bims-mibica 2024-02-25 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2024–02–25
27 papers selected by
Kelsey Fisher-Wellman, East Carolina University

Mitochondrial quinone redox states as a marker of mitochondrial metabolism.
Transport activity regulates mitochondrial bioenergetics and biogenesis in renal tubules.
Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.
Exposure of the inner mitochondrial membrane triggers apoptotic mitophagy.
MIMAS is a new giant multifunctional player in the mitochondrial megacomplex playground.
Dysregulated inter-mitochondrial crosstalk in glioblastoma cells revealed by in situ cryo-electron tomography.
Cancer resistance and metastasis are maintained through oxidative phosphorylation.
Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery.
Selpercatinib combination with the mitochondria-targeted antioxidant MitoQ effectively suppresses RET-mutant thyroid cancer.
Mitochondrial and cytosolic one-carbon metabolism is a targetable metabolic vulnerability in cisplatin-resistant ovarian cancer.
Calcium oscillations optimize the energetic efficiency of mitochondrial metabolism.
UDP-glucose dehydrogenase supports autophagy-deficient PDAC growth via increasing hyaluronic acid biosynthesis.
HMGB1 promotes mitochondrial transfer between hepatocellular carcinoma cells through RHOT1 and RAC1 under hypoxia.
Panobinostat sensitizes AraC-resistant AML cells to the combination of azacitidine and venetoclax.
Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy.
METTL17 coordinates ferroptosis and tumorigenesis by regulating mitochondrial translation in colorectal cancer.
An arms-race against resistance: leukemic stem cells and lineage plasticity.
αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation.
Monocarboxylate transporters facilitate succinate uptake into brown adipocytes.
Fumarate induces LncRNA-MIR4435-2HG to regulate glutamine metabolism remodeling and promote the development of FH-deficient renal cell carcinoma.
Mitophagy-Mediated Tumor Dormancy Protects Cancer Cells from Chemotherapy.
An engineered biosensor enables dynamic aspartate measurements in living cells.
Venetoclax and Cobimetinib in Relapsed/Refractory AML: A Phase 1b Trial.
Fumarate Hydratase Enhances the Therapeutic Effect of PD-1 Antibody in Colorectal Cancer by Regulating PCSK9.
HSP90 inhibition suppresses tumor glycolytic flux to potentiate the therapeutic efficacy of radiotherapy for head and neck cancer.
Metabolic adaptation towards glycolysis supports resistance to neoadjuvant chemotherapy in early triple negative breast cancers.
S-Adenosylmethionine Negatively Regulates the Mitochondrial Respiratory Chain Repressor MCJ in the Liver.

Biochim Biophys Acta Bioenerg. 2024 Feb 16. pii: S0005-2728(24)00003-3. [Epub ahead of print] 149033

Mitochondrial quinone redox states as a marker of mitochondrial metabolism.

M Martins Pinto, S Ransac, J P Mazat, L Schwartz, M Rigoulet, S Arbault, P Paumard, A Devin.

  Mitochondrial and thus cellular energetics are highly regulated both thermodynamically and kinetically. Cellular energetics is of prime importance in the regulation of cellular functions since it provides ATP for their accomplishment. However, cellular energetics is not only about ATP production but also about the ability to re-oxidize reduced coenzymes at a proper rate, such that the cellular redox potential remains at a level compatible with enzymatic reactions. However, this parameter is not only difficult to assess due to its dual compartmentation (mitochondrial and cytosolic) but also because it is well known that most NADH in the cells is bound to the enzymes. In this paper, we investigated the potential relevance of mitochondrial quinones redox state as a marker of mitochondrial metabolism and more particularly mitochondrial redox state. We were able to show that Q2 is an appropriate redox mediator to assess the mitochondrial quinone redox states. On isolated mitochondria, the mitochondrial quinone redox states depend on the mitochondrial substrate and the mitochondrial energetic state (phosphorylating or not phosphorylating). Last but not least, we show that the quinones redox state response allows to better understand the Krebs cycle functioning and respiratory substrates oxidation. Taken together, our results suggest that the quinones redox state is an excellent marker of mitochondrial metabolism.

