bims-mibica 2024-12-22 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2024–12–22
twenty-one papers selected by
Kelsey Fisher-Wellman, Wake Forest University

Lysosomal/mitochondrial interaction promotes tumor growth in squamous cell carcinoma of the head and neck.
Metformin targets mitochondrial complex I to lower blood glucose levels.
SLMO transfers phosphatidylserine between the outer and inner mitochondrial membrane in Drosophila.
USP39 regulates pyruvate handling in non-small cell lung cancer.
Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.
Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity.
Mapping mitochondrial aging.
A whole food, plant-based diet reduces amino acid levels in patients with metastatic breast cancer.
Increased mitochondrial mutation heteroplasmy induces aging phenotypes in pluripotent stem cells and their differentiated progeny.
Heme promotes venetoclax resistance in multiple myeloma through MEK-ERK signaling and purine biosynthesis.
Mitochondrial-targeting strategies with homoharringtonine: A novel approach for chemoresistant rectal cancer.
In-Gel Activity Assay of Mammalian Mitochondrial and Cytosolic Aconitases, Surrogate Markers of Compartment-Specific Oxidative Stress and Iron Status.
Meeting metformin again for the first time.
Early detection of colorectal cancer using aberrant circulating cell-free mitochondrial DNA fragmentomics.
Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.
Enhanced Oxidative Phosphorylation Driven by TACO1 Mitochondrial Translocation Promotes Stemness and Cisplatin Resistance in Bladder Cancer.
Crucial role and conservation of the three [2Fe-2S] clusters in the human mitochondrial ribosome.
Early downmodulation of tumor glycolysis predicts response to fasting-mimicking diet in triple-negative breast cancer patients.
A GIMEMA survey on therapeutic use and response rates of FLT3 inhibitors in acute myeloid leukemia: Insights from Italian real-world practice.
CPX-351 plus gemtuzumab ozogamicin for relapsed/refractory acute myelogenous leukemia: a University of California Hematologic Malignancies Consortium trial.
PGC1α is a key regulator of erastin-induced mitochondrial dysfunction during ferroptotic cell death.

Mol Cancer Res. 2024 Dec 19.

Lysosomal/mitochondrial interaction promotes tumor growth in squamous cell carcinoma of the head and neck.

Avani Gopalkrishnan, Nathaniel Wang, Silvia Cruz-Rangel, Abdul Yassin-Kassab, Sruti Shiva, Chareeni Kurukulasuriya, Satdarshan P Monga, Ralph J DeBerardinis, Heath D Skinner, Kirill Kiselyov, Umamaheswar Duvvuri.

Communication between intracellular organelles including lysosomes and mitochondria has recently been shown to regulate cellular proliferation and fitness. The way lysosomes and mitochondria communicate with each other (lysosomal/mitochondrial interaction, LMI) is, emerging as a major determinant of tumor proliferation and growth. About 30% of squamous carcinomas (including squamous cell carcinoma of the head and neck, SCCHN) overexpress TMEM16A, a calcium-activated chloride channel, which promotes cellular growth and negatively correlates with patient survival. We have recently shown that TMEM16A drives lysosomal biogenesis, but its impact on mitochondrial function has not been explored. Here, we show that in the context of high TMEM16A SCCHN, (1) patients display increased mitochondrial content, specifically complex I; (2) In vitro and in vivo models uniquely depend on mitochondrial complex I activity for growth and survival; (3) NRF2 signaling is a critical linchpin that drives mitochondrial function, and (4) mitochondrial complex I and lysosomal function are codependent for proliferation. Taken together, our data demonstrate that coordinated lysosomal and mitochondrial activity and biogenesis via LMI drive tumor proliferation and facilitates a functional interaction between lysosomal and mitochondrial networks. Therefore, inhibition of LMI instauration may serve as a therapeutic strategy for patients with SCCHN. Implications: Intervention of lysosome-mitochondria interaction may serve as a therapeutic approach for patients with high TMEM16A expressing SCCHN.

DOI: https://doi.org/10.1158/1541-7786.MCR-24-0337
Sci Adv. 2024 Dec 20. 10(51): eads5466

Metformin targets mitochondrial complex I to lower blood glucose levels.

Colleen R Reczek, Ram P Chakrabarty, Karis B D'Alessandro, Zachary L Sebo, Rogan A Grant, Peng Gao, G R Budinger, Navdeep S Chandel.

Metformin is among the most prescribed antidiabetic drugs, but the primary molecular mechanism by which metformin lowers blood glucose levels is unknown. Previous studies have proposed numerous mechanisms by which acute metformin lowers blood glucose, including the inhibition of mitochondrial complex I of the electron transport chain (ETC). Here, we used transgenic mice that globally express the Saccharomyces cerevisiae internal alternative NADH dehydrogenase (NDI1) protein to determine whether the glucose-lowering effect of acute oral administration of metformin requires inhibition of mitochondrial complex I of the ETC in vivo. NDI1 is a yeast NADH dehydrogenase enzyme that complements the loss of mammalian mitochondrial complex I electron transport function and is insensitive to pharmacologic mitochondrial complex I inhibitors including metformin. We demonstrate that NDI1 expression attenuates metformin's ability to lower blood glucose levels under standard chow and high-fat diet conditions. Our results indicate that acute oral administration of metformin targets mitochondrial complex I to lower blood glucose.

