bims-mibica 2024-06-23 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2024‒06‒23
seventeen papers selected by
Kelsey Fisher-Wellman, East Carolina University

DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring.
Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia.
Identifying Targetable Vulnerabilities to Circumvent or Overcome Venetoclax Resistance in Diffuse Large B-Cell Lymphoma.
Metabolic adaptation in epithelial ovarian cancer metastasis.
Dependence on mitochondrial respiration of malignant T cells reveals a new therapeutic target for angioimmunoblastic T-cell lymphoma.
CKB Promotes Mitochondrial ATP Production by Suppressing Permeability Transition Pore.
SETD3 is a mechanosensitive enzyme that methylates actin on His-73 to regulate mitochondrial dynamics and function.
Low BCL-xL expression in triple-negative breast cancer cells favors chemotherapy efficacy, and this effect is limited by cancer-associated fibroblasts.
Key role of glutamine metabolism in persistence of leukemic cells upon exposition to FLT3 tyrosine kinase inhibitors.
Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.
Mitochondria and cell death.
Mitochondrial division inhibitor (mdivi-1) induces extracellular matrix (ECM)-detachment of viable breast cancer cells by a DRP1-independent mechanism.
MALSU1-mediated regulation of mitochondrial function governs proliferation and doxorubicin resistance in triple-negative breast cancer cells.
Identification of PRODH as a mitochondria- and angiogenesis-related biomarker for lung adenocarcinoma.
PDZD8-FKBP8 tethering complex at ER-mitochondria contact sites regulates mitochondrial complexity.
Non-consecutive enzyme interactions within TCA cycle supramolecular assembly regulate carbon-nitrogen metabolism.
Association of mitochondrial phosphoenolpyruvate carboxykinase with prognosis and immune regulation in hepatocellular carcinoma.

Nat Commun. 2024 Jun 20. 15(1): 5265

DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring.

Adinarayana Marada, Corvin Walter, Tamara Suhm, Sahana Shankar, Arpita Nandy, Tilman Brummer, Ines Dhaouadi, F-Nora Vögtle, Chris Meisinger.

Mitochondria require an extensive proteome to maintain a variety of metabolic reactions, and changes in cellular demand depend on rapid adaptation of the mitochondrial protein composition. The TOM complex, the organellar entry gate for mitochondrial precursors in the outer membrane, is a target for cytosolic kinases to modulate protein influx. DYRK1A phosphorylation of the carrier import receptor TOM70 at Ser91 enables its efficient docking and thus transfer of precursor proteins to the TOM complex. Here, we probe TOM70 phosphorylation in molecular detail and find that TOM70 is not a CK2 target nor import receptor for MIC19 as previously suggested. Instead, we identify TOM20 as a MIC19 import receptor and show off-target inhibition of the DYRK1A-TOM70 axis with the clinically used CK2 inhibitor CX4945 which activates TOM20-dependent import pathways. Taken together, modulation of DYRK1A signalling adapts the central mitochondrial protein entry gate via synchronization of TOM70- and TOM20-dependent import pathways for metabolic rewiring. Thus, DYRK1A emerges as a cytosolic surveillance kinase to regulate and fine-tune mitochondrial protein biogenesis.

DOI: https://doi.org/10.1038/s41467-024-49611-4
Sci Transl Med. 2024 Jun 12. 16(751): eadi5336

Nutrient-sensitizing drug repurposing screen identifies lomerizine as a mitochondrial metabolism inhibitor of chronic myeloid leukemia.

Ahmed Khalaf, Lucie de Beauchamp, Eric Kalkman, Kevin Rattigan, Ekaterini Himonas, Joe Jones, Daniel James, Engy Shokry Abd Shokry, Mary T Scott, Karen Dunn, Saverio Tardito, Mhairi Copland, David Sumpton, Emma Shanks, G Vignir Helgason.

