bims-midysc 2025-03-30 papers

bims-midysc

Biomed News

on Mitochondria dysfunction in cancer

Issue of 2025–03–30
six papers selected by
Papachristodoulou Lab, NJ State University at Rutgers

MTFR1 phosphorylation-activated adaptive mitochondrial fusion is essential for colon cancer cell survival during glucose deprivation.
LRPPRC confers enhanced oxidative phosphorylation metabolism in triple-negative breast cancer and represents a therapeutic target.
Low dose Taxol causes mitochondrial dysfunction in actively respiring cancer cells.
The Warburg effect: the hacked mitochondrial-nuclear communication in cancer.
OmicsCam Enables Trimodal Profiling of Mitochondrial Genome Editing.
Fatty Acid Metabolism Provides an Essential Survival Signal in OxPhos and BCR DLBCL Cells.

Neoplasia. 2025 Mar 22. pii: S1476-5586(25)00038-7. [Epub ahead of print]63 101159

MTFR1 phosphorylation-activated adaptive mitochondrial fusion is essential for colon cancer cell survival during glucose deprivation.

Nan Zhang, Lu Dong, Sifan Liu, Tingting Ning, Shengtao Zhu.

   BACKGROUND: Mitochondrial dynamics are essential for maintaining cellular function under metabolic stress. However, their role in colon cancer's response to glucose deprivation remains poorly understood.
METHODS: The role of the mitochondrial protein MTFR1 in colon cancer proliferation was evaluated using CCK-8 and colony formation assays. Mass spectrometry identified MTFR1-interacting proteins and phosphorylation sites. Mitochondrial morphology was examined with Mitotracker staining, and mitochondrial function was evaluated using MitoSOX, JC-1 staining, and the Seahorse cell mitochondrial stress test.
RESULTS: We observed that MTFR1 is highly expressed in colon cancer cells and interacts with NEK1 under glucose deprivation. This interaction induces phosphorylation of MTFR1 at serine 119, which promotes mitochondrial fusion and supports mitochondrial function. Consequently, enhanced oxidative phosphorylation improves cellular tolerance to glucose deprivation.
CONCLUSIONS: Our findings highlight the importance of MTFR1 in modulating mitochondrial dynamics and its potential impact on colon cancer cell survival under metabolic stress. These results suggest that MTFR1 serine 119 could be a key regulator of colon cancer cell metabolism and a potential therapeutic target for enhancing cancer cell response to metabolic challenges.

Keywords:  Colorectal cancer; Glucose deprivation; MTFR1; Mitochondrial fusion; NEK1

DOI:  https://doi.org/10.1016/j.neo.2025.101159
J Transl Med. 2025 Mar 25. 23(1): 372

LRPPRC confers enhanced oxidative phosphorylation metabolism in triple-negative breast cancer and represents a therapeutic target.

Qiqi Xue, Wenxi Wang, Jie Liu, Dachi Wang, Tianyu Zhang, Tingting Shen, Xiangsheng Liu, Xiaojia Wang, Xiying Shao, Wei Zhou, Xiaohong Fang.

   BACKGROUND: Triple-negative breast cancer (TNBC) is a highly malignant tumor that requires effective therapeutic targets and drugs. Oxidative phosphorylation (OXPHOS) is a metabolic vulnerability of TNBC, but the molecular mechanism responsible for the enhanced OXPHOS remains unclear. The current strategies that target the electronic transfer function of OXPHOS cannot distinguish tumor cells from normal cells. Investigating the mechanism underlying OXPHOS regulation and developing corresponding therapy strategies for TNBC is of great significance.
METHODS: Immunohistochemistry and sequencing data reanalysis were used to investigate LRPPRC expression in TNBC. In vitro and in vivo assays were applied to investigate the roles of LRPPRC in TNBC progression. RT-qPCR, immunoblotting, and Seahorse XF assay were used to examine LRPPRC's functions in the expression of OXPHOS subunits and energy metabolism. In vitro and in vivo functional assays were used to test the therapeutic effect of gossypol acetate (GAA), a traditional gynecological drug, on LRPPRC suppression and OXPOHS inhibition.
RESULTS: LRPPRC was specifically overexpressed in TNBC. LRPPRC knockdown suppressed the proliferation, metastasis, and tumor formation of TNBC cells. LRPPRC enhanced OXPHOS metabolism by increasing the expression of OXPHOS complex subunits encoded by the mitochondrial genome. GAA inhibited OXPHOS metabolism by directly binding LRPPRC, causing LRPPRC degradation, and downregulating the expression of OXPHOS complex subunits encoded by the mitochondrial genome. GAA administration suppressed TNBC cell proliferation, metastasis in vitro, and tumor formation in vivo.
CONCLUSIONS: This work demonstrated a new regulatory pathway of TNBC to promote the expression of mitochondrial genes by upregulating the nuclear gene LRPPRC, resulting in increased OXPHOS. We also suggested a promising therapeutic target LRPPRC for TNBC, and its inhibitor, the traditional gynecological medicine GAA, presented significant antitumor activity.

