bims-mibica 2024-04-14 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2024–04–14
28 papers selected by
Kelsey Fisher-Wellman, East Carolina University

Inhibition of Carbohydrate Metabolism Potentiated by the Therapeutic Effects of Oxidative Phosphorylation Inhibitors in Colon Cancer Cells.
An Innovative Mitochondrial-targeted Gene Therapy for Cancer Treatment.
MITOCHONDRIAL IMPORT STRESS and PINK1-MEDIATED MITOPHAGY: THE ROLE of the PINK1-TOMM-TIMM23 SUPERCOMPLEX.
Mitochondria transcription and cancer.
Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria.
Bacterial muropeptides promote OXPHOS and suppress mitochondrial stress in mammals.
Purine salvage promotes treatment resistance in H3K27M-mutant diffuse midline glioma.
HIF1α-dependent uncoupling of glycolysis suppresses tumor cell proliferation.
A CRISPRi/a screening platform to study cellular nutrient transport in diverse microenvironments.
HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis.
Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.
A novel inhibitory BAK antibody enables assessment of non-activated BAK in cancer cells.
Respiratory complex I regulates dendritic cell maturation in explant model of human tumor immune microenvironment.
Cytosolic RNA binding of the mitochondrial TCA cycle enzyme malate dehydrogenase (MDH2).
Mechanical regulation of mitochondrial morphodynamics in cancer cells by extracellular microenvironment.
Metabolic reprogramming regulated by TRAF6 contributes to the leukemia progression.
Identification of cells of leukemic stem cell origin with non-canonical regenerative properties.
Blocking lipid synthesis induces DNA damage in prostate cancer and increases cell death caused by PARP inhibition.
DRP1 inhibition-mediated mitochondrial elongation abolishes cancer stemness, enhances glutaminolysis, and drives ferroptosis in oral squamous cell carcinoma.
Association of poly(rC)-binding protein-2 with sideroflexin-3 through TOM20 as an iron entry pathway to mitochondria.
The troglitazone derivative EP13 disrupts energy metabolism through respiratory chain complex I inhibition in breast cancer cells and potentiates the antiproliferative effect of glycolysis inhibitntriors.
Mitochondrial dysfunction of peripheral blood mononuclear cells is associated with lung carcinogenesis.
Metabolic Signaling in Cancer Metastasis.
Evaluation of Mitochondrial Phagy (Mitophagy) in Human Non-small Adenocarcinoma Tumor Cells.
A glycolytic metabolite bypasses "two-hit" tumor suppression by BRCA2.
Mitochondrial respiration atlas reveals differential changes in mitochondrial function across sex and age.
Silencing the Mitochondrial Gatekeeper VDAC1 as a Potential Treatment for Bladder Cancer.
A call for accessible tools to unlock single-cell immunometabolism research.

Cancers (Basel). 2024 Apr 02. pii: 1399. [Epub ahead of print]16(7):

Inhibition of Carbohydrate Metabolism Potentiated by the Therapeutic Effects of Oxidative Phosphorylation Inhibitors in Colon Cancer Cells.

Lichao Guo, Baochen Zhang, Wen Zhang, Yanqi Xie, Xi Chen, Xueke Sun, David S Watt, Chunming Liu, H Peter Spielmann, Xifu Liu.

  Cancer cells undergo a significant level of "metabolic reprogramming" or "remodeling" to ensure an adequate supply of ATP and "building blocks" for cell survival and to facilitate accelerated proliferation. Cancer cells preferentially use glycolysis for ATP production (the Warburg effect); however, cancer cells, including colorectal cancer (CRC) cells, also depend on oxidative phosphorylation (OXPHOS) for ATP production, a finding that suggests that both glycolysis and OXPHOS play significant roles in facilitating cancer progression and proliferation. Our prior studies identified a semisynthetic isoflavonoid, DBI-1, that served as an AMPK activator targeting mitochondrial complex I. Furthermore, DBI-1 and a glucose transporter 1 (GLUT1) inhibitor, BAY-876, synergistically inhibited CRC cell growth in vitro and in vivo. We now report a study of the structure-activity relationships (SARs) in the isoflavonoid family in which we identified a new DBI-1 analog, namely, DBI-2, with promising properties. Here, we aimed to explore the antitumor mechanisms of DBIs and to develop new combination strategies by targeting both glycolysis and OXPHOS. We identified DBI-2 as a novel AMPK activator using an AMPK phosphorylation assay as a readout. DBI-2 inhibited mitochondrial complex I in the Seahorse assays. We performed proliferation and Western blotting assays and conducted studies of apoptosis, necrosis, and autophagy to corroborate the synergistic effects of DBI-2 and BAY-876 on CRC cells in vitro. We hypothesized that restricting the carbohydrate uptake with a KD would mimic the effects of GLUT1 inhibitors, and we found that a ketogenic diet significantly enhanced the therapeutic efficacy of DBI-2 in CRC xenograft mouse models, an outcome that suggested a potentially new approach for combination cancer therapy.

Keywords:  OXPHOS; colorectal cancer; glycolysis; isoflavonoid; ketogenic diet; mitochondria complex I

DOI:  https://doi.org/10.3390/cancers16071399
bioRxiv. 2024 Mar 27. pii: 2024.03.24.584499. [Epub ahead of print]

An Innovative Mitochondrial-targeted Gene Therapy for Cancer Treatment.

Kai Chen, Patrick Ernst, Seulhee Kim, Yingnan Si, Tanvi Varadkar, Matthew D Ringel, Xiaoguang Margaret Liu, Lufang Zhou.

Targeting cancer cell mitochondria holds great therapeutic promise, yet current strategies to specifically and effectively destroy cancer mitochondria in vivo are limited. Here, we introduce mLumiOpto, an innovative mitochondrial-targeted luminoptogenetics gene therapy designed to directly disrupt the inner mitochondrial membrane (IMM) potential and induce cancer cell death. We synthesize a blue light-gated channelrhodopsin (CoChR) in the IMM and co-express a blue bioluminescence-emitting Nanoluciferase (NLuc) in the cytosol of the same cells. The mLumiOpto genes are selectively delivered to cancer cells in vivo by using adeno-associated virus (AAV) carrying a cancer-specific promoter or cancer-targeted monoclonal antibody-tagged exosome-associated AAV. Induction with NLuc luciferin elicits robust endogenous bioluminescence, which activates mitochondrial CoChR, triggering cancer cell IMM permeability disruption, mitochondrial damage, and subsequent cell death. Importantly, mLumiOpto demonstrates remarkable efficacy in reducing tumor burden and killing tumor cells in glioblastoma or triple-negative breast cancer xenografted mouse models. These findings establish mLumiOpto as a novel and promising therapeutic strategy by targeting cancer cell mitochondria in vivo .