Keywords:  Bioenergetics; Mitochondria respiratory chain; Quinones; Redox state

DOI:  https://doi.org/10.1016/j.bbabio.2024.149033
bioRxiv. 2024 Feb 08. pii: 2024.02.04.578838. [Epub ahead of print]

Transport activity regulates mitochondrial bioenergetics and biogenesis in renal tubules.

Chih-Jen Cheng, Jonathan M Nizar, Dao-Fu Dai, Chou-Long Huang.

Renal tubules are featured with copious mitochondria and robust transport activity. Mutations in mitochondrial genes cause congenital renal tubulopathies, and changes in transport activity affect mitochondrial morphology, suggesting mitochondrial function and transport activity are tightly coupled. Current methods of using bulk kidney tissues or cultured cells to study mitochondrial bioenergetics are limited. Here, we optimized an extracellular flux analysis (EFA) to study mitochondrial respiration and energy metabolism using microdissected mouse renal tubule segments. EFA detects mitochondrial respiration and glycolysis by measuring oxygen consumption and extracellular acidification rates, respectively. We show that both measurements positively correlate with sample sizes of a few centimeter-length renal tubules. The thick ascending limbs (TALs) and distal convoluted tubules (DCTs) predominantly utilize glucose/pyruvate as energy substrates, whereas proximal tubules (PTs) are significantly much less so. Acute inhibition of TALs' transport activity by ouabain treatment reduces basal and ATP-linked mitochondrial respiration. Chronic inhibition of transport activity by 2-week furosemide treatment or deletion of with-no-lysine kinase 4 (Wnk4) decreases maximal mitochondrial capacity. In addition, chronic inhibition downregulates mitochondrial DNA mass and mitochondrial length/density in TALs and DCTs. Conversely, gain-of-function Wnk4 mutation increases maximal mitochondrial capacity and mitochondrial length/density without increasing mitochondrial DNA mass. In conclusion, EFA is a sensitive and reliable method to investigate mitochondrial functions in isolated renal tubules. Transport activity tightly regulates mitochondrial bioenergetics and biogenesis to meet the energy demand in renal tubules. The system allows future investigation into whether and how mitochondria contribute to tubular remodeling adapted to changes in transport activity.
Key points: A positive correlation between salt reabsorption and oxygen consumption in mammalian kidneys hints at a potential interaction between transport activity and mitochondrial respiration in renal tubules.Renal tubules are heterogeneous in transport activity and mitochondrial metabolism, and traditional assays using bulk kidney tissues cannot provide segment-specific information.Here, we applied an extracellular flux analysis to investigate mitochondrial respiration and energy metabolism in isolated renal tubules. This assay is sensitive in detecting oxygen consumption and acid production in centimeter-length renal tubules and reliably recapitulates segment-specific metabolic features.Acute inhibition of transport activity reduces basal and ATP-linked mitochondrial respirations without changing maximal mitochondrial respiratory capacity. Chronic alterations of transport activity further adjust maximal mitochondrial respiratory capacity via regulating mitochondrial biogenesis or non-transcriptional mechanisms.Our findings support the concept that renal tubular cells finely adjust mitochondrial bioenergetics and biogenesis to match the new steady state of transport activity.

DOI: https://doi.org/10.1101/2024.02.04.578838
Cell Rep. 2024 Feb 21. pii: S2211-1247(24)00100-1. [Epub ahead of print]43(3): 113772

Identification of MIMAS, a multifunctional mega-assembly integrating metabolic and respiratory biogenesis factors of mitochondria.