DOI: https://doi.org/10.1126/sciadv.ads5466
PLoS Biol. 2024 Dec;22(12): e3002941

SLMO transfers phosphatidylserine between the outer and inner mitochondrial membrane in Drosophila.

Siwen Zhao, Xuguang Jiang, Ning Li, Tao Wang.

Phospholipids are critical building blocks of mitochondria, and proper mitochondrial function and architecture rely on phospholipids that are primarily transported from the endoplasmic reticulum (ER). Here, we show that mitochondrial form and function rely on synthesis of phosphatidylserine (PS) in the ER through phosphatidylserine synthase (PSS), trafficking of PS from ER to mitochondria (and within mitochondria), and the conversion of PS to phosphatidylethanolamine (PE) by phosphatidylserine decarboxylase (PISD) in the inner mitochondrial membrane (IMM). Using a forward genetic screen in Drosophila, we found that Slowmo (SLMO) specifically transfers PS from the outer mitochondrial membrane (OMM) to the IMM within the inner boundary membrane (IBM) domain. Thus, SLMO is required for shaping mitochondrial morphology, but its putative conserved binding partner, dTRIAP, is not. Importantly, SLMO's role in maintaining mitochondrial morphology is conserved in humans via the SLMO2 protein and is independent of mitochondrial dynamics. Our results highlight the importance of a conserved PSS-SLMO-PISD pathway in maintaining the structure and function of mitochondria.

DOI: https://doi.org/10.1371/journal.pbio.3002941
Cell Death Discov. 2024 Dec 18. 10(1): 502

USP39 regulates pyruvate handling in non-small cell lung cancer.

Tina Becirovic, Boxi Zhang, Helin Vakifahmetoglu-Norberg, Vitaliy O Kaminskyy, Elena Kochetkova, Erik Norberg.

The ubiquitin-specific peptidase 39 (USP39) belongs to the USP family of cysteine proteases representing the largest group of human deubiquitinases (DUBs). While the oncogenic function of USP39 has been investigated in various cancer types, its roles in non-small cell lung cancer (NSCLC) remain largely unknown. Here, by applying a gene set enrichment analysis (GSEA) on lung adenocarcinoma tissues and metabolite set enrichment analysis (MSEA) on NSCLC cells depleted of USP39, we identified a previously unknown link between USP39 and the metabolism in NSCLC cells. Mechanistically, we uncovered a component of the pyruvate dehydrogenase (PDH) complex, pyruvate dehydrogenase E1 subunit alpha (PDHA), as a target of USP39. We further present that USP39 silencing caused an elevation in Lys63 ubiquitination on PDHA and a reduction in the PDH complex activity, the levels of TCA cycle intermediates, mitochondrial respiration, cell proliferation in vitro, and of tumor growth in vivo. Consistently, citrate supplementation restored mitochondrial respiration and cell growth in USP39-depleted cells. Our study elucidates and describes how USP39 regulates pyruvate metabolism through a deubiquitylation process that affects NSCLC tumor growth.

DOI: https://doi.org/10.1038/s41420-024-02264-0
Nat Metab. 2024 Dec;6(12): 2319-2337

Subcellular NAD+ pools are interconnected and buffered by mitochondrial NAD.

Lena E Høyland, Magali R VanLinden, Marc Niere, Øyvind Strømland, Suraj Sharma, Jörn Dietze, Ingvill Tolås, Eva Lucena, Ersilia Bifulco, Lars J Sverkeli, Camila Cimadamore-Werthein, Hanan Ashrafi, Kjellfrid F Haukanes, Barbara van der Hoeven, Christian Dölle, Cédric Davidsen, Ina K N Pettersen, Karl J Tronstad, Svein A Mjøs, Faisal Hayat, Mikhail V Makarov, Marie E Migaud, Ines Heiland, Mathias Ziegler.

The coenzyme NAD+ is consumed by signalling enzymes, including poly-ADP-ribosyltransferases (PARPs) and sirtuins. Ageing is associated with a decrease in cellular NAD+ levels, but how cells cope with persistently decreased NAD+ concentrations is unclear. Here, we show that subcellular NAD+ pools are interconnected, with mitochondria acting as a rheostat to maintain NAD+ levels upon excessive consumption. To evoke chronic, compartment-specific overconsumption of NAD+, we engineered cell lines stably expressing PARP activity in mitochondria, the cytosol, endoplasmic reticulum or peroxisomes, resulting in a decline of cellular NAD+ concentrations by up to 50%. Isotope-tracer flux measurements and mathematical modelling show that the lowered NAD+ concentration kinetically restricts NAD+ consumption to maintain a balance with the NAD+ biosynthesis rate, which remains unchanged. Chronic NAD+ deficiency is well tolerated unless mitochondria are directly targeted. Mitochondria maintain NAD+ by import through SLC25A51 and reversibly cleave NAD+ to nicotinamide mononucleotide and ATP when NMNAT3 is present. Thus, these organelles can maintain an additional, virtual NAD+ pool. Our results are consistent with a well-tolerated ageing-related NAD+ decline as long as the vulnerable mitochondrial pool is not directly affected.