Keywords:  Gossypol acetate; Oxidative phosphorylation; Triple-negative breast cancer

DOI:  https://doi.org/10.1186/s12967-024-05946-6
J Biol Chem. 2025 Mar 25. pii: S0021-9258(25)00299-6. [Epub ahead of print] 108450

Low dose Taxol causes mitochondrial dysfunction in actively respiring cancer cells.

Rozhin Penjweini, Katie A Link, Shureed Qazi, Nikhil Mattu, Adam Zuchowski, Alexandra Vasta, Dan L Sackett, Jay R Knutson.

  Mitochondrial oxygen consumption, dynamics and morphology play roles in the occurrence, development and drug resistance of cancer; thus they are main targets for many anticancer drugs. Increased mitochondrial oxygen consumption and impaired oxygen delivery creates hypoxia, which influences the balance of metabolic co-factors for biogenesis, disease progression and response to therapeutics. We therefore investigated the effects of Taxol, a well-known anticancer drug, on mitochondrial respiration (principally via a measure of oxidative phosphorylation (OXPHOS) versus glycolysis), morphology and dynamics. The concomitant effects of Taxol on mitochondrial adenosine triphosphate (ATP) and reactive oxygen species (ROS) production, mitochondrial membrane potential, radical-induced formation of carbonyl groups, mitochondrial release of cytochrome c, as well as cell cycle were investigated. Cells used in this study include: A549 (non-small cell lung epithelial cancer cell line), A549-ρ0 (mitochondrial DNA-depleted derivative of A549), and BEAS-2B (a non-cancer cell line derived from normal bronchial epithelium), as well as PC3 (prostate cancer) and HepG2 (hepatocellular carcinoma); these cell lines are known to have disparate metabolic profiles. Using a multitude of fluorescence-based measurements, we show that Taxol, even at a low dose, still adversely effects mitochondria of actively respiring (aerobic) cancer cells. We find an increase in mitochondrial ROS and cytochrome c release, suppression of ATP production and OXPHOS, fragmentation of the mitochondrial network and disruption of mitochondria-microtubule linkage. We find these changes in oxidative, but not glycolytic, cancer cells. Non-cancer cells, which are oxidative, do not show these changes.

Keywords:  Low-dose Taxol; Mitochondrial metabolism; OXPHOS; morphology and dynamics

DOI:  https://doi.org/10.1016/j.jbc.2025.108450
Semin Cancer Biol. 2025 Mar 25. pii: S1044-579X(25)00053-7. [Epub ahead of print]

The Warburg effect: the hacked mitochondrial-nuclear communication in cancer.

Haowen Jiang, Jiangbin Ye.

  Mitochondrial-nuclear communication is vital for maintaining cellular homeostasis. This communication begins with mitochondria sensing environmental cues and transmitting signals to the nucleus through the retrograde cascade, involving metabolic signals such as substrates for epigenetic modifications, ATP and AMP levels, calcium flux, etc. These signals inform the nucleus about the cell's metabolic state, remodel epigenome and regulate gene expression, and modulate mitochondrial function and dynamics through the anterograde feedback cascade to control cell fate and physiology. Disruption of this communication can lead to cellular dysfunction and disease progression, particularly in cancer. The Warburg effect is the metabolic hallmark of cancer, characterized by disruption of mitochondrial respiration and increased lactate generation from glycolysis. This metabolic reprogramming rewires retrograde signaling, leading to epigenetic changes and dedifferentiation, further reprogramming mitochondrial function and promoting carcinogenesis. Understanding these processes and their link to tumorigenesis is crucial for uncovering tumorigenesis mechanisms. Therapeutic strategies targeting these disrupted pathways, including metabolic and epigenetic components, provide promising avenues for cancer treatment.