In chronic myeloid leukemia (CML), the persistence of leukemic stem cells (LSCs) after treatment with tyrosine kinase inhibitors (TKIs), such as imatinib, can lead to disease relapse. It is known that therapy-resistant LSCs rely on oxidative phosphorylation (OXPHOS) for their survival and that targeting mitochondrial respiration sensitizes CML LSCs to imatinib treatment. However, current OXPHOS inhibitors have demonstrated limited efficacy or have shown adverse effects in clinical trials, highlighting that identification of clinically safe oxidative pathway inhibitors is warranted. We performed a high-throughput drug repurposing screen designed to identify mitochondrial metabolism inhibitors in myeloid leukemia cells. This identified lomerizine, a US Food and Drug Administration (FDA)-approved voltage-gated Ca2+ channel blocker now used for the treatment of migraines, as one of the top hits. Transcriptome analysis revealed increased expression of voltage-gated CACNA1D and receptor-activated TRPC6 Ca2+ channels in CML LSCs (CD34+CD38-) compared with normal counterparts. This correlated with increased endoplasmic reticulum (ER) mass and increased ER and mitochondrial Ca2+ content in CML stem/progenitor cells. We demonstrate that lomerizine-mediated inhibition of Ca2+ uptake leads to ER and mitochondrial Ca2+ depletion, with similar effects seen after CACNA1D and TRPC6 knockdown. Through stable isotope-assisted metabolomics and functional assays, we observe that lomerizine treatment inhibits mitochondrial isocitrate dehydrogenase activity and mitochondrial oxidative metabolism and selectively sensitizes CML LSCs to imatinib treatment. In addition, combination treatment with imatinib and lomerizine reduced CML tumor burden, targeted CML LSCs, and extended survival in xenotransplantation model of human CML, suggesting this as a potential therapeutic strategy to prevent disease relapse in patients.

DOI: https://doi.org/10.1126/scitranslmed.adi5336
Cancers (Basel). 2024 Jun 03. pii: 2130. [Epub ahead of print]16(11):

Identifying Targetable Vulnerabilities to Circumvent or Overcome Venetoclax Resistance in Diffuse Large B-Cell Lymphoma.

Clare M Adams, Amanda McBride, Peter Michener, Irina Shkundina, Ramkrishna Mitra, Hyun Hwan An, Pierluigi Porcu, Christine M Eischen.

  Clinical trials with single-agent venetoclax/ABT-199 (anti-apoptotic BCL2 inhibitor) revealed that diffuse large B-cell lymphoma (DLBCL) is not solely dependent on BCL2 for survival. Gaining insight into pathways/proteins that increase venetoclax sensitivity or unique vulnerabilities in venetoclax-resistant DLBCL would provide new potential treatment avenues. Therefore, we generated acquired venetoclax-resistant DLBCL cells and evaluated these together with intrinsically venetoclax-resistant and -sensitive DLBCL lines. We identified resistance mechanisms, including alterations in BCL2 family members that differed between intrinsic and acquired venetoclax resistance and increased dependencies on specific pathways. Although combination treatments with BCL2 family member inhibitors may overcome venetoclax resistance, RNA-sequencing and drug/compound screens revealed that venetoclax-resistant DLBCL cells, including those with TP53 mutation, had a preferential dependency on oxidative phosphorylation. Mitochondrial electron transport chain complex I inhibition induced venetoclax-resistant, but not venetoclax-sensitive, DLBCL cell death. Inhibition of IDH2 (mitochondrial redox regulator) synergistically overcame venetoclax resistance. Additionally, both acquired and intrinsic venetoclax-resistant DLBCL cells were similarly sensitive to inhibitors of transcription, B-cell receptor signaling, and class I histone deacetylases. These approaches were also effective in DLBCL, follicular, and marginal zone lymphoma patient samples. Our results reveal there are multiple ways to circumvent or overcome the diverse venetoclax resistance mechanisms in DLBCL and other B-cell lymphomas and identify critical targetable pathways for future clinical investigations.

Keywords:  B-cell lymphoma; BCL2; IDH2; mitochondrial electron transport chain (ETC); venetoclax/ABT-199 resistance

DOI:  https://doi.org/10.3390/cancers16112130
Biochim Biophys Acta Mol Basis Dis. 2024 Jun 18. pii: S0925-4439(24)00305-3. [Epub ahead of print]1870(7): 167312

Metabolic adaptation in epithelial ovarian cancer metastasis.

Mallory I Frederick, Mohamed Z Nassef, Matthew J Borrelli, Siyun Kuang, Adrian Buensuceso, Tushar More, Thekla Cordes, Patrick O'Donoghue, Trevor G Shepherd, Karsten Hiller, Ilka U Heinemann.