Patrick Horten, Kuo Song, Joshua Garlich, Robert Hardt, Lilia Colina-Tenorio, Susanne E Horvath, Uwe Schulte, Bernd Fakler, Martin van der Laan, Thomas Becker, Rosemary A Stuart, Nikolaus Pfanner, Heike Rampelt.

  The mitochondrial inner membrane plays central roles in bioenergetics and metabolism and contains several established membrane protein complexes. Here, we report the identification of a mega-complex of the inner membrane, termed mitochondrial multifunctional assembly (MIMAS). Its large size of 3 MDa explains why MIMAS has escaped detection in the analysis of mitochondria so far. MIMAS combines proteins of diverse functions from respiratory chain assembly to metabolite transport, dehydrogenases, and lipid biosynthesis but not the large established supercomplexes of the respiratory chain, ATP synthase, or prohibitin scaffold. MIMAS integrity depends on the non-bilayer phospholipid phosphatidylethanolamine, in contrast to respiratory supercomplexes whose stability depends on cardiolipin. Our findings suggest that MIMAS forms a protein-lipid mega-assembly in the mitochondrial inner membrane that integrates respiratory biogenesis and metabolic processes in a multifunctional platform.

Keywords:  CP: Metabolism; CP: Molecular biology; membrane protein complex; metabolism; metabolite carriers; mitochondria; phosphatidylethanolamine; phospholipids; protein assembly; respiratory chain

DOI:  https://doi.org/10.1016/j.celrep.2024.113772
Cell Death Differ. 2024 Feb 23.

Exposure of the inner mitochondrial membrane triggers apoptotic mitophagy.

Tahnee L Saunders, Simon P Windley, Gediminas Gervinskas, Katherine R Balka, Caitlin Rowe, Rachael Lane, Maximilien Tailler, Thanh Ngoc Nguyen, Georg Ramm, Michael Lazarou, Dominic De Nardo, Benjamin T Kile, Kate McArthur.

During apoptosis mediated by the intrinsic pathway, BAX/BAK triggers mitochondrial permeabilization and the release of cytochrome-c, followed by a dramatic remodelling of the mitochondrial network that results in mitochondrial herniation and the subsequent release of pro-inflammatory mitochondrial components. Here, we show that mitochondrial herniation and subsequent exposure of the inner mitochondrial membrane (IMM) to the cytoplasm, initiates a unique form of mitophagy to deliver these damaged organelles to lysosomes. IMM-induced mitophagy occurs independently of canonical PINK1/Parkin signalling and is driven by ubiquitination of the IMM. Our data suggest IMM-induced mitophagy is an additional safety mechanism that cells can deploy to contain damaged mitochondria. It may have particular relevance in situations where caspase activation is incomplete or inhibited, and in contexts where PINK1/Parkin-mitophagy is impaired or overwhelmed.

DOI: https://doi.org/10.1038/s41418-024-01260-2
Cell Rep. 2024 Feb 21. pii: S2211-1247(24)00202-X. [Epub ahead of print]43(3): 113874

MIMAS is a new giant multifunctional player in the mitochondrial megacomplex playground.

Kostas Tokatlidis.

Mitochondria are rich in multi-protein assemblies that are usually dedicated to one function. In this issue of Cell Reports, Horten et al.1 describe a 3-nanometer megacomplex in the mitochondrial inner membrane, which serves multiple functions integrating mitochondria biogenesis and metabolism.

DOI: https://doi.org/10.1016/j.celrep.2024.113874
Proc Natl Acad Sci U S A. 2024 Feb 27. 121(9): e2311160121

Dysregulated inter-mitochondrial crosstalk in glioblastoma cells revealed by in situ cryo-electron tomography.

Rui Wang, Huan Lei, Hongxiang Wang, Lei Qi, Yu'e Liu, Yunhui Liu, Yufeng Shi, Juxiang Chen, Qing-Tao Shen.

