bims-midysc 2025-03-09 papers

bims-midysc

Biomed News

on Mitochondria dysfunction in cancer

Issue of 2025–03–09
seven papers selected by
Papachristodoulou Lab

Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis.
Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species.
Estrogen-related receptor alpha (ERRα) controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportation.
Defined cellular reprogramming of androgen receptor-active prostate cancer to neuroendocrine prostate cancer.
scMitoMut for calling mitochondrial lineage-related mutations in single cells.
Intact Glycopeptide Analysis of Human Prostate Tissue Reveals Site-Specific Heterogeneity of Protein Glycosylation in Prostate Cancer.
A mitochondrial outer membrane protein TOMM20 maintains protein stability of androgen receptor and regulates AR transcriptional activity in prostate cancer cells.

bioRxiv. 2025 Feb 19. pii: 2025.02.18.638948. [Epub ahead of print]

Succinate Dehydrogenase loss causes cascading metabolic effects that impair pyrimidine biosynthesis.

Madeleine L Hart, Kristian Davidsen, Serwah Danquah, Eric Zheng, David Sokolov, Lucas B Sullivan.

  Impaired availability of the amino acid aspartate can be a metabolic constraint of cell proliferation in diverse biological contexts. However, the kinetics of aspartate depletion, and its ramifications on downstream metabolism and cell proliferation, remain poorly understood. Here, we deploy the aspartate biosensor jAspSnFR3 with live cell imaging to resolve temporal relationships between aspartate and cell proliferation from genetic, pharmacological, and nutritional manipulations. In cells with impaired aspartate acquisition from mitochondrial complex I inhibition or constrained uptake in aspartate auxotrophs, we find that the proliferation defects lag changes in aspartate levels and only manifest once aspartate levels fall below a critical threshold, supporting the functional link between aspartate levels and cell proliferation in these contexts. In another context of aspartate synthesis inhibition, impairing succinate dehydrogenase (SDH), we find a more complex metabolic interaction, with initial aspartate depletion followed by a rebound of aspartate levels over time. We find that this aspartate rebound effect results from SDH inhibition disproportionately impairing pyrimidine synthesis by inhibiting aspartate transcarbamoylase (ATCase) through the dual effect of diminishing aspartate substrate availability while accumulating succinate, which functions as a competitive inhibitor of aspartate utilization. Finally, we uncover that the nucleotide imbalance from SDH inhibition causes replication stress and introduces a vulnerability to ATR kinase inhibition. Altogether, these findings identify a mechanistic role for succinate in modulating nucleotide synthesis and demonstrate how cascading metabolic interactions can unfold to impact cell function.

Keywords:  SDH; aspartate; biosensor; cancer; metabolism; metabolomics; proliferation; pyrimidines

DOI:  https://doi.org/10.1101/2025.02.18.638948
Nat Commun. 2025 Mar 06. 16(1): 2250

Cryptic mitochondrial DNA mutations coincide with mid-late life and are pathophysiologically informative in single cells across tissues and species.

Alistair P Green, Florian Klimm, Aidan S Marshall, Rein Leetmaa, Juvid Aryaman, Aurora Gómez-Durán, Patrick F Chinnery, Nick S Jones.

Ageing is associated with a range of chronic diseases and has diverse hallmarks. Mitochondrial dysfunction is implicated in ageing, and mouse-models with artificially enhanced mitochondrial DNA mutation rates show accelerated ageing. A scarcely studied aspect of ageing, because it is invisible in aggregate analyses, is the accumulation of somatic mitochondrial DNA mutations which are unique to single cells (cryptic mutations). We find evidence of cryptic mitochondrial DNA mutations from diverse single-cell datasets, from three species, and discover: cryptic mutations constitute the vast majority of mitochondrial DNA mutations in aged post-mitotic tissues, that they can avoid selection, that their accumulation is consonant with theory we develop, hitting high levels coinciding with species specific mid-late life, and that their presence covaries with a majority of the hallmarks of ageing including protein misfolding and endoplasmic reticulum stress. We identify mechanistic links to endoplasmic reticulum stress experimentally and further give an indication that aged brain cells with high levels of cryptic mutations show markers of neurodegeneration and that calorie restriction slows the accumulation of cryptic mutations.

DOI: https://doi.org/10.1038/s41467-025-57286-8
Cell Death Dis. 2025 Mar 05. 16(1): 154

Estrogen-related receptor alpha (ERRα) controls the stemness and cellular energetics of prostate cancer cells via its direct regulation of citrate metabolism and zinc transportation.

Taiyang Ma, Wenjuan Xie, Zhenyu Xu, Weijie Gao, Jianfu Zhou, Yuliang Wang, Franky Leung Chan.