  Epithelial ovarian cancer (EOC) is highly lethal due to its unique metastatic characteristics. EOC spheroids enter a non-proliferative state, with hypoxic cores and reduced oncogenic signaling, all of which contribute to tumour dormancy during metastasis. We investigated the metabolomic states of EOC cells progressing through the three steps to metastasis. Metabolomes of adherent, spheroid, and re-adherent cells were validated by isotopic metabolic flux analysis and mitochondrial functional assays to identify metabolic pathways that were previously unknown to promote EOC metastasis. Although spheroids were thought to exist in a dormant state, metabolomic analysis revealed an unexpected upregulation of energy production pathways in spheroids, accompanied by increased abundance of tricarboxylic acid (TCA) cycle and electron transport chain proteins. Tracing of 13C-labelled glucose and glutamine showed increased pyruvate carboxylation and decreased glutamine anaplerosis in spheroids. Increased reductive carboxylation suggests spheroids adjust redox homeostasis by shuttling cytosolic NADPH into mitochondria via isocitrate dehydrogenase. Indeed, we observed spheroids have increased respiratory capacity and mitochondrial ATP production. Relative to adherent cells, spheroids reduced serine consumption and metabolism, processes which were reversed upon spheroid re-adherence. The data reveal a distinct metabolism in EOC spheroids that enhances energy production by the mitochondria while maintaining a dormant state with respect to growth and proliferation. The findings advance our understanding of EOC metastasis and identify the TCA cycle and mitochondrional activity as novel targets to disrupt EOC metastasis, providing new approaches to treat advanced disease.

Keywords:  Anaplerosis; Metabolomics; Metastasis; Ovarian cancer; Oxidative phosphorylation; Serine; Spheroid; Tricarboxylic acid (TCA) cycle; electron transport chain

DOI:  https://doi.org/10.1016/j.bbadis.2024.167312
Cell Death Discov. 2024 Jun 19. 10(1): 292

Dependence on mitochondrial respiration of malignant T cells reveals a new therapeutic target for angioimmunoblastic T-cell lymphoma.

Adrien Krug, Rana Mhaidly, Marie Tosolini, Laura Mondragon, Gamze Tari, Adriana Martinez Turtos, Rachel Paul-Bellon, Vahid Asnafi, Sandrine Marchetti, Léa Di Mascio, Marion Travert, Frédéric Bost, Emmanuel Bachy, Rafael J Argüello, Jean-Jacques Fournié, Philippe Gaulard, François Lemonnier, Jean-Ehrland Ricci, Els Verhoeyen.

Cancer metabolic reprogramming has been recognized as one of the cancer hallmarks that promote cell proliferation, survival, as well as therapeutic resistance. Up-to-date regulation of metabolism in T-cell lymphoma is poorly understood. In particular, for human angioimmunoblastic T-cell lymphoma (AITL) the metabolic profile is not known. Metabolic intervention could help identify new treatment options for this cancer with very poor outcomes and no effective medication. Transcriptomic analysis of AITL tumor cells, identified that these cells use preferentially mitochondrial metabolism. By using our preclinical AITL mouse model, mimicking closely human AITL features, we confirmed that T follicular helper (Tfh) tumor cells exhibit a strong enrichment of mitochondrial metabolic signatures. Consistent with these results, disruption of mitochondrial metabolism using metformin or a mitochondrial complex I inhibitor such as IACS improved the survival of AITL lymphoma-bearing mice. Additionally, we confirmed a selective elimination of the malignant human AITL T cells in patient biopsies upon mitochondrial respiration inhibition. Moreover, we confirmed that diabetic patients suffering from T-cell lymphoma, treated with metformin survived longer as compared to patients receiving alternative treatments. Taking together, our findings suggest that targeting the mitochondrial metabolic pathway could be a clinically efficient approach to inhibit aggressive cancers such as peripheral T-cell lymphoma.

DOI: https://doi.org/10.1038/s41420-024-02061-9
Adv Sci (Weinh). 2024 Jun 19. e2403093

CKB Promotes Mitochondrial ATP Production by Suppressing Permeability Transition Pore.

Le He, Jianghua Lin, Shaojuan Lu, Hao Li, Jie Chen, Xinyi Wu, Qixin Yan, Hailiang Liu, Hui Li, Yufeng Shi.

