bims-mibica 2024-02-18 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2024–02–18
29 papers selected by
Kelsey Fisher-Wellman, East Carolina University

Deoxycytidine kinase inactivation enhances gemcitabine resistance and sensitizes mitochondrial metabolism interference in pancreatic cancer.
SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.
Decoding Serine Metabolism: Unveiling Novel Pathways for Evolving Cancer Therapies.
Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production.
Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA.
Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout ageing.
Methylation of Phenyl Rings in Ester-Stabilized Phosphorus Ylides Vastly Enhances Their Protonophoric Activity.
Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis.
Osthole impairs mitochondrial metabolism and the autophagic flux in colorectal cancer.
Targeting oxidative phosphorylation to increase the efficacy of immune-combination therapy in renal cell carcinoma.
BRD4-mediated epigenetic regulation of endoplasmic reticulum-mitochondria contact sites is governed by the mitochondrial complex III.
Glutaminase potentiates the glycolysis in esophageal squamous cell carcinoma by interacting with PDK1.
COQ4 is required for the oxidative decarboxylation of the C1 carbon of coenzyme Q in eukaryotic cells.
High expression of BCAT1 sensitizes AML cells to PARP inhibitor by suppressing DNA damage response.
Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer.
Restricting bioenergetic efficiency enhances longevity and mitochondrial redox capacity in Drosophila melanogaster.
Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control.
Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1.
The HRI branch of the integrated stress response selectively triggers mitophagy.
SLC25A39 links mitochondrial GSH sensing with iron metabolism.
Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth.
Mitochondrial Calcium Transport During Autophagy Initiation.
Proline restores mitochondrial function and reverses aging hallmarks in senescent cells.
A system for inducible mitochondria-specific protein degradation in vivo.
Rational design of mitochondria-targeted fluorescent biosensors for in vivo elucidation of the interaction between breast cancer metastasis and mitochondrial autophagy.
Long-term follow-up of VIALE-A: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia.
Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer.
Enhanced T cell immune activity mediated by Drp1 promotes the efficacy of PD-1 inhibitors in treating lung cancer.
Mitochondrial DNA copy number reduction via in vitro TFAM knockout remodels the nuclear epigenome and transcriptome.

Cell Death Dis. 2024 Feb 12. 15(2): 131

Deoxycytidine kinase inactivation enhances gemcitabine resistance and sensitizes mitochondrial metabolism interference in pancreatic cancer.

Suman Dash, Takeshi Ueda, Akiyoshi Komuro, Masahiko Honda, Ryoichi Sugisawa, Hitoshi Okada.

Pancreatic ductal adenocarcinoma (PDAC) is considered one of the most lethal forms of cancer. Although in the last decade, an increase in 5-year patient survival has been observed, the mortality rate remains high. As a first-line treatment for PDAC, gemcitabine alone or in combination (gemcitabine plus paclitaxel) has been used; however, drug resistance to this regimen is a growing issue. In our previous study, we reported MYC/glutamine dependency as a therapeutic target in gemcitabine-resistant PDAC secondary to deoxycytidine kinase (DCK) inactivation. Moreover, enrichment of oxidative phosphorylation (OXPHOS)-associated genes was a common property shared by PDAC cell lines, and patient clinical samples coupled with low DCK expression was also demonstrated, which implicates DCK in cancer metabolism. In this article, we reveal that the expression of most genes encoding mitochondrial complexes is remarkably upregulated in PDAC patients with low DCK expression. The DCK-knockout (DCK KO) CFPAC-1 PDAC cell line model reiterated this observation. Particularly, OXPHOS was functionally enhanced in DCK KO cells as shown by a higher oxygen consumption rate and mitochondrial ATP production. Electron microscopic observations revealed abnormal mitochondrial morphology in DCK KO cells. Furthermore, DCK inactivation exhibited reactive oxygen species (ROS) reduction accompanied with ROS-scavenging gene activation, such as SOD1 and SOD2. SOD2 inhibition in DCK KO cells clearly induced cell growth suppression. In combination with increased anti-apoptotic gene BCL2 expression in DCK KO cells, we finally reveal that venetoclax and a mitochondrial complex I inhibitor are therapeutically efficacious for DCK-inactivated CFPAC-1 cells in in vitro and xenograft models. Hence, our work provides insight into inhibition of mitochondrial metabolism as a novel therapeutic approach to overcome DCK inactivation-mediated gemcitabine resistance in PDAC patient treatment.

DOI: https://doi.org/10.1038/s41419-024-06531-x
Cell Metab. 2024 Feb 13. pii: S1550-4131(24)00013-5. [Epub ahead of print]

SLC25A51 decouples the mitochondrial NAD+/NADH ratio to control proliferation of AML cells.

Mu-Jie Lu, Jonathan Busquets, Valeria Impedovo, Crystal N Wilson, Hsin-Ru Chan, Yu-Tai Chang, William Matsui, Stefano Tiziani, Xiaolu A Cambronne.

  SLC25A51 selectively imports oxidized NAD+ into the mitochondrial matrix and is required for sustaining cell respiration. We observed elevated expression of SLC25A51 that correlated with poorer outcomes in patients with acute myeloid leukemia (AML), and we sought to determine the role SLC25A51 may serve in this disease. We found that lowering SLC25A51 levels led to increased apoptosis and prolonged survival in orthotopic xenograft models. Metabolic flux analyses indicated that depletion of SLC25A51 shunted flux away from mitochondrial oxidative pathways, notably without increased glycolytic flux. Depletion of SLC25A51 combined with 5-azacytidine treatment limits expansion of AML cells in vivo. Together, the data indicate that AML cells upregulate SLC25A51 to decouple mitochondrial NAD+/NADH for a proliferative advantage by supporting oxidative reactions from a variety of fuels. Thus, SLC25A51 represents a critical regulator that can be exploited by cancer cells and may be a vulnerability for refractory AML.

Keywords:  AML; MCART1; SLC25A51; glutamine utilization; oxidative mitochondria; tumor metabolism

DOI:  https://doi.org/10.1016/j.cmet.2024.01.013
Cancer Res. 2024 Feb 16.

Decoding Serine Metabolism: Unveiling Novel Pathways for Evolving Cancer Therapies.

Aristotle Lau, John Blenis, Guillermo Burgos-Barragan.