DOI: https://doi.org/10.1038/s42255-024-01174-w
Cancer Res. 2024 Dec 19.

Selenoprotein O Promotes Melanoma Metastasis and Regulates Mitochondrial Complex II Activity.

Luiza Martins Nascentes Melo, Marie Sabatier, Vijayashree Ramesh, Krystina J Szylo, Cameron S Fraser, Alexandra Pon, Evann C Mitchell, Kelly A Servage, Gabriele Allies, Isa V Westedt, Feyza Cansiz, Jonathan Krystkiewicz, Andrea Kutritz, Dirk Schadendorf, Sean J Morrison, Jessalyn M Ubellacker, Anju Sreelatha, Alpaslan Tasdogan.

Evolutionarily conserved selenoprotein O (SELENOO) catalyzes a post-translational protein modification known as AMPylation that is essential for the oxidative stress response in bacteria and yeast. Given that oxidative stress experienced in the blood limits survival of metastasizing melanoma cells, SELENOO might be able to impact metastatic potential. However, further work is needed to elucidate the substrates and functional relevance of the mammalian homologue of SELENOO. Here, we revealed that SELENOO promotes cancer metastasis and identified substrates of SELENOO in mammalian mitochondria. In patients with melanoma, high SELENOO expression was correlated with metastasis and poor overall survival. In a murine model of spontaneous melanoma metastasis, SELENOO deficiency significantly reduced metastasis to distant visceral organs, which could be rescued by treatment with the antioxidant N-acetylcysteine. Mechanistically, SELENOO AMPylated multiple mitochondrial substrates, including succinate dehydrogenase subunit A, one of the four key subunits of mitochondrial complex II. Consistently, SELENOO-deficient cells featured increased mitochondrial complex II activity. Together, these findings demonstrate that SELENOO deficiency limits melanoma metastasis by modulating mitochondrial function and oxidative stress.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2194
Elife. 2024 Dec 20. pii: e105191. [Epub ahead of print]13

Mapping mitochondrial aging.

Alessandro Bitto.

  Measuring mitochondrial respiration in frozen tissue samples provides the first comprehensive atlas of how aging affects mitochondrial function in mice.

Keywords:  aging; cellular respiration; computational biology; mitochondria; mouse; respiration atlas; sex; systems biology

DOI:  https://doi.org/10.7554/eLife.105191
Cancer Metab. 2024 Dec 19. 12(1): 38

A whole food, plant-based diet reduces amino acid levels in patients with metastatic breast cancer.

TashJaé Q Scales, Bradley Smith, Lisa M Blanchard, Nellie Wixom, Emily T Tuttle, Brian J Altman, Luke J Peppone, Joshua Munger, Thomas M Campbell, Erin K Campbell, Isaac S Harris.

   BACKGROUND: Amino acids are critical to tumor survival. Tumors can acquire amino acids from the surrounding microenvironment, including the serum. Limiting dietary amino acids is suggested to influence their serum levels. Further, a plant-based diet is reported to contain fewer amino acids than an animal-based diet. The extent to which a plant-based diet lowers the serum levels of amino acids in patients with cancer is unclear.
METHODS: Patients with metastatic breast cancer (n = 17) were enrolled in a clinical trial with an ad libitum whole food, plant-based diet for 8 weeks without calorie or portion restriction. Dietary changes by participants were monitored using a three-day food record. Serum was collected from participants at baseline and 8 weeks. Food records and serum were analyzed for metabolic changes.
RESULTS: We found that a whole food, plant-based diet resulted in a lower intake of calories, fat, and amino acids and higher levels of fiber. Additionally, body weight, serum insulin, and IGF were reduced in participants. The diet contained lower levels of essential and non-essential amino acids, except for arginine (glutamine and asparagine were not measured). Importantly, the lowered dietary intake of amino acids translated to reduced serum levels of amino acids in participants (5/9 essential amino acids; 4/11 non-essential amino acids).
CONCLUSIONS: These findings provide a tractable approach to limiting amino acid levels in persons with cancer. This data lays a foundation for studying the relationship between amino acids in patients and tumor progression. Further, a whole-food, plant-based diet has the potential to synergize with cancer therapies that exploit metabolic vulnerabilities.
TRIAL REGISTRATION: The clinical trial was registered with ClinicalTrials.gov identifier NCT03045289 on 2017-02-07.