  Creatine kinases are essential for maintaining cellular energy balance by facilitating the reversible transfer of a phosphoryl group from ATP to creatine, however, their role in mitochondrial ATP production remains unknown. This study shows creatine kinases, including CKMT1A, CKMT1B, and CKB, are highly expressed in cells relying on the mitochondrial F1F0 ATP synthase for survival. Interestingly, silencing CKB, but not CKMT1A or CKMT1B, leads to a loss of sensitivity to the inhibition of F1F0 ATP synthase in these cells. Mechanistically, CKB promotes mitochondrial ATP but reduces glycolytic ATP production by suppressing mitochondrial calcium (mCa2+) levels, thereby preventing the activation of mitochondrial permeability transition pore (mPTP) and ensuring efficient mitochondrial ATP generation. Further, CKB achieves this regulation by suppressing mCa2+ levels through the inhibition of AKT activity. Notably, the CKB-AKT signaling axis boosts mitochondrial ATP production in cancer cells growing in a mouse tumor model. Moreover, this study also uncovers a decline in CKB expression in peripheral blood mononuclear cells with aging, accompanied by an increase in AKT signaling in these cells. These findings thus shed light on a novel signaling pathway involving CKB that directly regulates mitochondrial ATP production, potentially playing a role in both pathological and physiological conditions.

Keywords:  AKT; F1F0 ATP synthase; aging; cancer; creatine kinase brain‐type (CKB); mitochondrial permeability transition pore (mPTP)

DOI:  https://doi.org/10.1002/advs.202403093
J Cell Sci. 2024 Jun 19. pii: jcs.261268. [Epub ahead of print]

SETD3 is a mechanosensitive enzyme that methylates actin on His-73 to regulate mitochondrial dynamics and function.

Vaibhav Deshmukh, James F Martin.

  Mitochondria, which act as sensors of metabolic homeostasis and metabolite signaling, form a dynamic intracellular network of continuously changing shape, size, and localization to respond to localized cellular energy demands. Mitochondrial dynamics and function depend on interactions with the F-actin cytoskeleton that are poorly understood. Here, we show that SET domain protein 3 (SETD3), a recently described actin histidine methyltransferase, directly methylates actin Histidine-73 and enhances F-actin polymerization on mitochondria. SETD3 is a mechano-sensitive enzyme which is localized on the outer mitochondrial membrane and promotes actin polymerization around mitochondrias. SETD3 loss of function leads to diminished F-actin around mitochondria and a decrease in mitochondrial branch length, branch number, and mitochondrial movement. Our functional analysis revealed that SETD3 is required for oxidative phosphorylation and mitochondrial complex I assembly, and function. Our data further indicate that SETD3 regulates F-actin formation around mitochondria and is essential for maintaining mitochondrial morphology, movement, and function. Finally, we discovered that SETD3 levels are regulated by ECM stiffness and regulate mitochondrial shape in response to changes in ECM stiffness. These findings provide new insight into the mechanism for F-actin polymerization around mitochondria.

Keywords:  Cytoskeleton; Mechanotransduction; Mitochondrial dynamics; Post-translational modifications

DOI:  https://doi.org/10.1242/jcs.261268
Sci Rep. 2024 06 19. 14(1): 14177

Low BCL-xL expression in triple-negative breast cancer cells favors chemotherapy efficacy, and this effect is limited by cancer-associated fibroblasts.

Lisa Nocquet, Julie Roul, Chloé C Lefebvre, Laurine Duarte, Mario Campone, Philippe P Juin, Frédérique Souazé.

  Triple negative breast cancers (TNBC) present a poor prognosis primarily due to their resistance to chemotherapy. This resistance is known to be associated with elevated expression of certain anti-apoptotic members within the proteins of the BCL-2 family (namely BCL-xL, MCL-1 and BCL-2). These regulate cell death by inhibiting pro-apoptotic protein activation through binding and sequestration and they can be selectively antagonized by BH3 mimetics. Yet the individual influences of BCL-xL, MCL-1, and BCL-2 on the sensitivity of TNBC cells to chemotherapy, and their regulation by cancer-associated fibroblasts (CAFs), major components of the tumor stroma and key contributors to therapy resistance remain to be delineated. Using gene editing or BH3 mimetics to inhibit anti-apoptotic BCL-2 family proteins in TNBC line MDA-MB-231, we show that BCL-xL and MCL-1 promote cancer cell survival through compensatory mechanisms. This cell line shows limited sensitivity to chemotherapy, in line with the clinical resistance observed in TNBC patients. We elucidate that BCL-xL plays a pivotal role in therapy response, as its depletion or pharmacological inhibition heightened chemotherapy effectiveness. Moreover, BCL-xL expression is associated with chemotherapy resistance in patient-derived tumoroids where its pharmacological inhibition enhances ex vivo response to chemotherapy. In a co-culture model of cancer cells and CAFs, we observe that even in a context where BCL-xL reduced expression renders cancer cells more susceptible to chemotherapy, those in contact with CAFs display reduced sensitivity to chemotherapy. Thus CAFs exert a profound pro-survival effect in breast cancer cells, even in a setting highly favoring cell death through combined chemotherapy and absence of the main actor of chemoresistance, BCL-xL.