Serine metabolism plays a pivotal role in cancer, making it an appealing therapeutic target. Two recent studies published in Nature Metabolism and Science Translational Medicine uncovered novel players and therapeutic opportunities within this crucial metabolic pathway. Papalazarou and colleagues employed genetic tools coupled with metabolomics and high-throughput imaging to identify and characterize membrane transporters involved in serine uptake and mitochondrial import in colorectal cancer. Notably, they showed that dual inhibition of these transporters in combination with impaired serine biosynthesis reduced tumor growth in xenograft models. In a parallel study, Zhang and colleagues identified isocitrate dehydrogenase I (IDH1) as a novel regulator of serine biosynthesis in non-small cell lung cancer (NSCLC). Through extensive mechanistic studies, they demonstrated that IDH1 enhances the expression of the key enzymes phosphoglycerate dehydrogenase (PHGDH) and phosphoserine aminotransferase 1 (PSAT1) via a non-canonical function independent of its enzymatic activity. Strikingly, pharmacological disruption of this novel function of IDH1 not only diminished tumor growth but also enhanced the anticancer efficacy of dietary serine restriction in mouse models of lung cancer. Together, these studies advance our mechanistic understanding of how cancer cells fulfill their serine requirements and reveal innovative therapeutic avenues to deprive tumors of this vital nutrient.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-0541
Proc Natl Acad Sci U S A. 2024 Feb 20. 121(8): e2317343121

Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production.

Evan K Noch, Laura Palma, Isaiah Yim, Nayah Bullen, Daniel Barnett, Alexander Walsh, Bhavneet Bhinder, Elisa Benedetti, Jan Krumsiek, Justin Gurvitch, Sumaiyah Khwaja, Daphne Atlas, Olivier Elemento, Lewis C Cantley.

  Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved single cysteine compound N-acetylcysteine (NAC) reduced GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Normal brain cells and other cancer cells showed no response to NAC. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. From analysis of the clinical proteomic tumor analysis consortium (CPTAC) database, we found that GBM cells exhibit lower expression of mitochondrial redox enzymes than four other cancers whose proteomic data are available in CPTAC. Knockdown of mitochondrial thioredoxin-2 in lung cancer cells induced NAC susceptibility, indicating the importance of mitochondrial redox enzyme expression in mitigating reductive stress. Intraperitoneal treatment of mice bearing orthotopic GBM xenografts with a two-cysteine peptide induced H2O2 in brain tumors in vivo. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.

Keywords:  cysteine; glioblastoma; hydrogen peroxide; mitochondrial metabolism; reductive stress

DOI:  https://doi.org/10.1073/pnas.2317343121
Nat Struct Mol Biol. 2024 Feb 12.

Single-nucleoid architecture reveals heterogeneous packaging of mitochondrial DNA.

R Stefan Isaac, Thomas W Tullius, Katja G Hansen, Danilo Dubocanin, Mary Couvillion, Andrew B Stergachis, L Stirling Churchman.

Cellular metabolism relies on the regulation and maintenance of mitochondrial DNA (mtDNA). Hundreds to thousands of copies of mtDNA exist in each cell, yet because mitochondria lack histones or other machinery important for nuclear genome compaction, it remains unresolved how mtDNA is packaged into individual nucleoids. In this study, we used long-read single-molecule accessibility mapping to measure the compaction of individual full-length mtDNA molecules at near single-nucleotide resolution. We found that, unlike the nuclear genome, human mtDNA largely undergoes all-or-none global compaction, with most nucleoids existing in an inaccessible, inactive state. Highly accessible mitochondrial nucleoids are co-occupied by transcription and replication components and selectively form a triple-stranded displacement loop structure. In addition, we showed that the primary nucleoid-associated protein TFAM directly modulates the fraction of inaccessible nucleoids both in vivo and in vitro, acting consistently with a nucleation-and-spreading mechanism to coat and compact mitochondrial nucleoids. Together, these findings reveal the primary architecture of mtDNA packaging and regulation in human cells.

DOI: https://doi.org/10.1038/s41594-024-01225-6
Nat Ecol Evol. 2024 Feb 15.

Mitochondrial haplotype and mito-nuclear matching drive somatic mutation and selection throughout ageing.

Isabel M Serrano, Misa Hirose, Charles C Valentine, Sharon Roesner, Elizabeth Schmidt, Gabriel Pratt, Lindsey Williams, Jesse Salk, Saleh Ibrahim, Peter H Sudmant.

Mitochondrial genomes co-evolve with the nuclear genome over evolutionary timescales and are shaped by selection in the female germline. Here we investigate how mismatching between nuclear and mitochondrial ancestry impacts the somatic evolution of the mitochondrial genome in different tissues throughout ageing. We used ultrasensitive duplex sequencing to profile ~2.5 million mitochondrial genomes across five mitochondrial haplotypes and three tissues in young and aged mice, cataloguing ~1.2 million mitochondrial somatic and ultralow-frequency inherited mutations, of which 81,097 are unique. We identify haplotype-specific mutational patterns and several mutational hotspots, including at the light strand origin of replication, which consistently exhibits the highest mutation frequency. We show that rodents exhibit a distinct mitochondrial somatic mutational spectrum compared with primates with a surfeit of reactive oxygen species-associated G > T/C > A mutations, and that somatic mutations in protein-coding genes exhibit signatures of negative selection. Lastly, we identify an extensive enrichment in somatic reversion mutations that 're-align' mito-nuclear ancestry within an organism's lifespan. Together, our findings demonstrate that mitochondrial genomes are a dynamically evolving subcellular population shaped by somatic mutation and selection throughout organismal lifetimes.

DOI: https://doi.org/10.1038/s41559-024-02338-3
Chembiochem. 2024 Feb 14. e202300848

Methylation of Phenyl Rings in Ester-Stabilized Phosphorus Ylides Vastly Enhances Their Protonophoric Activity.

Tatyana Rokitskaya, Roman S Kirsanov, Ljudmila S Khailova, Alisa A Panteleeva, Konstantin G Lyamzaev, Galina A Korshunova, Elena A Kotova, Yuri N Antonenko.

  We have recently discovered that ester-stabilized phosphorus ylides, resulting from deprotonation of a phosphonium salt such as [Ph3PCH2COOR]Br, can transfer protons across artificial and biological membranes. To create more effective cationic protonophores, we synthesized similar phosphonium salts with one ((heptyloxycarbonylmethyl)tri(p-tolyl)phosphonium bromide) or two ((butyloxycarbonylmethyl)tri(3,5-xylyl)phosphonium bromide) methyl substituents in the phenyl groups. The methylation enormously augmented both protonophoric activity of the ylides on planar bilayer lipid membrane (BLM) and uncoupling of mammalian mitochondria, which correlated with strongly accelerated flip-flop of their cationic precursors across the BLM.

Keywords:  lipid membranes; mitochondrial uncoupling; proton transport; protonophores; ylides

DOI:  https://doi.org/10.1002/cbic.202300848
Cell. 2024 Feb 08. pii: S0092-8674(24)00067-9. [Epub ahead of print]

Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis.