DOI: https://doi.org/10.1101/2024.03.24.584499
Autophagy. 2024 Apr 10.

MITOCHONDRIAL IMPORT STRESS and PINK1-MEDIATED MITOPHAGY: THE ROLE of the PINK1-TOMM-TIMM23 SUPERCOMPLEX.

Mohamed A Eldeeb, Armaan Fallahi, Andrea Soumbasis, Andrew N Bayne, Jean-François Trempe, Edward A Fon.

  Mutations in the PINK1 kinase cause Parkinson disease (PD) through physiological processes that are not yet fully elucidated. PINK1 kinase accumulates selectively on damaged mitochondria, where it recruits the E3 ubiquitin ligase PRKN/Parkin to mediate mitophagy. Upon mitochondrial import failure, PINK1 accumulates in association with the translocase of outer mitochondrial membrane (TOMM). However, the molecular basis of this PINK1 accumulation on the TOMM complex remain elusive. We recently demonstrated that TIMM23 (translocase of the inner mitochondrial membrane 23) is a component of the PINK1-supercomplex formed in response to mitochondrial stress. We also uncovered that PINK1 is required for the formation of this supercomplex and highlighted the biochemical regulation and significance of this supercomplex; expanding our understanding of mitochondrial quality control and PD pathogenesis.

Keywords:  Mitochondrial import; PINK1; Parkinson’s disease; mitochondrial quality control; mitophagy

DOI:  https://doi.org/10.1080/15548627.2024.2340399
Cell Death Discov. 2024 Apr 08. 10(1): 168

Mitochondria transcription and cancer.

Tang Lei, Yu Rui, Zhou Xiaoshuang, Zhang Jinglan, Zhang Jihong.

Mitochondria are major organelles involved in several processes related to energy supply, metabolism, and cell proliferation. The mitochondria function is transcriptionally regulated by mitochondria DNA (mtDNA), which encodes the key proteins in the electron transport chain that is indispensable for oxidative phosphorylation (OXPHOS). Mitochondrial transcriptional abnormalities are closely related to a variety of human diseases, such as cardiovascular diseases, and diabetes. The mitochondria transcription is regulated by the mtDNA, mitochondrial RNA polymerase (POLRMT), two transcription factors (TFAM and TF2BM), one transcription elongation (TEFM), and one known transcription termination factor (mTERFs). Dysregulation of these factors directly leads to altered expression of mtDNA in tumor cells, resulting in cellular metabolic reprogramming and mitochondrial dysfunction. This dysregulation plays a role in modulating tumor progression. Therefore, understanding the role of mitochondrial transcription in cancer can have implications for cancer diagnosis, prognosis, and treatment. Targeting mitochondrial transcription or related pathways may provide potential therapeutic strategies for cancer treatment. Additionally, assessing mitochondrial transcriptional profiles or biomarkers in cancer cells or patient samples may offer diagnostic or prognostic information.

DOI: https://doi.org/10.1038/s41420-024-01926-3
J Biol Chem. 2024 Apr 06. pii: S0021-9258(24)01770-8. [Epub ahead of print] 107269

Coenzyme Q4 is a functional substitute for coenzyme Q10 and can be targeted to the mitochondria.

Laura H Steenberge, Sean Rogers, Andrew Y Sung, Jing Fan, David J Pagliarini.

  Coenzyme Q10 (CoQ10) is an important cofactor and antioxidant for numerous cellular processes, and its deficiency has been linked to human disorders including mitochondrial disease, heart failure, Parkinson's disease, and hypertension. Unfortunately, treatment with exogenous CoQ10 is often ineffective, likely due to the extreme hydrophobicity and high molecular weight of CoQ10. Here, we show that less hydrophobic CoQ species with shorter isoprenoid tails can serve as viable substitutes for CoQ10 in human cells. We demonstrate that CoQ4 can perform multiple functions of CoQ10 in CoQ-deficient cells at markedly lower treatment concentrations, motivating further investigation of CoQ4 as a supplement for CoQ10 deficiencies. In addition, we describe the synthesis and evaluation of an initial set of compounds designed to target CoQ4 selectively to mitochondria using triphenylphosphonium (TPP). Our results indicate that select versions of these compounds can successfully be delivered to mitochondria in a cell model and be cleaved to produce CoQ4, laying the groundwork for further development.

Keywords:  Antioxidant; Bioenergetics; Coenzyme Q10 (CoQ10); Ferroptosis; Membrane lipid; Mitochondrial respiratory chain complex; Mitochondrial therapeutics; Pyrimidine biosynthesis; Ubiquinone

DOI:  https://doi.org/10.1016/j.jbc.2024.107269
Cell Rep. 2024 Apr 06. pii: S2211-1247(24)00395-4. [Epub ahead of print]43(4): 114067

Bacterial muropeptides promote OXPHOS and suppress mitochondrial stress in mammals.

Dong Tian, Mingxue Cui, Min Han.

  Mitochondrial dysfunction critically contributes to many major human diseases. The impact of specific gut microbial metabolites on mitochondrial functions of animals and the underlying mechanisms remain to be uncovered. Here, we report a profound role of bacterial peptidoglycan muropeptides in promoting mitochondrial functions in multiple mammalian models. Muropeptide addition to human intestinal epithelial cells (IECs) leads to increased oxidative respiration and ATP production and decreased oxidative stress. Strikingly, muropeptide treatment recovers mitochondrial structure and functions and inhibits several pathological phenotypes of fibroblast cells derived from patients with mitochondrial disease. In mice, muropeptides accumulate in mitochondria of IECs and promote small intestinal homeostasis and nutrient absorption by modulating energy metabolism. Muropeptides directly bind to ATP synthase, stabilize the complex, and promote its enzymatic activity in vitro, supporting the hypothesis that muropeptides promote mitochondria homeostasis at least in part by acting as ATP synthase agonists. This study reveals a potential treatment for human mitochondrial diseases.

Keywords:  ATP synthase; CP: Cell biology; CP: Metabolism; Leigh syndrome; PGN; ROS; antibiotic-induced microbiome depletion; electron transfer chain; energy metabolism; intestinal epithelial cells; intestinal homeostasis; mitochondrial diseases; oxidative phosphorylation; oxidative stress; peptidoglycan

DOI:  https://doi.org/10.1016/j.celrep.2024.114067
Cancer Metab. 2024 Apr 09. 12(1): 11

Purine salvage promotes treatment resistance in H3K27M-mutant diffuse midline glioma.