Keywords:  Apoptosis; BCL-2 family; Breast cancer; Cancer-associated fibroblasts; Chemotherapy

DOI:  https://doi.org/10.1038/s41598-024-64696-z
Exp Hematol. 2024 Jun 13. pii: S0301-472X(24)00112-7. [Epub ahead of print] 104253

Key role of glutamine metabolism in persistence of leukemic cells upon exposition to FLT3 tyrosine kinase inhibitors.

Raeeka Khamari, Claire Degand, Quentin Fovez, Anne Trinh, Axel Chomy, William Laine, Salim Dekiouk, Bart Ghesquiere, Bruno Quesnel, Philippe Marchetti, Salomon Manier, Jérôme Kluza.

  Acute myeloid leukemias are a group of hematological malignancies characterized by a poor prognosis for survival. The discovery of oncogenic mutations in the FLT3 gene has led to the development of tyrosine kinase inhibitors such as Quizartinib. However, achieving complete remission in patients remains challenging because these new TKIs are unable to completely eradicate all leukemic cells. Residual leukemic cells persist during Quizartinib treatment, leading to the rapid emergence of drug-resistant leukemia. Given that mitochondrial oxidative metabolism promotes the survival of leukemic cells after exposure to multiple anticancer drugs, we characterized the metabolism of leukemic cells that persisted during Quizartinib treatment and developed metabolic strategies to eradicate them. In our study, employing biochemical and metabolomics approaches, we confirmed that the survival of leukemic cells treated with FLT3 inhibitors critically depends on maintaining mitochondrial metabolism, specifically through glutamine oxidation. We uncovered a synergistic interaction between the FLT3 inhibitor Quizartinib and L-Asparaginase, operating through anti-metabolic mechanisms. Utilizing various models of persistent leukemia, we demonstrated that leukemic cells resistant to Quizartinib are susceptible to L-Asparaginase. This combined therapeutic strategy shows promise in reducing the development of resistance to FLT3 inhibitors, offering a potential strategy to enhance treatment outcomes.

Keywords:  AML; energy metabolism; glycolysis; leukemia; mitochondria; resistance

DOI:  https://doi.org/10.1016/j.exphem.2024.104253
Dev Cell. 2024 May 20. pii: S1534-5807(24)00295-8. [Epub ahead of print]

Suppressed basal mitophagy drives cellular aging phenotypes that can be reversed by a p62-targeting small molecule.

George Kelly, Tetsushi Kataura, Johan Panek, Gailing Ma, Hanna Salmonowicz, Ashley Davis, Hannah Kendall, Charlotte Brookes, Daniel Moscoh Ayine-Tora, Peter Banks, Glyn Nelson, Laura Dobby, Patricia R Pitrez, Laura Booth, Lydia Costello, Gavin D Richardson, Penny Lovat, Stefan Przyborski, Lino Ferreira, Laura Greaves, Karolina Szczepanowska, Thomas von Zglinicki, Satomi Miwa, Max Brown, Michael Flagler, John E Oblong, Charles C Bascom, Bernadette Carroll, Jóhannes Reynisson, Viktor I Korolchuk.

  Selective degradation of damaged mitochondria by autophagy (mitophagy) is proposed to play an important role in cellular homeostasis. However, the molecular mechanisms and the requirement of mitochondrial quality control by mitophagy for cellular physiology are poorly understood. Here, we demonstrated that primary human cells maintain highly active basal mitophagy initiated by mitochondrial superoxide signaling. Mitophagy was found to be mediated by PINK1/Parkin-dependent pathway involving p62 as a selective autophagy receptor (SAR). Importantly, this pathway was suppressed upon the induction of cellular senescence and in naturally aged cells, leading to a robust shutdown of mitophagy. Inhibition of mitophagy in proliferating cells was sufficient to trigger the senescence program, while reactivation of mitophagy was necessary for the anti-senescence effects of NAD precursors or rapamycin. Furthermore, reactivation of mitophagy by a p62-targeting small molecule rescued markers of cellular aging, which establishes mitochondrial quality control as a promising target for anti-aging interventions.