Baiyu Qiu, Fereshteh Zandkarimi, Carla T Bezjian, Eduard Reznik, Rajesh Kumar Soni, Wei Gu, Xuejun Jiang, Brent R Stockwell.

  Phospholipids containing a single polyunsaturated fatty acyl tail (PL-PUFA1s) are considered the driving force behind ferroptosis, whereas phospholipids with diacyl-PUFA tails (PL-PUFA2s) have been rarely characterized. Dietary lipids modulate ferroptosis, but the mechanisms governing lipid metabolism and ferroptosis sensitivity are not well understood. Our research revealed a significant accumulation of diacyl-PUFA phosphatidylcholines (PC-PUFA2s) following fatty acid or phospholipid treatments, correlating with cancer cell sensitivity to ferroptosis. Depletion of PC-PUFA2s occurred in aging and Huntington's disease brain tissue, linking it to ferroptosis. Notably, PC-PUFA2s interacted with the mitochondrial electron transport chain, generating reactive oxygen species (ROS) for initiating lipid peroxidation. Mitochondria-targeted antioxidants protected cells from PC-PUFA2-induced mitochondrial ROS (mtROS), lipid peroxidation, and cell death. These findings reveal a critical role for PC-PUFA2s in controlling mitochondria homeostasis and ferroptosis in various contexts and explain the ferroptosis-modulating mechanisms of free fatty acids. PC-PUFA2s may serve as diagnostic and therapeutic targets for modulating ferroptosis.

Keywords:  PUFA; ROS; complex I; diacyl-PUFA phosphatidylcholine; electron transport chain; ferroptosis; lipids; mitochondria; phospholipid; polyunsaturated fatty acid

DOI:  https://doi.org/10.1016/j.cell.2024.01.030
Phytomedicine. 2024 Mar;pii: S0944-7113(24)00048-5. [Epub ahead of print]125 155383

Osthole impairs mitochondrial metabolism and the autophagic flux in colorectal cancer.

Jisoo Song, Jiyeon Ham, Wonhyoung Park, Gwonhwa Song, Whasun Lim.

   BACKGROUND: Osthole is active constituent of Cnidium monnieri (L.) Cuss. with various physiological functions including anti-inflammation and anti-lipedemic effects. However, the regulatory activity of osthole in colorectal cancer development, focusing on mitochondrial metabolism, is not well known.
HYPOTHESIS/PURPOSE: We hypothesized that osthole may suppress progression of colorectal cancer and aimed to determine the underlying mitochondrial metabolism and the autophagic flux.
STUDY DESIGN: In this study, we elucidated the mechanism of action of osthole in colorectal cancer using an in vivo azoxymethane/dextran sodium sulfate (AOM/DSS) mouse model and an in vitro cell culture system.
METHODS: AOM/DSS mouse model was established and analyzed the effects of osthole on survival rate, diseases activity index, number of tumor and histopathology. Then, cell based assays including viability, cell cycle, reactive oxygen species (ROS), apoptosis, calcium efflux, and mitochondrial function were analyzed. Moreover, osthole-mediated signaling was demonstrated by western blot analyses.
RESULTS: Osthole effectively suppressed the growth of colorectal tumors and alleviated AOM/DSS-induced intestinal injury. Osthole restored the function of goblet cells and impaired the expression of Claudin1 and Axin1 impaired by AOM/DSS. In addition, osthole specifically showed cytotoxicity in colorectal carcinoma cells, but not in normal colon cells. Osthole decreased the ASC/caspase-1/IL-1β inflammasome pathway and induced mitochondrial dysfunction in redox homeostasis, calcium homeostasis. Furthermore, osthole inhibited both oxidative phosphorylation (OXPHOS) and glycolysis, leading to the suppression of ATP production. Moreover, via combination treatment with chloroquine (CQ), we demonstrated that osthole impaired autophagic flux, leading to apoptosis of HCT116 and HT29 cells. Finally, we elucidated that the functional role of tiRNAHisGTG regulated by osthole directly affects the cellular fate of colon cancer cells.
CONCLUSION: These results suggest that osthole has the potential to manage progression of colorectal cancer by regulating autophagy- and mitochondria-mediated signal transduction.

Keywords:  Autophagy; Colon cancer; Metabolism; Mitochondrial; tiRNA

DOI:  https://doi.org/10.1016/j.phymed.2024.155383
J Immunother Cancer. 2024 Feb 14. pii: e008226. [Epub ahead of print]12(2):

Targeting oxidative phosphorylation to increase the efficacy of immune-combination therapy in renal cell carcinoma.

Jihua Tian, Jing Luo, Xing Zeng, Chunjin Ke, Yanan Wang, Zhenghao Liu, Le Li, Yangjun Zhang, Zhiquan Hu, Chunguang Yang.

   BACKGROUND: Immune checkpoint inhibitors (ICIs) are the standard of care for metastatic renal cell carcinoma (RCC); however, most patients develop de novo or acquired resistance to ICIs. Oxidative phosphorylation (OXPHOS) has been rarely explored as a potential target for correcting ICI resistance.
METHODS: We systematically analyzed RNA sequencing and clinical data from CheckMate, JAVELIN Renal 101, and NCT01358721 clinical trials, and clinicopathological data of 25 patients from Tongji Hospital to investigate the relationship between OXPHOS and ICI resistance. The Ndufb8-knockdown Renca cell line was derived to determine the effect of OXPHOS on RCC immunotherapy in vivo.
RESULTS: An analysis of the CheckMate series data revealed that high OXPHOS levels are risk factors for ICI in patients with RCC, but are affected by thevon Hippel-Lindau protein (VHL) and hypoxia-inducible factor-1α status. This result is consistent with correlation between clinicopathological characteristics and prognostic observations at our institute. Knockdown of the mitochondrial complex I subunit Ndufb8 of the Renca cell line had no effect on cell growth and migration in vitro, but slowed down cell growth in vivo. Among anti-programmed death ligand 1 (PD-L1)-treated BALB/c mice, shNdufb8 Renca tumors grew slower than shControl Renca tumors and the corresponding mice survived longer. Flow cytometry revealed that CD8+ T cells in shNdufb8 Renca tumors, which were exposed to a lower degree of hypoxia and expressed less programmed death-1 (PD-1) and T-cell immunoglobulin domain and mucin domain 3 (TIM-3), secreted more interferon-γ after stimulation. Immunofluorescence demonstrated that the shNdufb8 Renca tumors had a higher proportion of CD8+ T cells and the proportion of these cells was lower in the hypoxic area.
CONCLUSIONS: OXPHOS is a reliable predictor of immunotherapy response in RCC and is more pronounced in metastatic lesions. RCC cells generate a hypoxic tumor microenvironment and inhibit T-cell function through oxidative metabolism, thereby leading to immunotherapy resistance.