  Glioblastomas (GBMs) are the most lethal primary brain tumors with limited survival, even under aggressive treatments. The current therapeutics for GBMs are flawed due to the failure to accurately discriminate between normal proliferating cells and distinctive tumor cells. Mitochondria are essential to GBMs and serve as potential therapeutical targets. Here, we utilize cryo-electron tomography to quantitatively investigate nanoscale details of randomly sampled mitochondria in their native cellular context of GBM cells. Our results show that compared with cancer-free brain cells, GBM cells own more inter-mitochondrial junctions of several types for communications. Furthermore, our tomograms unveil microtubule-dependent mitochondrial nanotunnel-like bridges in the GBM cells as another inter-mitochondrial structure. These quantified inter-mitochondrial features, together with other mitochondria-organelle and intra-mitochondrial ones, are sufficient to distinguish GBM cells from cancer-free brain cells under scrutiny with predictive modeling. Our findings decipher high-resolution inter-mitochondrial structural signatures and provide clues for diagnosis and therapeutic interventions for GBM and other mitochondria-related diseases.

Keywords:  cryo-electron tomography; glioblastoma; mitochondria; organelle crosstalk

DOI:  https://doi.org/10.1073/pnas.2311160121
Cancer Lett. 2024 Feb 17. pii: S0304-3835(24)00098-3. [Epub ahead of print] 216705

Cancer resistance and metastasis are maintained through oxidative phosphorylation.

Cemile Uslu, Eda Kapan, Alex Lyakhovich.

  Malignant tumors have increased energy requirements due to growth, differentiation or response to stress. A significant number of studies in recent years have described upregulation of mitochondrial genes responsible for oxidative phosphorylation (OXPHOS) in some tumors. Although OXPHOS is replaced by glycolysis in some tumors (Warburg effect), both processes can occur simultaneously during the evolution of the same malignancies. In particular, chemoresistant and/or cancer stem cells appear to find a way to activate OXPHOS and metastasize. In this paper, we discuss recent work showing upregulation of OXPHOS in chemoresistant tumors and cell models. In addition, we show an inverse correlation of OXPHOS gene expression with the survival time of cancer patients after chemotherapy and discuss combination therapies for resistant cancer tumors.

Keywords:  Cancer chemoprevention; Cancer chemoresistance; Cancer stem cells; Drug repurposing; Mitochondrial respiration; Oxidative phosphorylation; Personalized medicine; Targeted therapy

DOI:  https://doi.org/10.1016/j.canlet.2024.216705
Cell Rep. 2024 Feb 19. pii: S2211-1247(24)00133-5. [Epub ahead of print]43(3): 113805

Role of the small protein Mco6 in the mitochondrial sorting and assembly machinery.

Jon V Busto, Iniyan Ganesan, Hannah Mathar, Conny Steiert, Eva F Schneider, Sebastian P Straub, Lars Ellenrieder, Jiyao Song, Sebastian B Stiller, Philipp Lübbert, Ritwika Chatterjee, Jana Elsaesser, Laura Melchionda, Christina Schug, Fabian den Brave, Uwe Schulte, Till Klecker, Claudine Kraft, Bernd Fakler, Thomas Becker, Nils Wiedemann.

  The majority of mitochondrial precursor proteins are imported through the Tom40 β-barrel channel of the translocase of the outer membrane (TOM). The sorting and assembly machinery (SAM) is essential for β-barrel membrane protein insertion into the outer membrane and thus required for the assembly of the TOM complex. Here, we demonstrate that the α-helical outer membrane protein Mco6 co-assembles with the mitochondrial distribution and morphology protein Mdm10 as part of the SAM machinery. MCO6 and MDM10 display a negative genetic interaction, and a mco6-mdm10 yeast double mutant displays reduced levels of the TOM complex. Cells lacking Mco6 affect the levels of Mdm10 and show assembly defects of the TOM complex. Thus, this work uncovers a role of the SAMMco6 complex for the biogenesis of the mitochondrial outer membrane.