Keywords:  PINK1; Parkin; aging; autophagy; mitophagy; nicotinamide; nicotinamide riboside; p62; rapamycin; redox; senescence

DOI:  https://doi.org/10.1016/j.devcel.2024.04.020
Nat Cell Biol. 2024 Jun 20.

Mitochondria and cell death.

Hannah L Glover, Annabell Schreiner, Grant Dewson, Stephen W G Tait.

Mitochondria are cellular factories for energy production, calcium homeostasis and iron metabolism, but they also have an unequivocal and central role in intrinsic apoptosis through the release of cytochrome c. While the subsequent activation of proteolytic caspases ensures that cell death proceeds in the absence of collateral inflammation, other phlogistic cell death pathways have been implicated in using, or engaging, mitochondria. Here we discuss the emerging complexities of intrinsic apoptosis controlled by the BCL-2 family of proteins. We highlight the emerging theory that non-lethal mitochondrial apoptotic signalling has diverse biological roles that impact cancer, innate immunity and ageing. Finally, we delineate the role of mitochondria in other forms of cell death, such as pyroptosis, ferroptosis and necroptosis, and discuss mitochondria as central hubs for the intersection and coordination of cell death signalling pathways, underscoring their potential for therapeutic manipulation.

DOI: https://doi.org/10.1038/s41556-024-01429-4
Sci Rep. 2024 06 19. 14(1): 14178

Mitochondrial division inhibitor (mdivi-1) induces extracellular matrix (ECM)-detachment of viable breast cancer cells by a DRP1-independent mechanism.

Eduardo Silva-Pavez, Elizabeth Mendoza, Pablo Morgado-Cáceres, Ulises Ahumada-Castro, Galdo Bustos, Matías Kangme-Encalada, Amaia Lopez de Arbina, Andrea Puebla-Huerta, Felipe Muñoz, Lucas Cereceda, Manuel Varas-Godoy, Yessia Hidalgo, J Cesar Cardenas.

  Increasing evidence supports the hypothesis that cancer progression is under mitochondrial control. Mitochondrial fission plays a pivotal role in the maintenance of cancer cell homeostasis. The inhibition of DRP1, the main regulator of mitochondrial fission, with the mitochondrial division inhibitor (mdivi-1) had been associated with cancer cell sensitivity to chemotherapeutics and decrease proliferation. Here, using breast cancer cells we find that mdivi-1 induces the detachment of the cells, leading to a bulk of floating cells that conserved their viability. Despite a decrease in their proliferative and clonogenic capabilities, these floating cells maintain the capacity to re-adhere upon re-seeding and retain their migratory and invasive potential. Interestingly, the cell detachment induced by mdivi-1 is independent of DRP1 but relies on inhibition of mitochondrial complex I. Furthermore, mdivi-1 induces cell detachment rely on glucose and the pentose phosphate pathway. Our data evidence a novel DRP1-independent effect of mdivi-1 in the attachment of cancer cells. The generation of floating viable cells restricts the use of mdivi-1 as a therapeutic agent and demonstrates that mdivi-1 effect on cancer cells are more complex than anticipated.

Keywords:  Cancer; Cell detachment; Mdivi-1; Metabolism; Mitochondrial complex I

DOI:  https://doi.org/10.1038/s41598-024-64228-9
Mol Cell Biochem. 2024 Jun 19.

MALSU1-mediated regulation of mitochondrial function governs proliferation and doxorubicin resistance in triple-negative breast cancer cells.

Feifei Zhuang, Shaoyan Huang, Lei Liu.