Keywords:  Immunotherapy; Metabolic Networks and Pathways; Renal Cell Carcinoma

DOI:  https://doi.org/10.1136/jitc-2023-008226
bioRxiv. 2024 Feb 04. pii: 2024.02.02.578646. [Epub ahead of print]

BRD4-mediated epigenetic regulation of endoplasmic reticulum-mitochondria contact sites is governed by the mitochondrial complex III.

Brandon Chen, Theophilus M Lynn-Nguyen, Pankaj Jadhav, Benjamin S Halligan, Nicholas J Rossiter, Rachel M Guerra, Sergei Koshkin, Imhoi Koo, Pietro Morlacchi, David A Hanna, Jason Lin, Ruma Banerjee, David J Pagliarini, Andrew D Patterson, Shyamal Mosalaganti, Jonathan Z Sexton, Tito Calì, Costas A Lyssiotis, Yatrik M Shah.

Inter-organellar communication is critical for cellular metabolic homeostasis. One of the most abundant inter-organellar interactions are those at the endoplasmic reticulum and mitochondria contact sites (ERMCS). However, a detailed understanding of the mechanisms governing ERMCS regulation and their roles in cellular metabolism are limited by a lack of tools that permit temporal induction and reversal. Through unbiased screening approaches, we identified fedratinib, an FDA-approved drug, that dramatically increases ERMCS abundance by inhibiting the epigenetic modifier BRD4. Fedratinib rapidly and reversibly modulates mitochondrial and ER morphology and alters metabolic homeostasis. Moreover, ERMCS modulation depends on mitochondria electron transport chain complex III function. Comparison of fedratinib activity to other reported inducers of ERMCS revealed common mechanisms of induction and function, providing clarity and union to a growing body of experimental observations. In total, our results uncovered a novel epigenetic signaling pathway and an endogenous metabolic regulator that connects ERMCS and cellular metabolism.

DOI: https://doi.org/10.1101/2024.02.02.578646
Mol Carcinog. 2024 Feb 14.

Glutaminase potentiates the glycolysis in esophageal squamous cell carcinoma by interacting with PDK1.

Guangzhao Zhu, Fangxia Guan, Shenglei Li, Qing Zhang, Xueying Zhang, Yue Qin, Zhangzhan Sun, Shaohua Peng, Jiexing Cheng, Yiyang Li, Ruili Ren, Tianli Fan, Hongtao Liu.

  Increasing evidence has demonstrated that glutaminase (GLS) as a key mitochondrial enzyme plays a pivotal role in glutaminolysis, which widely participates in glutamine metabolism serving as main energy sources and building blocks for tumor growth. However, the roles and molecular mechanisms of GLS in esophageal squamous cell carcinoma (ESCC) remains unknown. Here, we found that GLS was highly expressed in ESCC tissues and cells. GLS inhibitor CB-839 significantly suppressed cell proliferation, colony formation, migration and invasion of ESCC cells, whereas GLS overexpression displayed the opposite effects. In addition, CB-839 markedly suppressed glucose consumption and lactate production, coupled with the downregulation of glycolysis-related proteins HK2, PFKM, PKM2 and LDHA, whereas GLS overexpression exhibited the adverse results. In vivo animal experiment revealed that CB-839 dramatically suppressed tumor growth, whereas GLS overexpression promoted tumor growth in ESCC cells xenografted nude mice. Mechanistically, GLS was localized in mitochondria of ESCC cells, which interacted with PDK1 protein. CB-839 attenuated the interaction of GLS and PDK1 in ESCC cells by suppressing PDK1 expression, which further evoked the downregulation of p-PDHA1 (s293), however, GLS overexpression markedly enhanced the level of p-PDHA1 (s293). These findings suggest that interaction of GLS with PDK1 accelerates the glycolysis of ESCC cells by inactivating PDH enzyme, and thus targeting GLS may be a novel therapeutic approach for ESCC patients.

Keywords:  esophageal squamous cell carcinoma; glutaminase; glycolysis; pyruvate dehydrogenase E1 subunit alpha 1; pyruvate dehydrogenase kinase isoform 1

DOI:  https://doi.org/10.1002/mc.23696
Mol Cell. 2024 Jan 24. pii: S1097-2765(24)00004-2. [Epub ahead of print]

COQ4 is required for the oxidative decarboxylation of the C1 carbon of coenzyme Q in eukaryotic cells.

Ludovic Pelosi, Laura Morbiato, Arthur Burgardt, Fiorella Tonello, Abigail K Bartlett, Rachel M Guerra, Katayoun Kazemzadeh Ferizhendi, Maria Andrea Desbats, Bérengère Rascalou, Marco Marchi, Luis Vázquez-Fonseca, Caterina Agosto, Giuseppe Zanotti, Morgane Roger-Margueritat, María Alcázar-Fabra, Laura García-Corzo, Ana Sánchez-Cuesta, Plácido Navas, Gloria Brea-Calvo, Eva Trevisson, Volker F Wendisch, David J Pagliarini, Leonardo Salviati, Fabien Pierrel.

  Coenzyme Q (CoQ) is a redox lipid that fulfills critical functions in cellular bioenergetics and homeostasis. CoQ is synthesized by a multi-step pathway that involves several COQ proteins. Two steps of the eukaryotic pathway, the decarboxylation and hydroxylation of position C1, have remained uncharacterized. Here, we provide evidence that these two reactions occur in a single oxidative decarboxylation step catalyzed by COQ4. We demonstrate that COQ4 complements an Escherichia coli strain deficient for C1 decarboxylation and hydroxylation and that COQ4 displays oxidative decarboxylation activity in the non-CoQ producer Corynebacterium glutamicum. Overall, our results substantiate that COQ4 contributes to CoQ biosynthesis, not only via its previously proposed structural role but also via the oxidative decarboxylation of CoQ precursors. These findings fill a major gap in the knowledge of eukaryotic CoQ biosynthesis and shed light on the pathophysiology of human primary CoQ deficiency due to COQ4 mutations.

Keywords:  COQ4; Corynebacterium; coenzyme Q; coenzyme Q biosynthesis; coenzyme Q deficiency; mitochondria; oxidative decarboxylation; respiratory chain

DOI:  https://doi.org/10.1016/j.molcel.2024.01.003
J Mol Med (Berl). 2024 Feb 10.

High expression of BCAT1 sensitizes AML cells to PARP inhibitor by suppressing DNA damage response.