Keywords:  CP: Cell biology; ERMES complex; Mdm10; SAM complex; TOM complex; mitochondria; outer membrane; protein import; protein translocation; β-barrel protein

DOI:  https://doi.org/10.1016/j.celrep.2024.113805
NPJ Precis Oncol. 2024 Feb 20. 8(1): 39

Selpercatinib combination with the mitochondria-targeted antioxidant MitoQ effectively suppresses RET-mutant thyroid cancer.

Wenjing Chen, Sophie Dream, Pui-Yin Leung, Pui-Kei Wu, Stuart Wong, Jong-In Park.

Genetic alternation of REarranged during Transfection (RET) that leads to constitutive RET activation is a crucial etiological factor for thyroid cancer. RET is known to regulate mitochondrial processes, although the underlying molecular mechanisms remain unclear. We previously showed that the multi-kinase inhibitors vandetanib and cabozantinib increase the mitochondrial membrane potential (Δψm) in RET-mutated thyroid tumor cells and that this effect can be exploited to increase mitochondrial enrichment of Δψm-sensitive agents in the tumor cells. In this study, we hypothesized that the RET-selective inhibitor, selpercatinib, can increase Δψm and, subsequently, tumor cell uptake of the mitochondria-targeted ubiquinone (MitoQ) to the level to break the mitochondrial homeostasis and induce lethal responses in RET-mutated thyroid tumor cells. We show that selpercatinib significantly increased Δψm, and its combination with MitoQ synergistically suppressed RET-mutated human thyroid tumor cells, which we validated using RET-targeted genetic approaches. Selpercatinib and MitoQ, in combination, also suppressed CCDC6-RET fusion cell line xenografts in mice and prolonged animal survival more effectively than single treatments of each agent. Moreover, we treated two patients with CCDC6-RET or RETM918T thyroid cancer, who could not take selpercatinib at regular doses due to adverse effects, with a dose-reduced selpercatinib and MitoQ combination. In response to this combination therapy, both patients showed tumor reduction. The quality of life of one patient significantly improved over a year until the tumor relapsed. This combination of selpercatinib with MitoQ may have therapeutic potential for patients with RET-mutated tumors and intolerant to regular selpercatinib doses.

DOI: https://doi.org/10.1038/s41698-024-00536-7
Mol Cancer Ther. 2024 Feb 20.

Mitochondrial and cytosolic one-carbon metabolism is a targetable metabolic vulnerability in cisplatin-resistant ovarian cancer.

Adrianne Wallace-Povirk, Carrie O'Connor, Aamod S Dekhne, Xun Bao, Md Junayed Nayeen, Mathew Schneider, Jade M Katinas, Jennifer Wong-Roushar, Seongho Kim, Lisa Polin, Jing Li, Jessica B Back, Charles E Dann, Aleem Gangjee, Zhanjun Hou, Larry H Matherly.