Keywords:  Amino acids; Calories; Cancer; Carbohydrate; Diet; Fat; Fiber; Plant-based; Protein; Whole food

DOI:  https://doi.org/10.1186/s40170-024-00368-w
Aging Cell. 2024 Dec 16. e14402

Increased mitochondrial mutation heteroplasmy induces aging phenotypes in pluripotent stem cells and their differentiated progeny.

Amy R Vandiver, Alejandro Torres, Amberly Sanden, Thang L Nguyen, Jasmine Gasilla, Mary T Doan, Vahan Martirosian, Austin Hoang, Jonathan Wanagat, Michael A Teitell.

  The mitochondrial genome (mtDNA) is an important source of inherited extranuclear variation. Clonal increases in mtDNA mutation heteroplasmy have been implicated in aging and disease, although the impact of this shift on cell function is challenging to assess. Reprogramming to pluripotency affects mtDNA mutation heteroplasmy. We reprogrammed three human fibroblast lines with known heteroplasmy for deleterious mtDNA point or deletion mutations. Quantification of mutation heteroplasmy in the resulting 76 induced pluripotent stem cell (iPSC) clones yielded a bimodal distribution, creating three sets of clones with high levels or absent mutation heteroplasmy with matched nuclear genomes. iPSC clones with elevated deletion mutation heteroplasmy show altered growth dynamics, which persist in iPSC-derived progenitor cells. We identify transcriptomic and metabolic shifts consistent with increased investment in neutral lipid synthesis as well as increased epigenetic age in high mtDNA deletion mutation iPSC, consistent with changes occurring in cellular aging. Together, these data demonstrate that high mtDNA mutation heteroplasmy induces changes occurring in cellular aging.

Keywords:  aging; iPSC; mitochondria; mtDNA mutation

DOI:  https://doi.org/10.1111/acel.14402
Blood. 2024 Dec 18. pii: blood.2024025690. [Epub ahead of print]

Heme promotes venetoclax resistance in multiple myeloma through MEK-ERK signaling and purine biosynthesis.

Remya Nair, An Vu, Abigail K Freer, Karanpreet S Bhatia, Dongxue Wang, Milan R Savani, Shannon M Matulis, Sagar Lonial, David L Jaye, Lawrence H Boise, Seung-Yong Seo, Timothy William Corson, Ajay K Nooka, Shruti Bhatt, Samuel K McBrayer, Vikas A Gupta, Xin Hu, Benjamin G Barwick, Amit R Reddi, Mala Shanmugam.

We previously demonstrated that reduced intrinsic electron transport chain (ETC) activity predicts and promotes sensitivity to the BCL-2 antagonist, venetoclax (Ven) in multiple myeloma (MM). Heme, an iron-containing prosthetic group, and metabolite is fundamental to maintaining ETC activity. Interrogation of the CD2 subgroup of MM from the CoMMpass trial (NCT01454297), which can be used as a proxy for Ven-sensitive MM (VS MM), shows reduced expression of the conserved heme biosynthesis pathway gene signature. Consistent with this, we identified that VS MM exhibit reduced heme biosynthesis and curiously elevated hemin (oxidized heme) uptake. Supplementation with hemin or protoporphyrin IX (heme lacking iron) promotes Ven resistance while targeting ferrochetalase, the penultimate enzyme involved in heme biosynthesis, increases Ven sensitivity in cell lines and primary MM cells. Mechanistically, heme-mediated activation of pro-survival RAS-RAF-MEK signaling and metabolic rewiring, increasing de novo purine synthesis, were found to contribute to heme-induced Ven resistance. Co-targeting BCL-2 and MCL-1 suppresses heme-induced Ven resistance. Interrogation of the MMRF CoMMpass study of patients shows increased purine and pyrimidine biosynthesis to corelate with poor progression free survival and overall survival. Elevated heme and purine biosynthesis gene signatures were also observed in matched relapse refractory MM, underscoring the relevance of heme metabolism in therapy refractory MM. Overall, our findings reveal for the first time a role for extrinsic heme, a physiologically relevant metabolite, in modulating proximity to the apoptotic threshold with translational implications for BCL-2 antagonism in MM therapy.

DOI: https://doi.org/10.1182/blood.2024025690
Biochem Biophys Res Commun. 2024 Dec 05. pii: S0006-291X(24)01677-2. [Epub ahead of print]743 151141

Mitochondrial-targeting strategies with homoharringtonine: A novel approach for chemoresistant rectal cancer.

Hu Chenghao, Liu Xuefeng, Pang Junli, Wang Ke, Li Haixia, Hu Guangyue, Luo Qingqin, Wu Feng.