Jiajia Pan, Yungui Wang, Shujuan Huang, Shihui Mao, Qing Ling, Chenying Li, Fenglin Li, Mengxia Yu, Xin Huang, Jiansong Huang, Yunfei Lv, Xia Li, Wenle Ye, Huafeng Wang, Jinghan Wang, Jie Jin.

  Previous evidence has confirmed that branched-chain aminotransferase-1 (BCAT1), a key enzyme governing branched-chain amino acid (BCAA) metabolism, has a role in cancer aggression partly by restricting αKG levels and inhibiting the activities of the αKG-dependent enzyme family. The oncogenic role of BCAT1, however, was not fully elucidated in acute myeloid leukemia (AML). In this study, we investigated the clinical significance and biological insight of BCAT1 in AML. Using q-PCR, we analyzed BCAT1 mRNAs in bone marrow samples from 332 patients with newly diagnosed AML. High BCAT1 expression independently predicts poor prognosis in patients with AML. We also established BCAT1 knockout (KO)/over-expressing (OE) AML cell lines to explore the underlying mechanisms. We found that BCAT1 affects cell proliferation and modulates cell cycle, cell apoptosis, and DNA damage/repair process. Additionally, we demonstrated that BCAT1 regulates histone methylation by reducing intracellular αKG levels in AML cells. Moreover, high expression of BCAT1 enhances the sensitivity of AML cells to the Poly (ADP-ribose) polymerase (PARP) inhibitor both in vivo and in vitro. Our study has demonstrated that BCAT1 expression can serve as a reliable predictor for AML patients, and PARP inhibitor BMN673 can be used as an effective treatment strategy for patients with high BCAT1 expression. KEY MESSAGES: High expression of BCAT1 is an independent risk factor for poor prognosis in patients with CN-AML. High BCAT1 expression in AML limits intracellular αKG levels, impairs αKG-dependent histone demethylase activity, and upregulates H3K9me3 levels. H3K9me3 inhibits ATM expression and blocks cellular DNA damage repair process. Increased sensitivity of BCAT1 high expression AML to PARP inhibitors may be used as an effective treatment strategy in AML patients.

Keywords:  AML; BCAT1; Histone methylation; PARP inhibitor; αKG

DOI:  https://doi.org/10.1007/s00109-023-02409-1
Mol Metab. 2024 Feb 12. pii: S2212-8778(24)00031-0. [Epub ahead of print] 101900

Loss of mitochondrial pyruvate carrier 1 supports proline-dependent proliferation and collagen biosynthesis in ovarian cancer.

M R Farook, Z Croxford, S Morgan, A D Horlock, A Holt, A Rees, B J Jenkins, C Tse, E Stanton, D M Davies, C A Thornton, N Jones, I M Sheldon, E E Vincent, J G Cronin.

The pyruvate transporter MPC1 (mitochondrial pyruvate carrier 1) acts as a tumour-suppressor, loss of which correlates with a pro-tumorigenic phenotype and poor survival in several tumour types. In high-grade serous ovarian cancers (HGSOC), patients display copy number loss of MPC1 in around 78% of cases and reduced MPC1 mRNA expression. To explore the metabolic effect of reduced expression, we demonstrate that depleting MPC1 in HGSOC cell lines drives expression of key proline biosynthetic genes; PYCR1, PYCR2 and PYCR3, and biosynthesis of proline. We show that altered proline metabolism underpins cancer cell proliferation, reactive oxygen species (ROS) production, and type I and type VI collagen formation in ovarian cancer cells. Furthermore, exploring The Cancer Genome Atlas, we discovered the PYCR3 isozyme to be highly expressed in a third of HGSOC patients, which was associated with more aggressive disease and diagnosis at a younger age. Taken together, our study highlights that targeting proline metabolism is a potential therapeutic avenue for the treatment of HGSOC.

DOI: https://doi.org/10.1016/j.molmet.2024.101900
Aging Cell. 2024 Feb 11. e14107

Restricting bioenergetic efficiency enhances longevity and mitochondrial redox capacity in Drosophila melanogaster.

Analisa L Taylor, Olga Dubuisson, Pritika Pandey, Elizabeth R M Zunica, Bolormaa Vandanmagsar, Wagner S Dantas, Alyssa Johnson, Christopher L Axelrod, John P Kirwan.

  Mitochondria are essential for survival and as such, impairments in organelle homeostasis significantly accelerate age-related morbidity and mortality. Here, we determined the contribution of bioenergetic efficiency to life span and health span in Drosophila melanogaster utilizing the mitochondrial uncoupler BAM15. Life span was determined in flies fed a normal diet (ND) or high fat diet (HFD) supplemented with vehicle or BAM15. Locomotor function was determined by negative geotaxis assay in middle-aged flies fed vehicle or BAM15 under ND or HFD conditions. Redox capacity (high-resolution respirometry/fluorometry), citrate synthase (enzyme activity), mtDNA content (qPCR), gene expression (qPCR), and protein expression (western blot) were assessed in flight muscle homogenates of middle-aged flies fed vehicle or BAM15 ND. The molar ratio of H2 O2 and O2 (H2 O2 :O2 ) in a defined respiratory state was calculated as a measure of redox balance. BAM15 extended life span by 9% on ND and 25% on HFD and improved locomotor activity by 125% on ND and 53% on HFD. Additionally, BAM15 enhanced oxidative phosphorylation capacity supported by pyruvate + malate, proline, and glycerol 3-phosphate. Concurrently, BAM15 enhanced the mitochondrial H2 O2 production rate, reverse electron flow from mitochondrial glycerol-3-phosphate dehydrogenase (mGPDH) to Complex I, mGPDH, and Complex I without altering the H2 O2 :O2 ratio. BAM15 upregulated transcriptional signatures associated with mitochondrial function and fitness as well as antioxidant defense. BAM15-mediated restriction of bioenergetic efficiency prolongs life span and health span in Drosophila fed a ND or HFD. Improvements in life span and health span in ND were supported by synergistic enhancement of muscular redox capacity.

Keywords:  BAM15; aging; bioenergetics; mitochondrial uncoupling

DOI:  https://doi.org/10.1111/acel.14107
Nat Commun. 2024 Feb 10. 15(1): 1252

Nutrient-dependent regulation of a stable intron modulates germline mitochondrial quality control.

Annabel Qi En Ng, Seow Neng Chan, Jun Wei Pek.