One-carbon (C1) metabolism is compartmentalized between the cytosol and mitochondria with the mitochondrial C1 pathway as the major source of glycine and C1 units for cellular biosynthesis. Expression of mitochondrial C1 genes including SLC25A32, serine hydroxymethyl transferase (SHMT) 2, 5,10-methylene tetrahydrofolate dehydrogenase 2, and 5,10-methylene tetrahydrofolate dehydrogenase 1-like was significantly elevated in primary epithelial ovarian cancer (EOC) specimens compared to normal ovaries. 5-Substituted pyrrolo[3,2-d]pyrimidine antifolates (AGF347, AGF359, AGF362) inhibited proliferation of cisplatin sensitive (A2780, CaOV3, IGROV1) and resistant (A2780-E80, SKOV3) EOC cells. In SKOV3 and A2780-E80 cells, colony formation was inhibited. AGF347 induced apoptosis in SKOV3 cells. In IGROV1 cells, AGF347 was transported by folate receptor (FR) α. AGF347 was also transported into IGROV1 and SKOV3 cells by the proton-coupled folate transporter (SLC46A1) and the reduced folate carrier (SLC19A1). AGF347 accumulated to high levels in the cytosol and mitochondria of SKOV3 cells. By targeted metabolomics with [2,3,3-2H]L-serine, AGF347, AGF359 and AGF362 inhibited SHMT2 in the mitochondria. In the cytosol, SHMT1 and de novo purine biosynthesis (i.e., glycinamide ribonucleotide formyltransferase, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase) were targeted; AGF359 also inhibited thymidylate synthase. Antifolate treatments of SKOV3 cells depleted cellular glycine, mitochondrial NADH and glutathione, and showed synergistic in vitro inhibition toward SKOV3 and A2780-E80 cells when combined with cisplatin. In vivo studies with subcutaneous SKOV3 EOC xenografts in SCID mice confirmed significant antitumor efficacy of AGF347. Collectively, our studies demonstrate a unique metabolic vulnerability in EOC involving mitochondrial and cytosolic C1 metabolism that offers a promising new platform for therapy.

DOI: https://doi.org/10.1158/1535-7163.MCT-23-0550
iScience. 2024 Mar 15. 27(3): 109078

Calcium oscillations optimize the energetic efficiency of mitochondrial metabolism.

Valérie Voorsluijs, Francesco Avanzini, Gianmaria Falasco, Massimiliano Esposito, Alexander Skupin.

  Energy transduction is central to living organisms, but the impact of enzyme regulation and signaling on its thermodynamic efficiency is generally overlooked. Here, we analyze the efficiency of ATP production by the tricarboxylic acid cycle and oxidative phosphorylation, which generate most of the chemical energy in eukaryotes. Calcium signaling regulates this pathway and can affect its energetic output, but the concrete energetic impact of this cross-talk remains elusive. Calcium enhances ATP production by activating key enzymes of the tricarboxylic acid cycle while calcium homeostasis is ATP-dependent. We propose a detailed kinetic model describing the calcium-mitochondria cross-talk and analyze it using nonequilibrium thermodynamics: after identifying the effective reactions driving mitochondrial metabolism out of equilibrium, we quantify the mitochondrial thermodynamic efficiency for different conditions. Calcium oscillations, triggered by extracellular stimulation or energy deficiency, boost the thermodynamic efficiency of mitochondrial metabolism, suggesting a compensatory role of calcium signaling in mitochondrial bioenergetics.

Keywords:  Biological sciences; Human metabolism; Molecular biology; Natural sciences

DOI:  https://doi.org/10.1016/j.isci.2024.109078
Cell Rep. 2024 Feb 16. pii: S2211-1247(24)00136-0. [Epub ahead of print]43(2): 113808

UDP-glucose dehydrogenase supports autophagy-deficient PDAC growth via increasing hyaluronic acid biosynthesis.

Minghe Fan, Sihan Huo, Yuyao Guo, Ruoxuan Wang, Wenqin Hao, Ziyang Zhang, Lina Wang, Ying Zhao.

  Autophagy is an essential degradation and recycling process that maintains cellular homeostasis during stress or nutrient deprivation. However, certain types of tumors such as pancreatic cancers can circumvent autophagy inhibition to sustain growth. The mechanism that autophagy-deficient pancreatic ductal adenocarcinoma (PDAC) uses to grow under nutrient deprivation is poorly understood. Our data show that nutrient deprivation in PDAC results in UDP-glucose dehydrogenase (UGDH) degradation, which is dependent on autophagic cargo receptor sequestosome 1 (p62). Moreover, we demonstrate that accumulated UGDH is indispensable for autophagy-deficient PDAC cells proliferation by promoting hyaluronic acid (HA) synthesis upon energy deprivation. Using an orthotopic mouse model of PDAC, we find that inhibition of HA synthesis by targeting UGDH in PDAC reduces tumor weight. Thus, the combined inhibition of HA and autophagy might be an attractive strategy for PDAC treatment.