Erik R Peterson, Peter Sajjakulnukit, Andrew J Scott, Caleb Heaslip, Anthony Andren, Kari Wilder-Romans, Weihua Zhou, Sravya Palavalasa, Navyateja Korimerla, Angelica Lin, Alexandra O'Brien, Ayesha Kothari, Zitong Zhao, Li Zhang, Meredith A Morgan, Sriram Venneti, Carl Koschmann, Nada Jabado, Costas A Lyssiotis, Maria G Castro, Daniel R Wahl.

   BACKGROUND: Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are a fatal form of brain cancer. These tumors often carry a driver mutation on histone H3 converting lysine 27 to methionine (H3K27M). DMG-H3K27M are characterized by altered metabolism and resistance to standard of care radiation (RT) but how the H3K27M mediates the metabolic response to radiation and consequent treatment resistance is uncertain.
METHODS: We performed metabolomics on irradiated and untreated H3K27M isogenic DMG cell lines and observed an H3K27M-specific enrichment for purine synthesis pathways. We profiled the expression of purine synthesis enzymes in publicly available patient data and our models, quantified purine synthesis using stable isotope tracing, and characterized the in vitro and in vivo response to de novo and salvage purine synthesis inhibition in combination with RT.
RESULTS: DMG-H3K27M cells activate purine metabolism in an H3K27M-specific fashion. In the absence of genotoxic treatment, H3K27M-expressing cells have higher relative activity of de novo synthesis and apparent lower activity of purine salvage demonstrated via stable isotope tracing of key metabolites in purine synthesis and by lower expression of hypoxanthine-guanine phosphoribosyltransferase (HGPRT), the rate-limiting enzyme of purine salvage into IMP and GMP. Inhibition of de novo guanylate synthesis radiosensitized DMG-H3K27M cells in vitro and in vivo. Irradiated H3K27M cells upregulated HGPRT expression and hypoxanthine-derived guanylate salvage but maintained high levels of guanine-derived salvage. Exogenous guanine supplementation decreased radiosensitization in cells treated with combination RT and de novo purine synthesis inhibition. Silencing HGPRT combined with RT markedly suppressed DMG-H3K27M tumor growth in vivo.
CONCLUSIONS: Our results indicate that DMG-H3K27M cells rely on highly active purine synthesis, both from the de novo and salvage synthesis pathways. However, highly active salvage of free purine bases into mature guanylates can bypass inhibition of the de novo synthetic pathway. We conclude that inhibiting purine salvage may be a promising strategy to overcome treatment resistance in DMG-H3K27M tumors.

Keywords:  Diffuse midline glioma; H3K27M; Purine metabolism; Radiation therapy resistance

DOI:  https://doi.org/10.1186/s40170-024-00341-7
Cell Rep. 2024 Apr 11. pii: S2211-1247(24)00431-5. [Epub ahead of print]43(4): 114103

HIF1α-dependent uncoupling of glycolysis suppresses tumor cell proliferation.

Andrés A Urrutia, Claudia Mesa-Ciller, Andrea Guajardo-Grence, H Furkan Alkan, Inés Soro-Arnáiz, Anke Vandekeere, Ana Margarida Ferreira Campos, Sebastian Igelmann, Lucía Fernández-Arroyo, Gianmarco Rinaldi, Doriane Lorendeau, Katrien De Bock, Sarah-Maria Fendt, Julián Aragonés.

  Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. However, lower glycolysis is compromised in human clear cell renal cell carcinomas, in which HIF1α acts as a tumor suppressor by inhibiting cell-autonomous proliferation. Here, we find that, unexpectedly, HIF1α suppresses lower glycolysis after the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step, leading to reduced lactate secretion in different tumor cell types when cells encounter a limited pyruvate supply such as that typically found in the tumor microenvironment in vivo. This is because HIF1α-dependent attenuation of mitochondrial oxygen consumption increases the NADH/NAD+ ratio that suppresses the activity of the NADH-sensitive GAPDH glycolytic enzyme. This is manifested when pyruvate supply is limited, since pyruvate acts as an electron acceptor that prevents the increment of the NADH/NAD+ ratio. Furthermore, this anti-glycolytic function provides a molecular basis to explain how HIF1α can suppress tumor cell proliferation by increasing the NADH/NAD+ ratio.

Keywords:  CP: Cancer; CP: Metabolism; HIF1α; NADH; glycolysis; hypoxia; mitochondria; oxygen; renal cell carcinoma; tumor

DOI:  https://doi.org/10.1016/j.celrep.2024.114103
Nat Cell Biol. 2024 Apr 11.

A CRISPRi/a screening platform to study cellular nutrient transport in diverse microenvironments.

Christopher Chidley, Alicia M Darnell, Benjamin L Gaudio, Evan C Lien, Anna M Barbeau, Matthew G Vander Heiden, Peter K Sorger.

Blocking the import of nutrients essential for cancer cell proliferation represents a therapeutic opportunity, but it is unclear which transporters to target. Here we report a CRISPR interference/activation screening platform to systematically interrogate the contribution of nutrient transporters to support cancer cell proliferation in environments ranging from standard culture media to tumours. We applied this platform to identify the transporters of amino acids in leukaemia cells and found that amino acid transport involves high bidirectional flux dependent on the microenvironment composition. While investigating the role of transporters in cystine starved cells, we uncovered a role for serotonin uptake in preventing ferroptosis. Finally, we identified transporters essential for cell proliferation in subcutaneous tumours and found that levels of glucose and amino acids can restrain proliferation in that environment. This study establishes a framework for systematically identifying critical cellular nutrient transporters, characterizing their function and exploring how the tumour microenvironment impacts cancer metabolism.

DOI: https://doi.org/10.1038/s41556-024-01402-1
J Exp Clin Cancer Res. 2024 Apr 11. 43(1): 110

HERC5 downregulation in non-small cell lung cancer is associated with altered energy metabolism and metastasis.

Svenja Schneegans, Jana Löptien, Angelika Mojzisch, Desirée Loreth, Oliver Kretz, Christoph Raschdorf, Annkathrin Hanssen, Antonia Gocke, Bente Siebels, Karthikeyan Gunasekaran, Yi Ding, Leticia Oliveira-Ferrer, Laura Brylka, Thorsten Schinke, Hartmut Schlüter, Ilkka Paatero, Hannah Voß, Stefan Werner, Klaus Pantel, Harriet Wikman.