Keywords:  Warburg effect; cell dedifferentiation; epigenetic remodeling; metabolic reprogramming; metabolic therapy; mitochondrial dynamics; mitochondrial dysfunction

DOI:  https://doi.org/10.1016/j.semcancer.2025.03.006
Anal Chem. 2025 Mar 25.

OmicsCam Enables Trimodal Profiling of Mitochondrial Genome Editing.

Guoqiang Zhou, Ting Li, Jingjing Du, Chengpeng He, Yu Yang, Guanju Chen, Jie Li, Bin Shen, Weilin Pu, Jingwei Zhang, Zhenglong Gu.

Mitochondrial DNA (mtDNA) editing can generate cellular and animal models of mitochondrial genetic disorders and holds promise for future ex vivo and in vivo therapeutic applications. However, due to the quantitative nature of mitochondrion genetics, as more base-editing tools evolve, it is crucial to evaluate not only their efficiency and specificity on the sequence level but also the resulting molecular phenotypes. Here, we devised a novel Omics Carrier microcapsule, abbreviated as OmicsCam, that achieves homogeneous reactions within a heterogeneous carrier membrane, enabling highly efficient multistep biochemistry workflows. Incorporating magnetic beads into the carrier enables high-throughput automation. We demonstrated simultaneous trimodal assessment of mtDNA editing efficiency, postediting cellular transcriptome, and chromatin accessibility in minute cell samples containing as few as 25,000 cells. Applying OmicsCam to two TALE-DdCBE-edited human cell lines revealed that ND4 gene knockdown led to the downregulation of the mitochondrial oxidative phosphorylation pathway and changes in NF-Y transcription factor-associated histone modification pathways in the cell nucleus. Our study provides the most comprehensive analysis of mitochondrial gene editing efficiency and molecular phenotypes to date, which not only facilitates the establishment of mitochondrial genotype-molecular phenotype relationships but also helps assess the global safety of mitochondrial genome nucleases prior to clinical use.

DOI: https://doi.org/10.1021/acs.analchem.4c05251
Biomedicines. 2025 Mar 13. pii: 707. [Epub ahead of print]13(3):

Fatty Acid Metabolism Provides an Essential Survival Signal in OxPhos and BCR DLBCL Cells.

Aurélie Montagne, Konstantina Kotta, Karoline Kielbassa-Elkadi, Isabelle Martins, José Ángel Martinez-Climent, Guido Kroemer, Catherine Thieblemont, Véronique Baud.

  Backgroung/objectives: Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of malignant lymphoma and is a heterogeneous disease with various gene and chromosomal abnormalities. The development of novel therapeutic treatments has improved DLBCL prognosis, but patients with early relapse or refractory disease have a poor outcome (with a mortality of around 40%). Metabolic reprogramming is a hallmark of cancer cells. Fatty acid (FA) metabolism is frequently altered in cancer cells and recently emerged as a critical survival path for cancer cell survival. Methods: We first performed the metabolic characterization of an extended panel of DLBCL cell lines, including lipid droplet content. Then, we investigated the effect of drugs targeting FA metabolism on DLBCL cell survival. Further, we studied how the combination of drugs targeting FA and either mitochondrial metabolism or mTOR pathway impacts on DLBCL cell death. Results: Here, we reveal, using a large panel of DLBCL cell lines characterized by their metabolic status, that targeting of FA metabolism induces massive DLBCL cell death regardless of their OxPhos or BCR/glycolytic subtype. Further, FA drives resistance of DLBCL cell death induced by mitochondrial stress upon treatment with either metformin or L-asparaginase, two FDA-approved antimetabolic drugs. Interestingly, combining inhibition of FA metabolism with that of the mTOR oncogenic pathway strongly potentiates DLBCL cell death. Conclusion: Altogether, our data highlight the central role played by FA metabolism in DLBCL cell survival, independently of their metabolic subtype, and provide the framework for the use of drugs targeting this metabolic vulnerability to overcome resistance in DLBCL patients.

Keywords:  B-cell lymphoma; DLBCL; fatty acid; metabolism; mitochondrial stress; survival

DOI:  https://doi.org/10.3390/biomedicines13030707