  5-Fluorouracil (5-FU) resistance poses a significant challenge in the treatment of rectal cancer, driving the need for novel therapeutic strategies. In this study, we established 5-FU-resistant rectal cancer cell lines (SW837-r, SNU-C1-r) and identified homoharringtonine (HHT) as a potent and selective anticancer agent through high-throughput drug screening of 291 compounds. HHT displayed the highest selective drug sensitivity score (sDSS), showing strong activity against resistant cells while sparing normal rectal epithelial cells. Further investigations revealed that 5-FU-resistant cells exhibited enhanced mitochondrial biogenesis and function compared to normal cells, and HHT exerted its cytotoxic effects by targeting mitochondrial respiration. HHT significantly reduced oxygen consumption rate (OCR), mitochondrial complex I activity, and ATP production in resistant cells, with mitochondrial respiration-deficient ρ0 cells showing reduced sensitivity to HHT. In vivo, HHT alone reduced tumor growth by 60 % in the resistant xenograft model. In the sensitive xenograft model, combination therapy with 5-FU achieved an 85 % reduction in tumor volume compared to controls, with tumors in the combination group displaying minimal regrowth. These results demonstrate that HHT effectively targets mitochondrial function in resistant rectal cancer cells and, in combination with 5-FU, offers synergistic antitumor effects and prolonged tumor suppression. The favorable safety profile of HHT further highlights its potential as a promising therapeutic agent for overcoming 5-FU resistance in rectal cancer.

Keywords:  5-FU resistance; DSS; HHT; High-throughput drug screening; Mitochondrial respiration; Rectal cancer

DOI:  https://doi.org/10.1016/j.bbrc.2024.151141
Bio Protoc. 2024 Dec 05. 14(23): e5126

In-Gel Activity Assay of Mammalian Mitochondrial and Cytosolic Aconitases, Surrogate Markers of Compartment-Specific Oxidative Stress and Iron Status.

Wing-Hang Tong, Tracey A Rouault.

  Two aconitase isoforms are present in mammalian cells: the mitochondrial aconitase (ACO2) that catalyzes the reversible isomerization of citrate to isocitrate in the citric acid cycle, and the bifunctional cytosolic enzyme (ACO1), which also plays a role as an RNA-binding protein in the regulation of intracellular iron metabolism. Aconitase activities in the different subcellular compartments can be selectively inactivated by different genetic defects, iron depletion, and oxidative or nitrative stress. Aconitase contains a [4Fe-4S]2+ cluster that is essential for substrate coordination and catalysis. Many Fe-S clusters are sensitive to oxidative stress, nitrative stress, and reduced iron availability, which forms the basis of redox- and iron-mediated regulation of intermediary metabolism via aconitase and other Fe-S cluster-containing metabolic enzymes, such as succinate dehydrogenase. As such, ACO1 and ACO2 activities can serve as compartment-specific surrogate markers of oxygen levels, reactive oxygen species (ROS), reactive nitrogen species (RNS), iron bioavailability, and the status of intermediary and iron metabolism. Here, we provide a protocol describing a non-denaturing polyacrylamide gel electrophoresis (PAGE)-based procedure that has been successfully used to monitor ACO1 and ACO2 aconitase activities simultaneously in human and mouse cells and tissues. Key features • Monitoring aconitase activity changes in the mitochondria and cytosol simultaneously in response to oxidative or nitrative stress, iron depletion, and various pathophysiological conditions. • Optimized for human and mouse cell lines and tissue samples. • Semi-quantitative detection of aconitase isoforms with different states of phosphorylation and/or post-translational modification.

Keywords:  ACO1; ACO2; Aconitase; IRE-BP1; IRP1; Iron metabolism; Iron regulatory protein 1; Iron response element binding protein 1; Nitrative stress; Oxidative stress

DOI:  https://doi.org/10.21769/BioProtoc.5126
Sci Adv. 2024 Dec 20. 10(51): eadu7436

Meeting metformin again for the first time.

Douglas R Green.

New evidence convincingly shows that metformin, a drug that reduces circulating glucose, acts by inhibiting mitochondrial complex I.

DOI: https://doi.org/10.1126/sciadv.adu7436
Gut. 2024 Dec 18. pii: gutjnl-2024-333533. [Epub ahead of print]

Early detection of colorectal cancer using aberrant circulating cell-free mitochondrial DNA fragmentomics.

Siyuan Wang, Fan Peng, Miao Dang, Huanmin Jiao, Huanqin Zhang, Kaixiang Zhou, Wenjie Guo, Zhiyun Gong, Lin Guo, Renquan Lu, Deliang Li, Bingrong Liu, Xu Guo, Jinliang Xing, Yang Liu.