Mitochondria are inherited exclusively from the mothers and are required for the proper development of embryos. Hence, germline mitochondrial quality is highly regulated during oogenesis to ensure oocyte viability. How nutrient availability influences germline mitochondrial quality control is unclear. Here we find that fasting leads to the accumulation of mitochondrial clumps and oogenesis arrest in Drosophila. Fasting induces the downregulation of the DIP1-Clueless pathway, leading to an increase in the expression of a stable intronic sequence RNA called sisR-1. Mechanistically, sisR-1 localizes to the mitochondrial clumps to inhibit the poly-ubiquitination of the outer mitochondrial protein Porin/VDAC1, thereby suppressing p62-mediated mitophagy. Alleviation of the fasting-induced high sisR-1 levels by either sisR-1 RNAi or refeeding leads to mitophagy, the resumption of oogenesis and an improvement in oocyte quality. Thus, our study provides a possible mechanism by which fasting can improve oocyte quality by modulating the mitochondrial quality control pathway. Of note, we uncover that the sisR-1 response also regulates mitochondrial clumping and oogenesis during protein deprivation, heat shock and aging, suggesting a broader role for this mechanism in germline mitochondrial quality control.

DOI: https://doi.org/10.1038/s41467-024-45651-y
Nat Commun. 2024 Feb 13. 15(1): 1328

Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1.

Kristy Rochon, Brianna L Bauer, Nathaniel A Roethler, Yuli Buckley, Chih-Chia Su, Wei Huang, Rajesh Ramachandran, Maria S K Stoll, Edward W Yu, Derek J Taylor, Jason A Mears.

Mitochondrial fission is a critical cellular event to maintain organelle function. This multistep process is initiated by the enhanced recruitment and oligomerization of dynamin-related protein 1 (Drp1) at the surface of mitochondria. As such, Drp1 is essential for inducing mitochondrial division in mammalian cells, and homologous proteins are found in all eukaryotes. As a member of the dynamin superfamily of proteins (DSPs), controlled Drp1 self-assembly into large helical polymers stimulates its GTPase activity to promote membrane constriction. Still, little is known about the mechanisms that regulate correct spatial and temporal assembly of the fission machinery. Here we present a cryo-EM structure of a full-length Drp1 dimer in an auto-inhibited state. This dimer reveals two key conformational rearrangements that must be unlocked through intramolecular rearrangements to achieve the assembly-competent state observed in previous structures. This structural insight provides understanding into the mechanism for regulated self-assembly of the mitochondrial fission machinery.

DOI: https://doi.org/10.1038/s41467-024-45524-4
Mol Cell. 2024 Feb 06. pii: S1097-2765(24)00052-2. [Epub ahead of print]

The HRI branch of the integrated stress response selectively triggers mitophagy.

Yogaditya Chakrabarty, Zheng Yang, Hsiuchen Chen, David C Chan.

  To maintain mitochondrial homeostasis, damaged or excessive mitochondria are culled in coordination with the physiological state of the cell. The integrated stress response (ISR) is a signaling network that recognizes diverse cellular stresses, including mitochondrial dysfunction. Because the four ISR branches converge to common outputs, it is unclear whether mitochondrial stress detected by this network can regulate mitophagy, the autophagic degradation of mitochondria. Using a whole-genome screen, we show that the heme-regulated inhibitor (HRI) branch of the ISR selectively induces mitophagy. Activation of the HRI branch results in mitochondrial localization of phosphorylated eukaryotic initiation factor 2, which we show is sufficient to induce mitophagy. The HRI mitophagy pathway operates in parallel with the mitophagy pathway controlled by the Parkinson's disease related genes PINK1 and PARKIN and is mechanistically distinct. Therefore, HRI repurposes machinery that is normally used for translational initiation to trigger mitophagy in response to mitochondrial damage.

Keywords:  autophagy; integrated stress response; iron metabolism; mitochondria; mitophagy; organelle quality control

DOI:  https://doi.org/10.1016/j.molcel.2024.01.016
Mol Cell. 2024 Feb 15. pii: S1097-2765(23)01083-3. [Epub ahead of print]84(4): 616-618

SLC25A39 links mitochondrial GSH sensing with iron metabolism.

Xiong Chen, Boyi Gan.

Two recent studies by Liu et al.1 in Science and Shi et al.2 in this issue of Molecular Cell identify a mitochondrial GSH-sensing mechanism that couples SLC25A39-mediated GSH import to iron metabolism, advancing our understanding of nutrient sensing within organelles.

DOI: https://doi.org/10.1016/j.molcel.2023.12.037
Nat Commun. 2024 Feb 14. 15(1): 1359

Leukemic stem cells activate lineage inappropriate signalling pathways to promote their growth.

Sophie G Kellaway, Sandeep Potluri, Peter Keane, Helen J Blair, Luke Ames, Alice Worker, Paulynn S Chin, Anetta Ptasinska, Polina K Derevyanko, Assunta Adamo, Daniel J L Coleman, Naeem Khan, Salam A Assi, Anja Krippner-Heidenreich, Manoj Raghavan, Peter N Cockerill, Olaf Heidenreich, Constanze Bonifer.

Acute Myeloid Leukemia (AML) is caused by multiple mutations which dysregulate growth and differentiation of myeloid cells. Cells adopt different gene regulatory networks specific to individual mutations, maintaining a rapidly proliferating blast cell population with fatal consequences for the patient if not treated. The most common treatment option is still chemotherapy which targets such cells. However, patients harbour a population of quiescent leukemic stem cells (LSCs) which can emerge from quiescence to trigger relapse after therapy. The processes that allow such cells to re-grow remain unknown. Here, we examine the well characterised t(8;21) AML sub-type as a model to address this question. Using four primary AML samples and a novel t(8;21) patient-derived xenograft model, we show that t(8;21) LSCs aberrantly activate the VEGF and IL-5 signalling pathways. Both pathways operate within a regulatory circuit consisting of the driver oncoprotein RUNX1::ETO and an AP-1/GATA2 axis allowing LSCs to re-enter the cell cycle while preserving self-renewal capacity.

DOI: https://doi.org/10.1038/s41467-024-45691-4
Mitochondrial Commun. 2024 ;2 14-20

Mitochondrial Calcium Transport During Autophagy Initiation.

Sujyoti Chandra, Parul Katiyar, Aarooran S Durairaj, Xinnan Wang.

  While it has been shown that Ca2+ dynamics at the ER membrane is essential for the initiation of certain types of autophagy such as starvation-induced autophagy, how mitochondrial Ca2+ transport changes during the first stage of autophagy is not systemically characterized. An investigation of mitochondrial Ca2+ dynamics during autophagy initiation may help us determine the relationship between autophagy and mitochondrial Ca2+ fluxes. Here we examine acute mitochondrial and ER calcium responses to a panel of autophagy inducers in different cell types. Mitochondrial Ca2+ transport and Ca2+ transients at the ER membrane are triggered by different autophagy inducers. The mitophagy-inducer-initiated mitochondrial Ca2+ uptake relies on mitochondrial calcium uniporter and may decelerate the following mitophagy. In neurons derived from a Parkinson's patient, mitophagy-inducer-triggered mitochondrial Ca2+ influx is faster, which may slow the ensuing mitophagy.