Compared to most tumors that are more glycolytic, primary prostate cancer is less glycolytic but more dependent on TCA cycle coupled with OXPHOS for its energy demand. This unique metabolic energetic feature is attributed to activation of mitochondrial m-aconitase in TCA caused by decreased cellular Zn level. Evidence suggests that a small subpopulation of cancer cells within prostate tumors, designated as prostate cancer stem cells (PCSCs), play significant roles in advanced prostate cancer progression. However, their cellular energetics status is still poorly understood. Nuclear receptor ERRα (ESRRA) is a key regulator of energy metabolism. Previous studies characterize that ERRα exhibits an upregulation in prostate cancer and can perform multiple oncogenic functions. Here, we demonstrate a novel role of ERRα in the control of stemness and energetics metabolism in PCSCs via a mechanism of combined transrepression of Zn transporter ZIP1 in reducing intracellular Zn uptake and transactivation of ACO2 (m-aconitase) in completion of TCA cycle. Results also showed that restoration of Zn accumulation by treatment with a Zn ionophore Clioquinol could significantly suppress both in vitro growth of PCSCs and also their in vivo tumorigenicity, implicating that enhanced cellular Zn uptake could be a potential therapeutic approach for targeting PCSCs in advanced prostate cancer.

DOI: https://doi.org/10.1038/s41419-025-07460-z
bioRxiv. 2025 Feb 17. pii: 2025.02.12.637904. [Epub ahead of print]

Defined cellular reprogramming of androgen receptor-active prostate cancer to neuroendocrine prostate cancer.

Shan Li, Kai Song, Huiyun Sun, Yong Tao, Arthur Huang, Vipul Bhatia, Brian Hanratty, Radhika A Patel, Henry W Long, Colm Morrissey, Michael C Haffner, Peter S Nelson, Thomas G Graeber, John K Lee.

Neuroendocrine prostate cancer (NEPC) arises primarily through neuroendocrine transdifferentiation (NEtD) as an adaptive mechanism of therapeutic resistance. Models to define the functional effects of putative drivers of this process on androgen receptor (AR) signaling and NE cancer lineage programs are lacking. We adapted a genetically defined strategy from the field of cellular reprogramming to directly convert AR-active prostate cancer (ARPC) to AR-independent NEPC using candidate factors. We delineated critical roles of the pioneer factors ASCL1 and NeuroD1 in NEtD and uncovered their abilities to silence AR expression and signaling by remodeling chromatin at the somatically acquired AR enhancer and global AR binding sites with enhancer activity. We also elucidated the dynamic temporal changes in the transcriptomic and epigenomic landscapes of cells undergoing acute lineage conversion from ARPC to NEPC which should inform future therapeutic development. Further, we distinguished the activities of ASCL1 and NeuroD1 from the inactivation of RE-1 silencing transcription factor (REST), a master suppressor of a major neuronal gene program, in establishing a NEPC lineage state and in modulating the expression of genes associated with major histocompatibility complex class I (MHC I) antigen processing and presentation. These findings provide important, clinically relevant insights into the biological processes driving NEtD of prostate cancer.

DOI: https://doi.org/10.1101/2025.02.12.637904
Brief Bioinform. 2024 Nov 22. pii: bbaf072. [Epub ahead of print]26(1):

scMitoMut for calling mitochondrial lineage-related mutations in single cells.

Wenjie Sun, Daphne van Ginneken, Leïla Perié.

  Tracing cell lineages has become a valuable tool for studying biological processes. Among the available tools for human data, mitochondrial DNA (mtDNA) has a high potential due to its ability to be used in conjunction with single-cell chromatin accessibility data, giving access to the cell phenotype. Nonetheless, the existing mutation calling tools are ill-equipped to deal with the polyploid nature of the mtDNA and lack a robust statistical framework. Here we introduce scMitoMut, an innovative R package that leverages statistical methodologies to accurately identify mitochondrial lineage-related mutations at the single-cell level. scMitoMut assigns a mutation quality q-value based on beta-binomial distribution to each mutation at each locus within individual cells, ensuring higher sensitivity and precision of lineage-related mutation calling in comparison to current methodologies. We tested scMitoMut using single-cell DNA sequencing, single-cell transposase-accessible chromatin (scATAC) sequencing, and 10× Genomics single-cell multiome datasets. Using a single-cell DNA sequencing dataset from a mixed population of cell lines, scMitoMut demonstrated superior sensitivity in identifying a small proportion of cancer cell line compared to existing methods. In a human colorectal cancer scATAC dataset, scMitoMut identified more mutations than state-of-the-art methods. Applied to 10× Genomics multiome datasets, scMitoMut effectively measured the lineage distance in cells from blood or brain tissues. Thus, the scMitoMut is a freely available, and well-engineered toolkit (https://www.bioconductor.org/packages/devel/bioc/html/scMitoMut.html) for mtDNA mutation calling with high memory and computational efficiency. Consequently, it will significantly advance the application of single-cell sequencing, facilitating the precise delineation of mitochondrial mutations for lineage-tracing purposes in development, tumour, and stem cell biology.