  Triple-negative breast cancer (TNBC) poses a formidable challenge in oncology due to its aggressive nature and limited treatment options. Although doxorubicin, a widely used chemotherapeutic agent, shows efficacy in TNBC treatment, acquired resistance remains a significant obstacle. Our study explores the role of MALSU1, a regulator of mitochondrial translation, in TNBC and its impact on cell proliferation and doxorubicin resistance. We observed increased MALSU1 expression in TNBC, correlating with poor patient prognosis. MALSU1 knockdown in TNBC cells significantly reduced proliferation, indicating its pivotal role in sustaining cell growth. Mechanistically, MALSU1 depletion resulted in decreased activities of mitochondrial respiratory chain complexes, cellular ATP levels, and mitochondrial respiration. Notably, exogenous addition of normal mitochondria restored proliferation and mitochondrial respiration in MALSU1-depleted TNBC cells. Importantly, MALSU1 knockdown enhanced the sensitivity of doxorubicin-resistant TNBC cells to doxorubicin treatment. Furthermore, pharmacological inhibition of mitochondrial translation using tigecycline and chloramphenicol mimicked the effects of MALSU1 knockdown, suggesting mitochondrial translation as a potential therapeutic target. Taken together, our findings not only elucidate the intricate role of MALSU1 in TNBC biology and doxorubicin resistance but also lay the groundwork for future investigations targeting MALSU1 and/or mitochondrial translation as a promising avenue for developing innovative therapeutic strategies against TNBC.

Keywords:  Doxorubicin resistance; Doxorubicin sensitivity; Mitochondrial respiration; Triple-negative breast cancer

DOI:  https://doi.org/10.1007/s11010-024-05053-6
Transl Cancer Res. 2024 May 31. 13(5): 2073-2093

Identification of PRODH as a mitochondria- and angiogenesis-related biomarker for lung adenocarcinoma.

Xinran Xi, Meng Zhang, Yonghua Li, Xianghai Wang.

  Background: Proline dehydrogenase (PRODH) encodes a mitochondrial protein that catalyzes the first step of proline degradation and is related to angiogenesis. Angiogenesis is a critical process in the development and progression of tumors, including lung adenocarcinoma (LUAD), as tumor growth and metastasis are dependent on angiogenesis. The mitochondria and their associated genes thus play a vital role in tumor therapy. However, the specific mechanism of action of PRODH in LUAD is not yet clear. The aim of this study was thus to clarify the specific mechanism of PRODH as a mitochondrial gene in LUAD.Methods: This study identified genes related to mitochondria and angiogenesis in LUAD. Based on the high and low expression of the genes in LUAD, we grouped them and conducted relevant bioinformatics analysis on the differentially expressed genes.
Results: We screened genes related to mitochondria and angiogenesis in the differential genes of LUAD, and identified PRODH as a gene of interest. The expression of PRODH was associated with the survival outcome of patients with LUAD. Additionally, PRODH was found to be associated with immune cell infiltration and tumor mutations.
Conclusions: Mitochondrial metabolism and angiogenesis may have significant therapeutic ramifications for patients with LUAD. We identified PRODH, a gene exerts a dual role in cancer. PRODH may be a prospective therapeutic target in LUAD and a possible diagnostic and prognostic biomarker associated with immune infiltration and tumor mutational burden.

Keywords:  Lung cancer; angiogenesis; bioinformatics; mitochondria-related genes

DOI:  https://doi.org/10.21037/tcr-23-2109
bioRxiv. 2024 Jun 03. pii: 2023.08.22.554218. [Epub ahead of print]

PDZD8-FKBP8 tethering complex at ER-mitochondria contact sites regulates mitochondrial complexity.

Koki Nakamura, Saeko Aoyama-Ishiwatari, Takahiro Nagao, Mohammadreza Paaran, Christopher J Obara, Yui Sakurai-Saito, Jake Johnston, Yudan Du, Shogo Suga, Masafumi Tsuboi, Makoto Nakakido, Kouhei Tsumoto, Yusuke Kishi, Yukiko Gotoh, Chulhwan Kwak, Hyun-Woo Rhee, Jeong Kon Seo, Hidetaka Kosako, Clint Potter, Bridget Carragher, Jennifer Lippincott-Schwartz, Franck Polleux, Yusuke Hirabayashi.