   BACKGROUND: Metastasis is the leading cause of cancer-related death in non-small cell lung cancer (NSCLC) patients. We previously showed that low HERC5 expression predicts early tumor dissemination and a dismal prognosis in NSCLC patients. Here, we performed functional studies to unravel the mechanism underlying the "metastasis-suppressor" effect of HERC5, with a focus on mitochondrial metabolism pathways.
METHODS: We assessed cell proliferation, colony formation potential, anchorage-independent growth, migration, and wound healing in NSCLC cell line models with HERC5 overexpression (OE) or knockout (KO). To study early tumor cell dissemination, we used these cell line models in zebrafish experiments and performed intracardial injections in nude mice. Mass spectrometry (MS) was used to analyze protein changes in whole-cell extracts. Furthermore, electron microscopy (EM) imaging, cellular respiration, glycolytic activity, and lactate production were used to investigate the relationships with mitochondrial energy metabolism pathways.
RESULTS: Using different in vitro NSCLC cell line models, we showed that NSCLC cells with low HERC5 expression had increased malignant and invasive properties. Furthermore, two different in vivo models in zebrafish and a xenograft mouse model showed increased dissemination and metastasis formation (in particular in the brain). Functional enrichment clustering of MS data revealed an increase in mitochondrial proteins in vitro when HERC5 levels were high. Loss of HERC5 leads to an increased Warburg effect, leading to improved adaptation and survival under prolonged inhibition of oxidative phosphorylation.
CONCLUSIONS: Taken together, these results indicate that low HERC5 expression increases the metastatic potential of NSCLC in vitro and in vivo. Furthermore, HERC5-induced proteomic changes influence mitochondrial pathways, ultimately leading to alterations in energy metabolism and demonstrating its role as a new potential metastasis suppressor gene.

Keywords:  Cancer metabolism; DTC; HERC5; Metastasis; Mitochondria; NSCLC; OXPHOS; Warburg effect

DOI:  https://doi.org/10.1186/s13046-024-03020-z
Nat Cell Biol. 2024 Apr 09.

Fatty acyl-coenzyme A activates mitochondrial division through oligomerization of MiD49 and MiD51.

Ao Liu, Frieda Kage, Asan F Abdulkareem, Mac Pholo Aguirre-Huamani, Gracie Sapp, Halil Aydin, Henry N Higgs.

Mitochondrial fission occurs in many cellular processes, but the regulation of fission is poorly understood. We show that long-chain acyl-coenzyme A (LCACA) activates two related mitochondrial fission proteins, MiD49 and MiD51, by inducing their oligomerization, which activates their ability to stimulate the DRP1 GTPase. The 1:1 stoichiometry of LCACA:MiD in the oligomer suggests interaction in the previously identified nucleotide-binding pocket, and a point mutation in this pocket reduces LCACA binding and LCACA-induced oligomerization for MiD51. In cells, this LCACA binding mutant does not assemble into puncta on mitochondria or rescue MiD49/51 knockdown effects on mitochondrial length and DRP1 recruitment. Furthermore, cellular treatment with BSA-bound oleic acid, which causes increased LCACA, promotes mitochondrial fission in an MiD49/51-dependent manner. These results suggest that LCACA is an endogenous ligand for MiDs, inducing mitochondrial fission and providing a potential mechanism for fatty-acid-induced mitochondrial division. Finally, MiD49 or MiD51 oligomers synergize with Mff, but not with actin filaments, in DRP1 activation, suggesting distinct pathways for DRP1 activation.

DOI: https://doi.org/10.1038/s41556-024-01400-3
Cell Death Differ. 2024 Apr 06.

A novel inhibitory BAK antibody enables assessment of non-activated BAK in cancer cells.

Hema Preethi Subas Satish, Sweta Iyer, Melissa X Shi, Agnes W Wong, Karla C Fischer, Ahmad Z Wardak, Daisy Lio, Jason M Brouwer, Rachel T Uren, Peter E Czabotar, Michelle S Miller, Ruth M Kluck.

BAX and BAK are pro-apoptotic members of the BCL2 family that are required to permeabilize the mitochondrial outer membrane. The proteins can adopt a non-activated monomeric conformation, or an activated conformation in which the exposed BH3 domain facilitates binding either to a prosurvival protein or to another activated BAK or BAX protein to promote pore formation. Certain cancer cells are proposed to have high levels of activated BAK sequestered by MCL1 or BCLXL, thus priming these cells to undergo apoptosis in response to BH3 mimetic compounds that target MCL1 or BCLXL. Here we report the first antibody, 14G6, that is specific for the non-activated BAK conformer. A crystal structure of 14G6 Fab bound to BAK revealed a binding site encompassing both the α1 helix and α5-α6 hinge regions of BAK, two sites involved in the unfolding of BAK during its activation. In mitochondrial experiments, 14G6 inhibited BAK unfolding triggered by three diverse BAK activators, supporting crucial roles for both α1 dissociation and separation of the core (α2-α5) and latch (α6-α9) regions in BAK activation. 14G6 bound the majority of BAK in several leukaemia cell lines, and binding decreased following treatment with BH3 mimetics, indicating only minor levels of constitutively activated BAK in those cells. In summary, 14G6 provides a new means of assessing BAK status in response to anti-cancer treatments.

DOI: https://doi.org/10.1038/s41418-024-01289-3
J Immunother Cancer. 2024 Apr 11. pii: e008053. [Epub ahead of print]12(4):

Respiratory complex I regulates dendritic cell maturation in explant model of human tumor immune microenvironment.

Rita Turpin, Ruixian Liu, Pauliina M Munne, Aino Peura, Jenna H Rannikko, Gino Philips, Bram Boeckx, Natasha Salmelin, Elina Hurskainen, Ilida Suleymanova, July Aung, Elisa M Vuorinen, Laura Lehtinen, Minna Mutka, Panu E Kovanen, Laura Niinikoski, Tuomo J Meretoja, Johanna Mattson, Satu Mustjoki, Päivi Saavalainen, Andrei Goga, Diether Lambrechts, Jeroen Pouwels, Maija Hollmén, Juha Klefström.

   BACKGROUND: Combining cytotoxic chemotherapy or novel anticancer drugs with T-cell modulators holds great promise in treating advanced cancers. However, the response varies depending on the tumor immune microenvironment (TIME). Therefore, there is a clear need for pharmacologically tractable models of the TIME to dissect its influence on mono- and combination treatment response at the individual level.
METHODS: Here we establish a patient-derived explant culture (PDEC) model of breast cancer, which retains the immune contexture of the primary tumor, recapitulating cytokine profiles and CD8+T cell cytotoxic activity.
RESULTS: We explored the immunomodulatory action of a synthetic lethal BCL2 inhibitor venetoclax+metformin drug combination ex vivo, discovering metformin cannot overcome the lymphocyte-depleting action of venetoclax. Instead, metformin promotes dendritic cell maturation through inhibition of mitochondrial complex I, increasing their capacity to co-stimulate CD4+T cells and thus facilitating antitumor immunity.
CONCLUSIONS: Our results establish PDECs as a feasible model to identify immunomodulatory functions of anticancer drugs in the context of patient-specific TIME.