Keywords:  lineage tracing; mitochondrial mutation; single-cell sequencing

DOI:  https://doi.org/10.1093/bib/bbaf072
Glycobiology. 2025 Feb 27. pii: cwaf010. [Epub ahead of print]

Intact Glycopeptide Analysis of Human Prostate Tissue Reveals Site-Specific Heterogeneity of Protein Glycosylation in Prostate Cancer.

Kathryn L Kapp, Fernando Garcia-Marques, Sarah M Totten, Abel Bermudez, Cheylene Tanimoto, James D Brooks, Sharon J Pitteri.

  Approximately 300,000 American men were diagnosed with prostate cancer in 2024. Existing screening approaches based on measuring levels of prostate-specific antigen in the blood lack specificity for prostate cancer. Studying the glycans attached to proteins has the potential to generate new biomarker candidates and/or increase the specificity of existing protein biomarkers, and studying protein glycosylation changes in prostate cancer could also add new information to our understanding of prostate cancer biology. Here, we present the analysis of N-glycoproteins in clinical prostate cancer tissue and patient-matched, non-cancerous adjacent tissue using LC-MS/MS-based intact N-linked glycopeptide analysis. This analysis allowed us to characterize protein N-linked glycosylation changes in prostate cancer at the glycoprotein, glycopeptide, and glycosite levels. Overall, 1894 unique N-glycosites on 7022 unique N-glycopeptides from 1354 unique glycoproteins were identified. Importantly, we observed an overall increase in glycoprotein, glycopeptide, and glycosite counts in prostate cancer tissue than non-cancerous tissue. We identified biological functions enriched in prostate cancer that relate to cancer development. Additionally, we characterized N-glycosite-specific changes in prostate cancer, demonstrating significant meta- and micro-heterogeneity in N-glycan composition in prostate cancer in comparison to non-cancerous tissue. Our findings support the idea that protein glycosylation is heavily impacted and aberrant in prostate cancer and provide examples of N-glycosite-specific changes that could be exploited for more specific markers of prostate cancer.

Keywords:  cancer; glycosylation; mass spectrometry; prostate

DOI:  https://doi.org/10.1093/glycob/cwaf010
Oncogene. 2025 Mar 06.

A mitochondrial outer membrane protein TOMM20 maintains protein stability of androgen receptor and regulates AR transcriptional activity in prostate cancer cells.

Linglong Yin, Yi Dai, Yue Wang, Shiwen Liu, Yubing Ye, Yongming Fu, Yuchong Peng, Ruizheng Tan, Li Fang, Haoran Suo, Xuli Qi, Bowen Yuan, Yingxue Gao, Youhong Liu, Xiong Li.

Prostate cancer (PCa) is an androgen-dependent malignancy, with HSP90 and HSP70 serving as classical molecular chaperones that maintain androgen receptor (AR) protein stability and regulate its transcriptional activation. Surprisingly, our study identified TOMM20, a mitochondrial outer membrane protein, as a potential molecular chaperone with similar roles to HSP90/HSP70. We found that TOMM20 expression is elevated in PCa tissues and cell lines and positively correlates with AR levels. RNA-seq analysis revealed that TOMM20 knockdown significantly reduced the mRNA levels of AR-regulated genes. Additionally, the protein level of KLK3 (PSA) decreased, and AR binding to the androgen response element (ARE) of the KLK3 promoter was diminished following TOMM20 knockdown, leading to decreased KLK3 gene transcription. Furthermore, TOMM20 depletion reduced both cytoplasmic and nuclear AR protein levels and facilitated AR degradation via an E3 ubiquitin ligase SKP2-mediated ubiquitin-proteasome pathway, independent of heat shock proteins (HSPs). To our knowledge, this is the first report demonstrating that TOMM20, a mitochondrial outer translocase protein, stabilizes AR protein and enhances its transcriptional activity, while its knockdown promotes AR degradation through the SKP2-mediated ubiquitin-proteasome pathway. These findings suggest that TOMM20 may serve as a potential biomarker for PCa progression and a promising therapeutic target for drug development.

DOI: https://doi.org/10.1038/s41388-025-03328-w