Mitochondria-ER membrane contact sites (MERCS) represent a fundamental ultrastructural feature underlying unique biochemistry and physiology in eukaryotic cells. The ER protein PDZD8 is required for the formation of MERCS in many cell types, however, its tethering partner on the outer mitochondrial membrane (OMM) is currently unknown. Here we identified the OMM protein FKBP8 as the tethering partner of PDZD8 using a combination of unbiased proximity proteomics, CRISPR-Cas9 endogenous protein tagging, Cryo-Electron Microscopy (Cryo-EM) tomography, and correlative light-EM (CLEM). Single molecule tracking revealed highly dynamic diffusion properties of PDZD8 along the ER membrane with significant pauses and capture at MERCS. Overexpression of FKBP8 was sufficient to narrow the ER-OMM distance, whereas independent versus combined deletions of these two proteins demonstrated their interdependence for MERCS formation. Furthermore, PDZD8 enhances mitochondrial complexity in a FKBP8-dependent manner. Our results identify a novel ER-mitochondria tethering complex that regulates mitochondrial morphology in mammalian cells.

DOI: https://doi.org/10.1101/2023.08.22.554218
Nat Commun. 2024 Jun 20. 15(1): 5285

Non-consecutive enzyme interactions within TCA cycle supramolecular assembly regulate carbon-nitrogen metabolism.

Weronika Jasinska, Mirco Dindo, Sandra M C Cordoba, Adrian W R Serohijos, Paola Laurino, Yariv Brotman, Shimon Bershtein.

Enzymes of the central metabolism tend to assemble into transient supramolecular complexes. However, the functional significance of the interactions, particularly between enzymes catalyzing non-consecutive reactions, remains unclear. Here, by co-localizing two non-consecutive enzymes of the TCA cycle from Bacillus subtilis, malate dehydrogenase (MDH) and isocitrate dehydrogenase (ICD), in phase separated droplets we show that MDH-ICD interaction leads to enzyme agglomeration with a concomitant enhancement of ICD catalytic rate and an apparent sequestration of its reaction product, 2-oxoglutarate. Theory demonstrates that MDH-mediated clustering of ICD molecules explains the observed phenomena. In vivo analyses reveal that MDH overexpression leads to accumulation of 2-oxoglutarate and reduction of fluxes flowing through both the catabolic and anabolic branches of the carbon-nitrogen intersection occupied by 2-oxoglutarate, resulting in impeded ammonium assimilation and reduced biomass production. Our findings suggest that the MDH-ICD interaction is an important coordinator of carbon-nitrogen metabolism.

DOI: https://doi.org/10.1038/s41467-024-49646-7
Sci Rep. 2024 06 18. 14(1): 14051

Association of mitochondrial phosphoenolpyruvate carboxykinase with prognosis and immune regulation in hepatocellular carcinoma.

Chenxuan Li, En-di Zhang, Youzhi Ye, Zhongyun Xiao, Hanfei Huang, Zhong Zeng.

  Mitochondrial phosphoenolpyruvate carboxykinase (PCK2), a mitochondrial isoenzyme, supports the growth of cancer cells under glucose deficiency conditions in vitro. This study investigated the role and potential mechanism of PCK2 in the occurrence and development of Hepatocellular carcinoma (HCC). The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and other databases distinguish the expression of PCK2 and verified by qRT-PCR and Western blotting. Kaplan-Meier was conducted to assess PCK2 survival in HCC. The potential biological function of PCK2 was verified by enrichment analysis and gene set enrichment analysis (GSEA). The correlation between PCK2 expression and immune invasion and checkpoint was found by utilizing Tumor Immune Estimation Resource (TIMER). Lastly, the effects of PCK2 on the proliferation and metastasis of hepatocellular carcinoma cells were evaluated by cell tests, and the expressions of Epithelial mesenchymal transformation (EMT) and apoptosis related proteins were detected. PCK2 is down-regulated in HCC, indicating a poor prognosis. PCK2 gene mutation accounted for 1.3% of HCC. Functional enrichment analysis indicated the potential of PCK2 as a metabolism-related therapeutic target. Subsequently, we identified several signaling pathways related to the biological function of PCK2. The involvement of PCK2 in immune regulation was verified and key immune checkpoints were predicted. Ultimately, after PCK2 knockdown, cell proliferation and migration were significantly increased, and N-cadherin and vimentin expression were increased. PCK2 has been implicated in immune regulation, proliferation, and metastasis of hepatocellular carcinoma, and is emerging as a novel predictive biomarker and metabolic-related clinical target.

Keywords:  Epithelial–mesenchymal transition; Hepatocellular carcinoma; Immune checkpoints; Immune infiltrates; PCK2; Prognosis

DOI:  https://doi.org/10.1038/s41598-024-64907-7