediated calcium signaling networks.

The mitochondrial calcium uniporter channel (MCUC) mediates mitochondrial calcium entry, regulating energy metabolism and cell death. Although several MCUC components have been identified, the molecular basis of mitochondrial calcium signaling networks and their remodeling upon changes in uniporter activity have not been assessed. Here, we map the MCUC interactome under resting conditions and upon chronic loss or gain of mitochondrial calcium uptake. We identify 89 high-confidence interactors that link MCUC to several mitochondrial complexes and pathways, half of which are associated with human disease. As a proof-of-concept, we validate the mitochondrial intermembrane space protein EFHD1 as a binding partner of the MCUC subunits MCU, EMRE, and MCUB. We further show a MICU1-dependent inhibitory effect of EFHD1 on calcium uptake. Next, we systematically survey compensatory mechanisms and functional consequences of mitochondrial calcium dyshomeostasis by analyzing the MCU interactome upon EMRE, MCUB, MICU1, or MICU2 knockdown. While silencing EMRE reduces MCU interconnectivity, MCUB loss-of-function leads to a wider interaction network. Our study provides a comprehensive and high-confidence resource to gain insights into players and mechanisms regulating mitochondrial calcium signaling and their relevance in human diseases.

Keywords: Calcium Signaling; Mitochondria; Mitochondrial Calcium Uniporter; Organelle; Proteomics

DOI: https://doi.org/10.1038/s44318-024-00219-w

JCI Insight. 2024 Sep 10. pii: e172336. [Epub ahead of print]9(17):

Mitochondrial reprogramming by activating OXPHOS via glutamine metabolism in African American patients with bladder cancer.

Bladder cancer (BLCA) mortality is higher in African American (AA) patients compared with European American (EA) patients, but the molecular mechanism underlying race-specific differences are unknown. To address this gap, we conducted comprehensive RNA-Seq, proteomics, and metabolomics analysis of BLCA tumors from AA and EA. Our findings reveal a distinct metabolic phenotype in AA BLCA characterized by elevated mitochondrial oxidative phosphorylation (OXPHOS), particularly through the activation of complex I. The results provide insight into the complex I activation-driven higher OXPHOS activity resulting in glutamine-mediated metabolic rewiring and increased disease progression, which was also confirmed by [U]13C-glutamine tracing. Mechanistic studies further demonstrate that knockdown of NDUFB8, one of the components of complex I in AA BLCA cells, resulted in reduced basal respiration, ATP production, GLS1 expression, and proliferation. Moreover, preclinical studies demonstrate the therapeutic potential of targeting complex I, as evidenced by decreased tumor growth in NDUFB8-depleted AA BLCA tumors. Additionally, genetic and pharmacological inhibition of GLS1 attenuated mitochondrial respiration rates and tumor growth potential in AA BLCA. Taken together, these findings provide insight into BLCA disparity for targeting GLS1-Complex I for future therapy.

Keywords: Cancer; Metabolism; Mitochondria; Oncology; Urology

DOI: https://doi.org/10.1172/jci.insight.172336

iScience. 2024 Sep 20. 27(9): 110710

The mitochondrial stress signaling tunes immunity from a view of systemic tumor microenvironment and ecosystem.

Cheng-Liang Kuo, Ying-Chen Lin, Yu Kang Lo, Yu-Zhi Lu, Ananth Ponneri Babuharisankar, Hui-Wen Lien, Han-Yu Chou, Alan Yueh-Luen Lee.

Mitochondria play important roles in cell fate, calcium signaling, mitophagy, and the signaling through reactive oxygen species (ROS). Recently, mitochondria are considered as a signaling organelle in the cell and communicate with other organelles to constitute the mitochondrial information processing system (MIPS) that transduce input-to-output biological information. The success in immunotherapy, a concept of systemic therapy, has been proved to be dependent on paracrine interactions within the tumor microenvironment (TME) and distant organs including microbiota and immune components. We will adopt a broader view from the concept of TME to tumor micro- and macroenvironment (TM 2 E) or tumor-organ ecosystem (TOE). In this review, we will discuss the role of mitochondrial signaling by mitochondrial ROS, calcium flux, metabolites, mtDNA, vesicle transportation, and mitochondria-derived peptide in the TME and TOE, in particular immune regulation and effective cancer immunotherapy.

Keywords: Cancer; Immune response; Microenvironment

DOI: https://doi.org/10.1016/j.isci.2024.110710

Life Sci Alliance. 2024 Nov;pii: e202402918. [Epub ahead of print]7(11):

Novel imaging tools to study mitochondrial morphology in Caenorhabditis elegans.

Miriam Valera-Alberni, Pallas Yao, Silvia Romero-Sanz, Anne Lanjuin, William B Mair.

Mitochondria exhibit a close interplay between their structure and function. Understanding this intricate relationship requires advanced imaging techniques that can capture the dynamic nature of mitochondria and their impact on cellular processes. However, much of the work on mitochondrial dynamics has been performed in single celled organisms or in vitro cell culture. Here, we introduce novel genetic tools for live imaging of mitochondrial morphology in the nematode Caenorhabditis elegans, addressing a pressing need for advanced techniques in studying organelle dynamics within live intact multicellular organisms. Through a comprehensive analysis, we directly compare our tools with existing methods, demonstrating their advantages for visualizing mitochondrial morphology and contrasting their impact on organismal physiology. We reveal limitations of conventional techniques, whereas showcasing the utility and versatility of our approaches, including endogenous CRISPR tags and ectopic labeling. By providing a guide for selecting the most suitable tools based on experimental goals, our work advances mitochondrial research in C. elegans and enhances the strategic integration of diverse imaging modalities for a holistic understanding of organelle dynamics in living organisms.

DOI: https://doi.org/10.26508/lsa.202402918

Light Sci Appl. 2024 Sep 09. 13(1): 244

Visualizing mitochondrial dynamics at the nanoscale.

Till Stephan, Peter Ilgen, Stefan Jakobs.

The study of mitochondria is a formidable challenge for super-resolution microscopy due to their dynamic nature and complex membrane architecture. In this issue, Ren et al. introduce HBmito Crimson, a fluorogenic and photostable mitochondrial probe for STED microscopy and investigate how mitochondrial dynamics influence the spatial organization of mitochondrial DNA.

DOI: https://doi.org/10.1038/s41377-024-01582-3

Nat Cell Biol. 2024 Sep;26(9): 1374

Mitophagy protects against ferroptosis.

Petra Gross.

DOI: https://doi.org/10.1038/s41556-024-01507-7