   BACKGROUND: Early detection of colorectal cancer (CRC) is crucial for improving the survival rates of patients.
OBJECTIVE: We aimed to develop a novel strategy for early CRC detection using the fragmentomic features of circulating cell-free mitochondrial DNA (ccf-mtDNA).
DESIGN: Here, a total of 1147 participants, including 478 healthy controls (HCs), 112 patients with advanced adenomas (AAs) and 557 patients with CRC, were enrolled from five hospitals and plasma samples were collected for capture-based ccf-mtDNA sequencing.
RESULTS: Our data analysis revealed significantly aberrant ccf-mtDNA fragmentomic features in patients with CRC and AA when compared with HCs. Then, a CRC detection (CD) model was constructed based on the fragmentomic features of ccf-mtDNA from 246 patients with CRC and 168 HC in the training cohort, showing area under the curve of 0.9863, sensitivity of 92.68% and specificity of 93.45%. Both internal and two external validation cohorts demonstrated the excellent capacity of CD model in distinguishing patients with early-stage CRC from HCs, greatly surpassing the performance of serum biomarkers. Furthermore, our CD model can also detect patients with AA with a sensitivity of 79.35% in AA cohort 1 and 85.00% in AA cohort 2.
CONCLUSION: In conclusion, based on aberrant ccf-mtDNA fragmentomic features, a novel and non-invasive approach was established for the detection of patients with early-stage CRC or AA, with high performance.

Keywords:  CANCER GENETICS; COLORECTAL CANCER

DOI:  https://doi.org/10.1136/gutjnl-2024-333533
Elife. 2024 Dec 20. pii: RP96926. [Epub ahead of print]13

Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.

Dylan C Sarver, Muzna Saqib, Fangluo Chen, G William Wong.

  Organ function declines with age, and large-scale transcriptomic analyses have highlighted differential aging trajectories across tissues. The mechanism underlying shared and organ-selective functional changes across the lifespan, however, still remains poorly understood. Given the central role of mitochondria in powering cellular processes needed to maintain tissue health, we therefore undertook a systematic assessment of respiratory activity across 33 different tissues in young (2.5 months) and old (20 months) mice of both sexes. Our high-resolution mitochondrial respiration atlas reveals: (1) within any group of mice, mitochondrial activity varies widely across tissues, with the highest values consistently seen in heart, brown fat, and kidney; (2) biological sex is a significant but minor contributor to mitochondrial respiration, and its contributions are tissue-specific, with major differences seen in the pancreas, stomach, and white adipose tissue; (3) age is a dominant factor affecting mitochondrial activity, especially across most brain regions, different fat depots, skeletal muscle groups, eyes, and different regions of the gastrointestinal tract; (4) age effects can be sex- and tissue-specific, with some of the largest effects seen in pancreas, heart, adipose tissue, and skeletal muscle; and (5) while aging alters the functional trajectories of mitochondria in a majority of tissues, some are remarkably resilient to age-induced changes. Altogether, our data provide the most comprehensive compendium of mitochondrial respiration and illuminate functional signatures of aging across diverse tissues and organ systems.

Keywords:  aging; computational biology; mitochondria; mouse; respiration atlas; sex; systems biology

DOI:  https://doi.org/10.7554/eLife.96926
Adv Sci (Weinh). 2024 Dec 10. e2408599

Enhanced Oxidative Phosphorylation Driven by TACO1 Mitochondrial Translocation Promotes Stemness and Cisplatin Resistance in Bladder Cancer.

Minhua Deng, Zhaohui Zhou, Jiawei Chen, Xiangdong Li, Zefu Liu, Jingwei Ye, Wensu Wei, Ning Wang, Yulu Peng, Xin Luo, Lijuan Jiang, Fangjian Zhou, Xianchong Zheng, Zhuowei Liu.

  Chemoresistance poses a critical obstacle in bladder cancer (BCa) treatment, and effective interventions are currently limited. Elevated oxidative phosphorylation (OXPHOS) has been linked to cancer stemness, a determinant of chemoresistance. However, the mechanisms underlying increased OXPHOS during cancer cell chemoresistance remain unclear. This study revealed that the mitochondrial translational activator of cytochrome oxidase subunit 1 (TACO1) is linked to stemness and cisplatin resistance in BCa cells. Mechanistically, mitochondrial TACO1 enhances the translation of the mitochondrial cytochrome c oxidase I (MTCO1), promoting mitochondrial reactive oxygen species (mtROS) by upregulating OXPHOS, consequently driving cancer stemness and cisplatin resistance. Intriguingly, the mitochondrial translocation of TACO1 is mediated by the heat shock protein 90 β (HSP90β), a process that requires circFOXK2 as a scaffold for the TACO1-HSP90β interaction. The mutations at the binding sites of TACO1-circFOXK2-HSP90β disturb the ternary complex and inhibit cancer stemness and cisplatin resistance in BCa cells by suppressing the MTCO1/OXPHOS/mtROS axis. Clinically, BCa patients with increased mitochondrial TACO1 expression respond poorly to cisplatin treatment. This study elucidates the mechanisms by which TACO1 promotes BCa stemness and cisplatin resistance, providing a potential target for mitigating cisplatin resistance for BCa and a biomarker for predicting cisplatin response.

Keywords:  TACO1; bladder cancer; cancer stemness; chemoresistance; oxidative phosphorylation

DOI:  https://doi.org/10.1002/advs.202408599
J Biol Chem. 2024 Dec 13. pii: S0021-9258(24)02589-4. [Epub ahead of print] 108087

Crucial role and conservation of the three [2Fe-2S] clusters in the human mitochondrial ribosome.