Keywords:  Breast Neoplasms; Dendritic Cells; Drug Evaluation, Preclinical; Immunity, Innate; Immunomodulation

DOI:  https://doi.org/10.1136/jitc-2023-008053
RNA. 2024 Apr 12. pii: rna.079925.123. [Epub ahead of print]

Cytosolic RNA binding of the mitochondrial TCA cycle enzyme malate dehydrogenase (MDH2).

Michelle Noble, Aindrila Chatterjee, Thileepan Sekaran, Thomas Schwarzl, Matthias W Hentze.

  Several enzymes of intermediary metabolism have been identified to bind RNA in 2 cells, with potential consequences for the bound RNAs and/or the enzyme. In this 3 study, we investigate the RNA-binding activity of the mitochondrial enzyme malate 4 dehydrogenase 2 (MDH2), which functions in the tricarboxylic acid (TCA) cycle and 5 the malate-aspartate shuttle. We confirmed in cellulo RNA-binding of MDH2 using 6 orthogonal biochemical assays and performed enhanced crosslinking and 7 immunoprecipitation (eCLIP) to identify the cellular RNAs associated with endogenous 8 MDH2. Surprisingly, MDH2 preferentially binds cytosolic over mitochondrial RNAs, 9 although the latter are abundant in the milieu of the mature protein. Subcellular 10 fractionation followed by RNA-binding assays revealed that MDH2-RNA interactions 11 occur predominantly outside of mitochondria. We also found that a cytosolically-12 retained N-terminal deletion mutant of MDH2 is competent to bind RNA, indicating that 13 mitochondrial targeting is dispensable for MDH2-RNA interactions. MDH2 RNA 14 binding increased when cellular NAD+ levels (MDH2's co-factor) was 15 pharmacologically diminished, suggesting that the metabolic state of cells affects RNA 16 binding. Taken together, our data implicate an as yet unidentified function of MDH2 17 binding RNA in the cytosol.

Keywords:  MDH2; RNA-binding proteins; metabolic enzymes

DOI:  https://doi.org/10.1261/rna.079925.123
Biomater Biosyst. 2024 Jun;14 100093

Mechanical regulation of mitochondrial morphodynamics in cancer cells by extracellular microenvironment.

Mariia Lunova, Milan Jirsa, Alexandr Dejneka, Gareth John Sullivan, Oleg Lunov.

  Recently, it has been recognized that physical abnormalities (e.g. elevated solid stress, elevated interstitial fluid pressure, increased stiffness) are associated with tumor progression and development. Additionally, these mechanical forces originating from tumor cell environment through mechanotransduction pathways can affect metabolism. On the other hand, mitochondria are well-known as bioenergetic, biosynthetic, and signaling organelles crucial for sensing stress and facilitating cellular adaptation to the environment and physical stimuli. Disruptions in mitochondrial dynamics and function have been found to play a role in the initiation and advancement of cancer. Consequently, it is logical to hypothesize that mitochondria dynamics subjected to physical cues may play a pivotal role in mediating tumorigenesis. Recently mitochondrial biogenesis and turnover, fission and fusion dynamics was linked to mechanotransduction in cancer. However, how cancer cell mechanics and mitochondria functions are connected, still remain poorly understood. Here, we discuss recent studies that link mechanical stimuli exerted by the tumor cell environment and mitochondria dynamics and functions. This interplay between mechanics and mitochondria functions may shed light on how mitochondria regulate tumorigenesis.

Keywords:  Cancer; Mechanotransduction; Mitochondria; Mitochondrial dynamics; Tumor metabolism

DOI:  https://doi.org/10.1016/j.bbiosy.2024.100093
Leukemia. 2024 Apr 12.

Metabolic reprogramming regulated by TRAF6 contributes to the leukemia progression.

Shinichiro Matsui, Chihiro Ri, Lyndsey C Bolanos, Kwangmin Choi, Asuka Shibamiya, Arata Ishii, Koji Takaishi, Nagisa Oshima-Hasegawa, Shokichi Tsukamoto, Yusuke Takeda, Naoya Mimura, Akihide Yoshimi, Koutaro Yokote, Daniel T Starczynowski, Emiko Sakaida, Tomoya Muto.

TNF receptor associated factor 6 (TRAF6) is an E3 ubiquitin ligase that has been implicated in myeloid malignancies. Although altered TRAF6 expression is observed in human acute myeloid leukemia (AML), its role in the AML pathogenesis remains elusive. In this study, we showed that the loss of TRAF6 in AML cells significantly impairs leukemic function in vitro and in vivo, indicating its functional importance in AML subsets. Loss of TRAF6 induces metabolic alterations, such as changes in glycolysis, TCA cycle, and nucleic acid metabolism as well as impaired mitochondrial membrane potential and respiratory capacity. In leukemic cells, TRAF6 expression shows a positive correlation with the expression of O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT), which catalyzes the addition of O-GlcNAc to target proteins involved in metabolic regulation. The restoration of growth capacity and metabolic activity in leukemic cells with TRAF6 loss, achieved through either forced expression of OGT or pharmacological inhibition of O-GlcNAcase (OGA) that removes O-GlcNAc, indicates the significant role of O-GlcNAc modification in the TRAF6-related cellular and metabolic dynamics. Our findings highlight the oncogenic function of TRAF6 in leukemia and illuminate the novel TRAF6/OGT/O-GlcNAc axis as a potential regulator of metabolic reprogramming in leukemogenesis.

DOI: https://doi.org/10.1038/s41375-024-02245-3
Cell Rep Med. 2024 Mar 23. pii: S2666-3791(24)00131-9. [Epub ahead of print] 101485

Identification of cells of leukemic stem cell origin with non-canonical regenerative properties.

Cameron G Hollands, Allison L Boyd, Xueli Zhao, Jennifer C Reid, Charisa Henly, Amro ElRafie, David Boylan, Emily Broder, Olivia Kalau, Paige Johnson, Alyssa Mark, Jamie McNicol, Anargyros Xenocostas, Tobias Berg, Ronan Foley, Michael Trus, Brian Leber, Alejandro Garcia-Horton, Clinton Campbell, Mickie Bhatia.