Keywords:  ER Ca2+ transient; IP3R; MCU; Parkinson; RyR; autophagy; mitochondrial Ca2+ uptake; mitophagy

DOI:  https://doi.org/10.1016/j.mitoco.2024.01.002
Cell Rep. 2024 Feb 12. pii: S2211-1247(24)00066-4. [Epub ahead of print]43(2): 113738

Proline restores mitochondrial function and reverses aging hallmarks in senescent cells.

Debanik Choudhury, Na Rong, Hamsa Vardini Senthil Kumar, Sydney Swedick, Ronel Z Samuel, Pihu Mehrotra, John Toftegaard, Nika Rajabian, Ramkumar Thiyagarajan, Ashis K Podder, Yulun Wu, Shahryar Shahini, Kenneth L Seldeen, Bruce Troen, Pedro Lei, Stelios T Andreadis.

  Mitochondrial dysfunction is a hallmark of cellular senescence, with the loss of mitochondrial function identified as a potential causal factor contributing to senescence-associated decline in cellular functions. Our recent findings revealed that ectopic expression of the pluripotency transcription factor NANOG rejuvenates dysfunctional mitochondria of senescent cells by rewiring metabolic pathways. In this study, we report that NANOG restores the expression of key enzymes, PYCR1 and PYCR2, in the proline biosynthesis pathway. Additionally, senescent mesenchymal stem cells manifest severe mitochondrial respiratory impairment, which is alleviated through proline supplementation. Proline induces mitophagy by activating AMP-activated protein kinase α and upregulating Parkin expression, enhancing mitochondrial clearance and ultimately restoring cell metabolism. Notably, proline treatment also mitigates several aging hallmarks, including DNA damage, senescence-associated β-galactosidase, inflammatory cytokine expressions, and impaired myogenic differentiation capacity. Overall, this study highlights the role of proline in mitophagy and its potential in reversing senescence-associated mitochondrial dysfunction and aging hallmarks.

Keywords:  AMPKα; CP: Cell biology; CP: Metabolism; Parkin; aging; amino acid; autophagy; mitochondria; mitophagy; proline; senescence

DOI:  https://doi.org/10.1016/j.celrep.2024.113738
Nat Commun. 2024 Feb 16. 15(1): 1454

A system for inducible mitochondria-specific protein degradation in vivo.

Swastika Sanyal, Anna Kouznetsova, Lena Ström, Camilla Björkegren.

Targeted protein degradation systems developed for eukaryotes employ cytoplasmic machineries to perform proteolysis. This has prevented mitochondria-specific analysis of proteins that localize to multiple locations, for example, the mitochondria and the nucleus. Here, we present an inducible mitochondria-specific protein degradation system in Saccharomyces cerevisiae based on the Mesoplasma florum Lon (mf-Lon) protease and its corresponding ssrA tag (called PDT). We show that mitochondrially targeted mf-Lon protease efficiently and selectively degrades a PDT-tagged reporter protein localized to the mitochondrial matrix. The degradation can be induced by depleting adenine from the medium, and tuned by altering the promoter strength of the MF-LON gene. We furthermore demonstrate that mf-Lon specifically degrades endogenous, PDT-tagged mitochondrial proteins. Finally, we show that mf-Lon-dependent PDT degradation can also be achieved in human mitochondria. In summary, this system provides an efficient tool to selectively analyze the mitochondrial function of dually localized proteins.

DOI: https://doi.org/10.1038/s41467-024-45819-6
Biosens Bioelectron. 2024 Feb 09. pii: S0956-5663(24)00128-3. [Epub ahead of print]251 116123

Rational design of mitochondria-targeted fluorescent biosensors for in vivo elucidation of the interaction between breast cancer metastasis and mitochondrial autophagy.

Liangchao Yuan, Yuyao Cao, Qing Zhang, Jiancheng Pan, Changjian Wu, Yaxi Ye, Qingcai Jiao, Hai-Liang Zhu, Zhongchang Wang.

  Breast cancer lung metastases (BCLM) are a major cause of high mortality in patients. The shortage of therapeutic targets and rapid drug screening tools for BCLM is a major challenge at present. Mitochondrial autophagy, which involves the degradation of proteins associated with cancer cell aggressiveness, represents a possible therapeutic approach for the treatment of BCLM. Herein, four fluorescent biosensors with different alkyl chains were designed and synthesized to monitor mitochondrial autophagy. Among them, PMV-12 demonstrated the highest sensitivity to viscosity variance, the least impact on polarity, and the longest imaging time. The introduction of the C12-chain made PMV-12 anchored in the mitochondrial membrane without being disturbed by changes of the mitochondrial membrane potential (MMP), thereby achieving the long-term monitor in situ for mitochondrial autophagy. Mitochondria stained with PMV-12 induced swelling and viscosity increase after treating with apigenin, which indicated that apigenin is a potential mitochondrial autophagy inducer. Apigenin was subsequently verified to inhibit cancer cell invasion by 92%. Furthermore, PMV-12 could monitor the process of BCLM in vivo and evaluate the therapeutic effects of apigenin. This work provides a fluorescent tool for elucidating the role of mitochondrial autophagy in the BCLM process and for anti-metastatic drug development.

Keywords:  Breast cancer metastasis; Fluorescence imaging; Long-term visualization; Mitochondrial autophagy

DOI:  https://doi.org/10.1016/j.bios.2024.116123
Am J Hematol. 2024 Feb 11.

Long-term follow-up of VIALE-A: Venetoclax and azacitidine in chemotherapy-ineligible untreated acute myeloid leukemia.

Keith W Pratz, Brian A Jonas, Vinod Pullarkat, Michael J Thirman, Jacqueline S Garcia, Hartmut Döhner, Christian Récher, Walter Fiedler, Kazuhito Yamamoto, Jianxiang Wang, Sung-Soo Yoon, Ofir Wolach, Su-Peng Yeh, Brian Leber, Jordi Esteve, Jiri Mayer, Kimmo Porkka, Árpád Illés, Roberto M Lemoli, Mehmet Turgut, Grace Ku, Catherine Miller, Ying Zhou, Meng Zhang, Brenda Chyla, Jalaja Potluri, Courtney D DiNardo.