Linda Boß, Oliver Stehling, Hans-Peter Elsässer, Roland Lill.

  Mitochondria synthesize only a small set of their proteins on endogenous mitoribosomes. These particles differ in structure and composition from both their bacterial 70S ancestors and cytosolic 80S ribosomes. Recently published high resolution structures of the human mitoribosome revealed the presence of three [2Fe-2S] clusters in the small and large subunits. Each of these clusters is coordinated in a bridging fashion by cysteine residues from two different mitoribosomal proteins. Here, we investigated the cell biological and biochemical roles of all three Fe/S clusters in mitochondrial function and assembly. First, we found a requirement of both early and late factors of the mitochondrial iron-sulfur cluster assembly machinery for protein translation indicating that not only the mitoribosome [2Fe-2S] clusters but also the [4Fe-4S] cluster of the mitoribosome assembly factor METTL17 are required for mitochondrial translation. Second, siRNA-mediated depletion of the cluster-coordinating ribosomal proteins bS18m, mS25 or mL66 and complementation with either the respective wild-type or cysteine-exchange proteins unveiled the importance of the clusters for assembly, stability, and function of the human mitoribosome. As a consequence, the lack of cluster binding to mitoribosomes impaired the activity of the mitochondrial respiratory chain complexes and led to altered mitochondrial morphology with a loss of cristae membranes. Finally, in silico investigation of the phylogenetic distribution of the cluster-coordinating cysteine motifs indicated their presence in most metazoan mitoribosomes, with exception of ray-finned fish. Collectively, our study highlights the functional need of mitochondrial Fe/S protein biogenesis for both protein translation and respiratory energy supply in most metazoan mitochondria.

Keywords:  Protein synthesis; biogenesis; iron-sulfur protein assembly; mitochondria; mitochondrial respiratory chain; ribosome assembly

DOI:  https://doi.org/10.1016/j.jbc.2024.108087
Cell Metab. 2024 Dec 14. pii: S1550-4131(24)00450-9. [Epub ahead of print]

Early downmodulation of tumor glycolysis predicts response to fasting-mimicking diet in triple-negative breast cancer patients.

Francesca Ligorio, Andrea Vingiani, Tommaso Torelli, Caterina Sposetti, Lorenzo Drufuca, Fabio Iannelli, Lucrezia Zanenga, Catherine Depretto, Secondo Folli, Gianfranco Scaperrotta, Giuseppe Capri, Giulia V Bianchi, Cristina Ferraris, Gabriele Martelli, Ilaria Maugeri, Leonardo Provenzano, Federico Nichetti, Luca Agnelli, Riccardo Lobefaro, Giovanni Fucà, Giuseppe Fotia, Luigi Mariani, Daniele Morelli, Vito Ladisa, Maria Carmen De Santis, Laura Lozza, Giovanna Trecate, Antonino Belfiore, Silvia Brich, Alessia Bertolotti, Daniele Lorenzini, Angela Ficchì, Antonia Martinetti, Elisa Sottotetti, Alessio Arata, Paola Corsetto, Luca Sorrentino, Mattia Rediti, Giulia Salvadori, Saverio Minucci, Marco Foiani, Giovanni Apolone, Massimiliano Pagani, Giancarlo Pruneri, Filippo de Braud, Claudio Vernieri.

  In preclinical experiments, cyclic fasting-mimicking diets (FMDs) showed broad anticancer effects in combination with chemotherapy. Among different tumor types, triple-negative breast cancer (TNBC) is exquisitely sensitive to FMD. However, the antitumor activity and efficacy of cyclic FMD in TNBC patients remain unclear. Here, we show that a severely calorie-restricted, triweekly, 5-day FMD regimen results in excellent pathologic complete response (pCR) rates (primary endpoint) and long-term clinical outcomes (secondary endpoints) when combined with preoperative chemotherapy in 30 patients with early-stage TNBC enrolled in the phase 2 trial BREAKFAST. Bulk and single-cell RNA sequencing analysis revealed that highly glycolytic cancer cells, myeloid cells, and pericytes from tumors achieving pCR undergo a significant, early downmodulation of pathways related to glycolysis and pyruvate metabolism. Our findings pave the wave for conducting larger clinical trials to investigate the efficacy of cyclic FMD in early-stage TNBC patients and to validate early changes of intratumor glycolysis as a predictor of clinical benefit from nutrient restriction. This study was registered at Clinicaltrials.gov (NCT04248998).

Keywords:  body composition analysis; bulk RNA-seq analysis; fasting-mimicking diet; neoadjuvant treatment; phase 2 trial; single-cell RNA-seq analysis; triple-negative breast cancer

DOI:  https://doi.org/10.1016/j.cmet.2024.11.004
EJHaem. 2024 Dec;5(6): 1274-1277

A GIMEMA survey on therapeutic use and response rates of FLT3 inhibitors in acute myeloid leukemia: Insights from Italian real-world practice.