  Despite most acute myeloid leukemia (AML) patients entering remission following chemotherapy, outcomes remain poor due to surviving leukemic cells that contribute to relapse. The nature of these enduring cells is poorly understood. Here, through temporal single-cell transcriptomic characterization of AML hierarchical regeneration in response to chemotherapy, we reveal a cell population: AML regeneration enriched cells (RECs). RECs are defined by CD74/CD68 expression, and although derived from leukemic stem cells (LSCs), are devoid of stem/progenitor capacity. Based on REC in situ proximity to CD34-expressing cells identified using spatial transcriptomics on AML patient bone marrow samples, RECs demonstrate the ability to augment or reduce leukemic regeneration in vivo based on transfusion or depletion, respectively. Furthermore, RECs are prognostic for patient survival as well as predictive of treatment failure in AML cohorts. Our study reveals RECs as a previously unknown functional catalyst of LSC-driven regeneration contributing to the non-canonical framework of AML regeneration.

Keywords:  Regen71; acute myeloid leukemia; chemotherapy; injury; leukemia stem cells; non-canonical regeneration; regeneration enriched cells; relapse

DOI:  https://doi.org/10.1016/j.xcrm.2024.101485
Sci Signal. 2024 Apr 09. 17(831): eadh1922

Blocking lipid synthesis induces DNA damage in prostate cancer and increases cell death caused by PARP inhibition.

Caroline Fidalgo Ribeiro, Silvia Rodrigues, Debora Campanella Bastos, Giuseppe Nicolò Fanelli, Hubert Pakula, Marco Foiani, Giorgia Zadra, Massimo Loda.

Androgen deprivation therapy (ADT) is the primary treatment for prostate cancer; however, resistance to ADT invariably develops, leading to castration-resistant prostate cancer (CRPC). Prostate cancer progression is marked by increased de novo synthesis of fatty acids due to overexpression of fatty acid synthase (FASN), making this enzyme a therapeutic target for prostate cancer. Inhibition of FASN results in increased intracellular amounts of ceramides and sphingomyelin, leading to DNA damage through the formation of DNA double-strand breaks and cell death. We found that combining a FASNi with the poly-ADP ribose polymerase (PARP) inhibitor olaparib, which induces cell death by blocking DNA damage repair, resulted in a more pronounced reduction in cell growth than that caused by either drug alone. Human CRPC organoids treated with a combination of PARP and FASNi were smaller, had decreased cell proliferation, and showed increased apoptosis and necrosis. Together, these data indicate that targeting FASN increases the therapeutic efficacy of PARP inhibitors by impairing DNA damage repair, suggesting that combination therapies should be explored for CRPC.

DOI: https://doi.org/10.1126/scisignal.adh1922
Br J Cancer. 2024 Apr 06.

DRP1 inhibition-mediated mitochondrial elongation abolishes cancer stemness, enhances glutaminolysis, and drives ferroptosis in oral squamous cell carcinoma.

Zhen Wang, Shouyi Tang, Luyao Cai, Qing Wang, Dan Pan, Yunmei Dong, Hao Zhou, Jing Li, Ning Ji, Xin Zeng, Yu Zhou, Ying-Qiang Shen, Qianming Chen.

BACKGROUND: Mitochondrial dynamics play a fundamental role in determining stem cell fate. However, the underlying mechanisms of mitochondrial dynamics in the stemness acquisition of cancer cells are incompletely understood.
METHODS: Metabolomic profiling of cells were analyzed by MS/MS. The genomic distribution of H3K27me3 was measured by CUT&Tag. Oral squamous cell carcinoma (OSCC) cells depended on glucose or glutamine fueling TCA cycle were monitored by 13C-isotope tracing. Organoids and tumors from patients and mice were treated with DRP1 inhibitors mdivi-1, ferroptosis inducer erastin, or combination with mdivi-1 and erastin to evaluate treatment effects.
RESULTS: Mitochondria of OSCC stem cells own fragment mitochondrial network and DRP1 is required for maintenance of their globular morphology. Imbalanced mitochondrial dynamics induced by DRP1 knockdown suppressed stemness of OSCC cells. Elongated mitochondria increased α-ketoglutarate levels and enhanced glutaminolysis to fuel the TCA cycle by increasing glutamine transporter ASCT2 expression. α-KG promoted the demethylation of histone H3K27me3, resulting in downregulation of SNAI2 associated with stemness and EMT. Significantly, suppressing DRP1 enhanced the anticancer effects of ferroptosis.
CONCLUSION: Our study reveals a novel mechanism underlying mitochondrial dynamics mediated cancer stemness acquisition and highlights the therapeutic potential of mitochondria elongation to increase the susceptibility of cancer cells to ferroptosis.

DOI: https://doi.org/10.1038/s41416-024-02670-2
Free Radic Res. 2024 Apr 10. 1-40

Association of poly(rC)-binding protein-2 with sideroflexin-3 through TOM20 as an iron entry pathway to mitochondria.

Danyang Mi, Izumi Yanatori, Hao Zheng, Yingyi Kong, Tasuku Hirayama, Shinya Toyokuni.

  Iron is essential for all the lives and mitochondria integrate iron into heme and Fe-S clusters for diverse use as cofactors. Here we screened mitochondrial proteins in KU812 human chronic myelogenous leukemia cells by glutathione S-transferase pulldown assay with PCBP2 to identify mitochondrial receptors for PCBP2, a major cytosolic Fe(II) chaperone. LC-MS analyses identified TOM20, sideroflexin-3 (SFXN3), SFXN1 and TOM70 in the affinity-score sequence. Stimulated emission depletion microscopy and proteinase-K digestion of mitochondria in HeLa cells revealed that TOM20 is located in the outer membrane of mitochondria whereas SFXN3 is located in the inner membrane. Though direct association was not observed between PCBP2 and SFXN3 with co-immunoprecipitation, proximity ligation assay demonstrated proximal localization of PCBP2 with TOM20 and there was a direct binding between TOM20 and SFXN3. Single knockdown either of PCBP2 and SFXN3 in K562 leukemia cells significantly decreased mitochondrial catalytic Fe(II) and mitochondrial maximal respiration. SFXN3 but not MFRN1 knockout (KO) in mouse embryonic fibroblasts decreased FBXL5 and heme oxygenase-1 (HO-1) but increased transferrin uptake and induced ferritin, indicating that mitochondrial iron entry through SFXN3 is distinct. MFRN1 KO revealed more intense mitochondrial Fe(II) deficiency than SFXN3 KO. Insufficient mitochondrial heme synthesis was evident under iron overload both with SFXN3 and MFRN KO, which was partially reversed by HO-1 inhibitor. Conversely, SFXN3 overexpression caused cytosolic iron deficiency with mitochondrial excess Fe(II), which further sensitized HeLa cells to RSL3-induced ferroptosis. In conclusion, we discovered a novel pathway of iron entry into mitochondria from cytosol through PCBP2-TOM20-SFXN3 axis.