Venetoclax-azacitidine is approved for treatment of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy based on the interim overall survival (OS) analysis of the VIALE-A study (NCT02993523). Here, long-term follow-up is presented to address survival benefit and long-term outcomes with venetoclax-azacitidine. Patients with newly diagnosed AML who were ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax-azacitidine or placebo-azacitidine. OS was the primary endpoint; complete remission with/without blood count recovery (CR/CRi) was a key secondary endpoint. This final analysis was conducted when 100% of the predefined 360 OS events occurred. In VIALE-A, 431 patients were enrolled to venetoclax-azacitidine (n = 286) or placebo-azacitidine (n = 145). At 43.2 months median follow-up, median OS was 14.7 months (95% confidence interval [CI], 12.1-18.7) with venetoclax-azacitidine, and 9.6 months (95% CI, 7.4-12.7) with placebo-azacitidine (hazard ratio, 0.58 [95% CI, 0.47-0.72], p < .001); the estimated 24-month OS rate was 37.5% and 16.9%, respectively. Median OS for patients with IDH1/2 mutations and those with measurable residual disease responses was reached in this final analysis. CR/CRi rate was similar to interim analysis. Any-grade hematologic and gastrointestinal adverse events were most common in venetoclax-azacitidine and placebo-azacitidine arms, including thrombocytopenia (47% and 42%) and neutropenia (43% and 29%). No new safety signals were identified. Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities.

DOI: https://doi.org/10.1002/ajh.27246
Nat Genet. 2024 Feb 13.

Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer.

Sudhir B Malla, Ryan M Byrne, Maxime W Lafarge, Shania M Corry, Natalie C Fisher, Petros K Tsantoulis, Megan L Mills, Rachel A Ridgway, Tamsin R M Lannagan, Arafath K Najumudeen, Kathryn L Gilroy, Raheleh Amirkhah, Sarah L Maguire, Eoghan J Mulholland, Hayley L Belnoue-Davis, Elena Grassi, Marco Viviani, Emily Rogan, Keara L Redmond, Svetlana Sakhnevych, Aoife J McCooey, Courtney Bull, Emily Hoey, Nicoleta Sinevici, Holly Hall, Baharak Ahmaderaghi, Enric Domingo, Andrew Blake, Susan D Richman, Claudio Isella, Crispin Miller, Andrea Bertotti, Livio Trusolino, Maurice B Loughrey, Emma M Kerr, Sabine Tejpar, Timothy S Maughan, Mark Lawler, Andrew D Campbell, Simon J Leedham, Viktor H Koelzer, Owen J Sansom, Philip D Dunne.

Molecular stratification using gene-level transcriptional data has identified subtypes with distinctive genotypic and phenotypic traits, as exemplified by the consensus molecular subtypes (CMS) in colorectal cancer (CRC). Here, rather than gene-level data, we make use of gene ontology and biological activation state information for initial molecular class discovery. In doing so, we defined three pathway-derived subtypes (PDS) in CRC: PDS1 tumors, which are canonical/LGR5+ stem-rich, highly proliferative and display good prognosis; PDS2 tumors, which are regenerative/ANXA1+ stem-rich, with elevated stromal and immune tumor microenvironmental lineages; and PDS3 tumors, which represent a previously overlooked slow-cycling subset of tumors within CMS2 with reduced stem populations and increased differentiated lineages, particularly enterocytes and enteroendocrine cells, yet display the worst prognosis in locally advanced disease. These PDS3 phenotypic traits are evident across numerous bulk and single-cell datasets, and demark a series of subtle biological states that are currently under-represented in pre-clinical models and are not identified using existing subtyping classifiers.

DOI: https://doi.org/10.1038/s41588-024-01654-5
Cancer Immunol Immunother. 2024 Feb 10. 73(2): 40

Enhanced T cell immune activity mediated by Drp1 promotes the efficacy of PD-1 inhibitors in treating lung cancer.

Jietao Ma, Jun Song, Xiaofang Yi, Shuling Zhang, Li Sun, Letian Huang, Chengbo Han.

   BACKGROUND: Dynamin-related protein 1 (Drp1)-mediated mitochondrial fission plays important roles in the activation, proliferation, and migration of T cells.
METHODS: We investigated the synergistic effect of Drp1-mediated T cell antitumor activities and programmed cell death protein 1 (PD-1) blockade for treating lung cancer through in vitro co-culture experiments and an in vivo nude mouse xenograft model.
RESULTS: High expression levels of Drp1 positively regulated T cell activation, enhanced T cell-induced suppression of lung cancer cells, promoted CD8+ T cell infiltration in the tumor and spleen, and significantly enhanced the antitumor immune response of the PD-1 inhibitor pembrolizumab. The mechanism of this synergistic antitumor effect involved the secretion of immune killing-related cytokines and the regulation of the PD-1-ERK/Drp1 pathway in T cells.
CONCLUSIONS: Our findings suggest that modifying Drp1 expression in T cells could serve as a potential therapeutic target for enhancing the antitumor immune response in future immunotherapies.

Keywords:  Dynamin-related protein 1; Immunotherapy; Lung cancer; Programmed cell death protein 1; T cells

DOI:  https://doi.org/10.1007/s00262-023-03582-5
bioRxiv. 2024 Feb 10. pii: 2024.01.29.577835. [Epub ahead of print]

Mitochondrial DNA copy number reduction via in vitro TFAM knockout remodels the nuclear epigenome and transcriptome.

Julia Nguyen, Phyo W Win, Tyler Shin Nagano, Elly H Shin, Charles Newcomb, Dan E Arking, Christina A Castellani.

Mitochondrial DNA copy number (mtDNA-CN) is associated with several age-related chronic diseases and is a predictor of all-cause mortality. Here, we examine site-specific differential nuclear DNA (nDNA) methylation and differential gene expression resulting from in vitro reduction of mtDNA-CN to uncover shared genes and biological pathways mediating the effect of mtDNA-CN on disease. Epigenome and transcriptome profiles were generated for three independent human embryonic kidney (HEK293T) cell lines harbouring a mitochondrial transcription factor A ( TFAM ) heterozygous knockout generated via CRISPR-Cas9, and matched control lines. We identified 4,242 differentially methylated sites, 228 differentially methylated regions, and 179 differentially expressed genes associated with mtDNA-CN. Integrated analysis uncovered 381 Gene-CpG pairs. GABAA receptor genes and related pathways, the neuroactive ligand receptor interaction pathway, ABCD1/2 gene activity, and cell signalling processes were overrepresented, providing insight into the underlying biological mechanisms facilitating these associations. We also report evidence implicating chromatin state regulatory mechanisms as modulators of mtDNA-CN effect on gene expression. We demonstrate that mitochondrial DNA variation signals to the nuclear DNA epigenome and transcriptome and may lead to nuclear remodelling relevant to development, aging, and complex disease.

DOI: https://doi.org/10.1101/2024.01.29.577835