Monica Messina, Alfonso Piciocchi, Leonardo M Siena, Stefano Soddu, Francesco Buccisano, Cristina Mecucci, Giovanni Martinelli, Antonio Curti, Roberto Cairoli, Paola Fazi, Marco Vignetti, Maria Teresa Voso, Adriano Venditti, Anna Candoni.

  Given the limited data on the real-life therapeutic use of feline McDonough sarcoma (FMS)-like tyrosine kinase 3 (FLT3) inhibitors in Italy, we surveyed investigators at 59 Italian hematology centers to gain insight into the proportion of acute myeloid leukemia (AML) patients receiving FLT3 inhibitors and we collected data on the efficacy and safety of these agents. The survey results showed that in the real-life setting the response rate of the 3/7 + midostaurin regimen in newly diagnosed FLT3-mutated AML and of gilteritinib in the relapsed/refractory AML were comparable to that reported in the registrative clinical trials. The 3/7 + midostaurin treatment resulted in a 63% of complete remission (CR) rates and gilteritinib in a 44% of CR rates. The discontinuation rate of gilteritinib for intolerance or toxicity was low (accounting for 4% of treated cases).

Keywords:  FLT3 inhibitors; acute myeloid leukemia; gilteritinib; midostaurin; real‐world

DOI:  https://doi.org/10.1002/jha2.1045
Leuk Lymphoma. 2024 Dec 17. 1-7

CPX-351 plus gemtuzumab ozogamicin for relapsed/refractory acute myelogenous leukemia: a University of California Hematologic Malignancies Consortium trial.

Caspian Oliai, Sunmin Park, Lloyd E Damon, Brian A Jonas, Deepa Jeyakumar, Matthew J Wieduwilt, Aaron C Logan, Bradley Callas, Chris A Hannigan, Daria L Gaut, Gary J Schiller.

  In this multicenter phase Ib trial, we investigated the combination of CPX-351 and gemtuzumab ozogamicin (GO) in relapsed/refractory acute myeloid leukemia (AML). Cohort A received CPX-351 plus a single dose of GO, while cohort B received two doses of GO. Thirteen participants received investigational treatment. Dose-limiting toxicities (DLTs) occurred in one participant in each cohort, with manageable adverse events. No cases of hepatic sinusoidal obstructive syndrome occurred. Out of 12 evaluable participants, four achieved complete remission (CR), three of whom were negative for measurable residual disease. The median time to recovery of hematopoiesis for responders was 37 days. CPX-351 with GO was feasible with acceptable toxicity and marrow recovery kinetics. Further evaluation in a larger patient cohort is necessary to assess the efficacy of this regimen in relapsed/refractory AML.

Keywords:  AML; CPX-351; gemtuzumab ozogamicin

DOI:  https://doi.org/10.1080/10428194.2024.2438809
BMB Rep. 2024 Dec 17. pii: 6336. [Epub ahead of print]

PGC1α is a key regulator of erastin-induced mitochondrial dysfunction during ferroptotic cell death.

Byeong Geun Seok, Eunhee Park, Young-Jun Park, Young-Jun Park, Hyuk Nam Kwon, Su Wol Chung.

A type of programmed cell death called ferroptosis is defined by increased iron-dependent lipid peroxidation. Mitochondria play a central role in iron metabolism. Mitochondrial defects include decreased cristae density, membrane rupture, and decreased mitochondrial membrane density, which occur as a result of ferroptosis. One of the important regulator of mitochondrial biogenesis is PGC1α. While recent studies have begun to explore the association between PGC1α and ferroptosis, the specific role of PGC1α in erastin-induced mitochondrial dysfunction during ferroptotic cell death has not been fully elucidated. In this study, we demonstrate for the first time that PGC1α is a key regulator of erastin-induced mitochondrial-dependent lipid peroxidation and dysfunction during ferroptosis in HT1080 fibrosarcoma cells. In this study, we examined PGC1α function in ferroptosis. Erastin, an inducer of ferroptosis, boosted the expression of PGC1α. Moreover, PGC1α down-regulation reduced erastin-induced ferroptosis. The most important biochemical feature of ferroptosis is the increase in iron ion (Fe2+)-dependent lipid peroxide (LOOH) concentration. Mitochondrial-dependent lipid peroxidation was abolished by PGC1α downregulation. In addition, PGC1α was induced during mitochondrial dysfunction in erastin-induced ferroptosis. Mitochondrial membrane potential loss and mitochondrial ROS production associated with erastin-induced mitochondrial dysfunction were blocked by PGC1α inhibition. In addition, erastin-induced lipid peroxidation in HT1080 fibrosarcoma cells was regulated by PGC1α inhibitor. This phenomenon was also consistent in HT1080 cells transfected with PGC1α shRNA transfected cells. Taken together, these results suggest that PGC1α is a key factor in erastin-induced mitochondrial-dependent lipid peroxidation and dysfunction during ferroptosis cell death.