Keywords:  PCBP2; iron; mitochondria; sideroflexin-3

DOI:  https://doi.org/10.1080/10715762.2024.2340711
Cancer Cell Int. 2024 Apr 10. 24(1): 132

The troglitazone derivative EP13 disrupts energy metabolism through respiratory chain complex I inhibition in breast cancer cells and potentiates the antiproliferative effect of glycolysis inhibitntriors.

Claire Muller, Victorine Lacroix-Malgras, Jérôme Kluza, William Laine, Yonca Güler, Frédéric Bost, Michel Boisbrun, Sabine Mazerbourg, Stéphane Flament.

   BACKGROUND: The metabolism of cancer cells generally differs from that of normal cells. Indeed, most cancer cells have a high rate of glycolysis, even at normal oxygen concentrations. These metabolic properties can potentially be exploited for therapeutic intervention. In this context, we have developed troglitazone derivatives to treat hormone-sensitive and triple-negative breast cancers, which currently lack therapeutic targets, have an aggressive phenotype, and often have a worse prognosis than other subtypes. Here, we studied the metabolic impact of the EP13 compound, a desulfured derivative of Δ2-troglitazone that we synthetized and is more potent than its parent compounds.
METHODS: EP13 was tested on two triple-negative breast cancer cell lines, MDA-MB-231 and Hs578T, and on the luminal cell line MCF-7. The oxygen consumption rate (OCR) of the treated cell lines, Hs578T mammospheres and isolated mitochondria was measured using the XFe24 Seahorse analyser. ROS production was quantified using the MitoSOX fluorescent probe. Glycolytic activity was evaluated through measurement of the extracellular acidification rate (ECAR), glucose consumption and lactate production in extracellular medium. The synergistic effect of EP13 with glycolysis inhibitors (oxamate and 2-deoxyglucose) on cell cytotoxicity was established using the Chou-Talalay method.
RESULTS: After exposure to EP13, we observed a decrease in the mitochondrial oxygen consumption rate in MCF7, MDA-MB-231 and Hs578T cells. EP13 also modified the maximal OCR of Hs578T spheroids. EP13 reduced the OCR through inhibition of respiratory chain complex I. After 24 h, ATP levels in EP13-treated cells were not altered compared with those in untreated cells, suggesting compensation by glycolysis activity, as shown by the increase in ECAR, the glucose consumption and lactate production. Finally, we performed co-treatments with EP13 and glycolysis inhibitors (oxamate and 2-DG) and observed that EP13 potentiated their cytotoxic effects.
CONCLUSION: This study demonstrates that EP13 inhibits OXPHOS in breast cancer cells and potentiates the effect of glycolysis inhibitors.

Keywords:  Breast cancer; Energy metabolism; Glycolysis; Mitochondria; Oxygen consumption; Thiazolidinediones; Troglitazone

DOI:  https://doi.org/10.1186/s12935-024-03319-z
Int Immunopharmacol. 2024 Apr 11. pii: S1567-5769(24)00476-4. [Epub ahead of print]133 111958

Mitochondrial dysfunction of peripheral blood mononuclear cells is associated with lung carcinogenesis.

Weili Liu, Hua Li, Yuan Gao, Xuelian Zhang, Zilin Wei, Dong Yang, Min Jin, Zhigang Qiu, Zhiqiang Shen, Zhaoli Chen, Yamei Qiao, Lingling Pu, Changqing Yan, Shuang Zhang, Xinxing Wang, Junwen Li.

  The composition, quantity, and function of peripheral blood mononuclear cells (PBMCs) are closely correlated with tumorigenesis. However, the mechanisms of PBMCs in lung cancer are not clear. Mitochondria are energy factories of cells, and almost all cellular functions rely on their energy metabolism level. The present study aimed to test whether the mitochondrial function of PBMCs directly determines their tumor immune monitoring function. We recruited 211 subjects, including 105 healthy controls and 106 patients with recently diagnosed with lung cancer. The model of lung carcinogenesis induced by BaP was used in animal experiment, and the Bap carcinogenic metabolite, Benzo(a)pyren-7,8-dihydrodiol-9,10-epoxide (BPDE), was used in cell experiment. We found that mitochondrial function of PBMCs decreased significantly in patients with new lung cancer, regardless of age. In vivo, BaP caused PBMC mitochondrial dysfunction in mice before the appearance of visible malignant tissue. Moreover, mitochondrial function decreased significantly in mice with lung cancers induced by BaP compared to those without lung cancer after BaP intervention. In vitro, BPDE also induced mitochondrial dysfunction and reduced the aggressiveness of PBMCs toward cancer cells. Furthermore, the changes in mitochondrial energy metabolism gene expression caused by BPDE are involved in this process. Thus, the mitochondrial function of PBMCs is a potential prognostic biomarker or therapeutic target to improve clinical outcomes in patients with lung cancer.

Keywords:  Benzo(a)pyrene (BaP); Lung cancer; Mitochondrial dysfunction; PBMCs

DOI:  https://doi.org/10.1016/j.intimp.2024.111958
Cancer Discov. 2024 Mar 29. OF1-OF19

Metabolic Signaling in Cancer Metastasis.

Sarah Krieg, Sara Isabel Fernandes, Constantinos Kolliopoulos, Ming Liu, Sarah-Maria Fendt.

Metastases, which are the leading cause of death in patients with cancer, have metabolic vulnerabilities. Alterations in metabolism fuel the energy and biosynthetic needs of metastases but are also needed to activate cell state switches in cells leading to invasion, migration, colonization, and outgrowth in distant organs. Specifically, metabolites can activate protein kinases as well as receptors and they are crucial substrates for posttranslational modifications on histone and nonhistone proteins. Moreover, metabolic enzymes can have moonlighting functions by acting catalytically, mainly as protein kinases, or noncatalytically through protein-protein interactions. Here, we summarize the current knowledge on metabolic signaling in cancer metastasis.
SIGNIFICANCE: Effective drugs for the prevention and treatment of metastases will have an immediate impact on patient survival. To overcome the current lack of such drugs, a better understanding of the molecular processes that are an Achilles heel in metastasizing cancer cells is needed. One emerging opportunity is the metabolic changes cancer cells need to undergo to successfully metastasize and grow in distant organs. Mechanistically, these metabolic changes not only fulfill energy and biomass demands, which are often in common between cancer and normal but fast proliferating cells, but also metabolic signaling which enables the cell state changes that are particularly important for the metastasizing cancer cells.

DOI: https://doi.org/10.1158/2159-8290.CD-24-0174
Methods Mol Biol. 2024 Apr 13.

Evaluation of Mitochondrial Phagy (Mitophagy) in Human Non-small Adenocarcinoma Tumor Cells.

Javad Alizadeh, Simone C da Silva Rosa, Marco Cordani, Saeid Ghavami.

  Non-small cell lung cancer (NSCLC) is a predominant form of lung cancer characterized by its aggressive nature and high mortality rate, primarily due to late-stage diagnosis and metastatic spread. Recent studies underscore the pivotal role of mitophagy, a selective form of autophagy targeting damaged or superfluous mitochondria, in cancer biology, including NSCLC. Mitophagy regulation may influence cancer cell survival, proliferation, and metastasis by modulating mitochondrial quality and cellular energy homeostasis. Herein, we present a comprehensive methodology developed in our laboratory for the evaluation of mitophagy in NSCLC tumor cells. Utilizing a combination of immunoblotting, immunocytochemistry, and fluorescent microscopy, we detail the steps to quantify early and late mitophagy markers and mitochondrial dynamics. Our findings highlight the potential of targeting mitophagy pathways as a novel therapeutic strategy in NSCLC, offering insights into the complex interplay between mitochondrial dysfunction and tumor progression. This study not only sheds light on the significance of mitophagy in NSCLC but also establishes a foundational approach for its investigation, paving way for future research in this critical area of cancer biology.

Keywords:  Autophagy; Cellular homeostasis; Mitochondrial dynamics; Mitophagy; Non-small cell adenocarcinoma

DOI:  https://doi.org/10.1007/7651_2024_532
Cell. 2024 Apr 08. pii: S0092-8674(24)00255-1. [Epub ahead of print]

A glycolytic metabolite bypasses "two-hit" tumor suppression by BRCA2.

Li Ren Kong, Komal Gupta, Andy Jialun Wu, David Perera, Roland Ivanyi-Nagy, Syed Moiz Ahmed, Tuan Zea Tan, Shawn Lu-Wen Tan, Alessandra Fuddin, Elayanambi Sundaramoorthy, Grace Shiqing Goh, Regina Tong Xin Wong, Ana S H Costa, Callum Oddy, Hannan Wong, C Pawan K Patro, Yun Suen Kho, Xiao Zi Huang, Joan Choo, Mona Shehata, Soo Chin Lee, Boon Cher Goh, Christian Frezza, Jason J Pitt, Ashok R Venkitaraman.

  Knudson's "two-hit" paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson's paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in nonmalignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes. An analogous SBS signature, again without biallelic BRCA2 inactivation, accompanies MGO accumulation and DNA damage in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2's tumor suppressive functions in DNA repair and replication, causing functional haploinsufficiency. Intermittent MGO exposure incites episodic SBS mutations without permanent BRCA2 inactivation. Thus, a metabolic mechanism wherein MGO-induced BRCA2 haploinsufficiency transiently bypasses Knudson's two-hit requirement could link glycolysis activation by oncogenes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution.

Keywords:  DNA repair and replication; breast cancer gene BRCA2; cancer genome; cancer metabolism; environmental carcinogenesis; gene-environment interaction; glycolysis; methylglyoxal; mutational signature; tumor suppression

DOI:  https://doi.org/10.1016/j.cell.2024.03.006
bioRxiv. 2024 Mar 29. pii: 2024.03.26.586781. [Epub ahead of print]

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 mechanisms 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 different fat depots and skeletal muscle groups, and most brain regions; 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.

DOI: https://doi.org/10.1101/2024.03.26.586781
Cells. 2024 Apr 04. pii: 627. [Epub ahead of print]13(7):

Silencing the Mitochondrial Gatekeeper VDAC1 as a Potential Treatment for Bladder Cancer.

Belal Alhozeel, Swaroop Kumar Pandey, Anna Shteinfer-Kuzmine, Manikandan Santhanam, Varda Shoshan-Barmatz.

  The strategy for treating bladder cancer (BC) depends on whether there is muscle invasion or not, with the latter mostly treated with intravesical therapy, such as with bacillus Calmette-Guérin (BCG). However, BCG treatment is unsuccessful in 70% of patients, who are then subjected to radical cystectomy. Although immune-checkpoint inhibitors have been approved as a second-line therapy for a subset of BC patients, these have failed to meet primary endpoints in clinical trials. Thus, it is crucial to find a new treatment. The mitochondrial gatekeeper protein, the voltage-dependent anion channel 1 (VDAC1), mediates metabolic crosstalk between the mitochondria and cytosol and is involved in apoptosis. It is overexpressed in many cancer types, as shown here for BC, pointing to its significance in high-energy-demanding cancer cells. The BC cell lines UM-UC3 and HTB-5 express high VDAC1 levels compared to other cancer cell lines. VDAC1 silencing in these cells using siRNA that recognizes both human and mouse VDAC1 (si-m/hVDAC1-B) reduces cell viability, mitochondria membrane potential, and cellular ATP levels. Here, we used two BC mouse models: subcutaneous UM-UC3 cells and chemically induced BC using the carcinogen N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Subcutaneous UM-UC3-derived tumors treated with si-m/hVDAC1 showed inhibited tumor growth and reprogrammed metabolism, as reflected in the reduced expression of metabolism-related proteins, including Glut1, hexokinase, citrate synthase, complex-IV, and ATP synthase, suggesting reduced metabolic activity. Furthermore, si-m/hVDAC1-B reduced the expression levels of cancer-stem-cell-related proteins (cytokeratin-14, ALDH1a), modifying the tumor microenvironment, including decreased angiogenesis, extracellular matrix, tumor-associated macrophages, and inhibited epithelial-mesenchymal transition. The BBN-induced BC mouse model showed a clear carcinoma, with damaged bladder morphology and muscle-invasive tumors. Treatment with si-m/hVDAC1-B encapsulated in PLGA-PEI nanoparticles that were administered intravesically directly to the bladder showed a decreased tumor area and less bladder morphology destruction and muscle invasion. Overall, the obtained results point to the potential of si-m/hVDAC1-B as a possible therapeutic tool for treating bladder cancer.

Keywords:  VDAC1; bladder cancer; mitochondria; si-RNA

DOI:  https://doi.org/10.3390/cells13070627
Nat Metab. 2024 Apr 11.

A call for accessible tools to unlock single-cell immunometabolism research.

Jason Cosgrove, Antoine Marçais, Felix J Hartmann, Andreas Bergthaler, Ivan Zanoni, Mauro Corrado, Leïla Perié, Nina Cabezas-Wallscheid, Philippe Bousso, Theodore Alexandrov, Tammy Kielian, Nuria Martínez-Martín, Christiane A Opitz, Costas A Lyssiotis, Rafael J Argüello, Jan Van den Bossche.

DOI: https://doi.org/10.1038/s42255-024-01031-w