Keywords:  CP: Cancer; CP: Metabolism; HA; PDAC; UDP-glucose dehydrogenase; UGDH; autophagy; hyaluronic acid; p62; pancreatic ductal adenocarcinoma; sequestosome 1

DOI:  https://doi.org/10.1016/j.celrep.2024.113808
Cell Death Dis. 2024 Feb 20. 15(2): 155

HMGB1 promotes mitochondrial transfer between hepatocellular carcinoma cells through RHOT1 and RAC1 under hypoxia.

Mengjia Jing, Xiaofeng Xiong, Xin Mao, Qianben Song, Lumiao Zhang, Yiming Ouyang, Yingzhi Pang, Yu Fu, Wei Yan.

Mitochondrial transfer plays an important role in various diseases, and many mitochondrial biological functions can be regulated by HMGB1. To explore the role of mitochondrial transfer in hepatocellular carcinoma (HCC) and its relationship with HMGB1, field emission scanning electron microscopy, immunofluorescence, and flow cytometry were used to detect the mitochondrial transfer between HCC cells. We found that mitochondrial transfer between HCC cells was confirmed using tunnel nanotubes (TNTs). The transfer of mitochondria from the highly invasive HCC cells to the less invasive HCC cells could enhance the migration and invasion ability of the latter. The hypoxic conditions increased the mitochondrial transfer between HCC cells. Then the mechanism was identified using co-immunoprecipitation, luciferase reporter assay, and chromatin immunoprecipitation. We found that RHOT1, a mitochondrial transport protein, promoted mitochondrial transfer and the migration and metastasis of HCC cells during this process. Under hypoxia, HMGB1 further regulated RHOT1 expression by increasing the expression of NFYA and NFYC subunits of the NF-Y complex. RAC1, a protein associated with TNTs formation, promoted mitochondrial transfer and HCC development. Besides, HMGB1 regulated RAC1 aggregation to the cell membrane under hypoxia. Finally, the changes and significance of related molecules in clinical samples of HCC were analyzed using bioinformatics and tissue microarray analyses. We found that HCC patients with high HMGB1, RHOT1, or RAC1 expression exhibited a relatively shorter overall survival period. In conclusion, under hypoxic conditions, HMGB1 promoted mitochondrial transfer and migration and invasion of HCC cells by increasing the expression of mitochondrial transport protein RHOT1 and TNTs formation-related protein RAC1.

DOI: https://doi.org/10.1038/s41419-024-06536-6
Biochem Pharmacol. 2024 Feb 17. pii: S0006-2952(24)00048-0. [Epub ahead of print] 116065

Panobinostat sensitizes AraC-resistant AML cells to the combination of azacitidine and venetoclax.

Jianlei Zhao, Shuangshuang Wu, Deying Wang, Holly Edwards, Jenna Thibodeau, Seongho Kim, Paul Stemmer, Guan Wang, Jingji Jin, Süreyya Savasan, Jeffrey W Taub, Yubin Ge.

  The majority of acute myeloid leukemia (AML) patients respond to intensive induction therapy, consisting of cytarabine (AraC) and an anthracycline, though more than half experience relapse. Relapsed/refractory (R/R) AML patients are difficult to treat, and their clinical outcomes remain dismal. Venetoclax (VEN) in combination with azacitidine (AZA) has provided a promising treatment option for R/R AML, though the overall survival (OS) could be improved (OS ranges from 4.3 to 9.1 months). Overexpression of c-Myc is associated with chemoresistance in AML. Histone deacetylase (HDAC) inhibitors have been shown to suppress c-Myc and enhance the antileukemic activity of VEN, as well as AZA, though combination of all three has not been fully explored. In this study, we investigated the HDAC inhibitor, panobinostat, in combination with VEN + AZA against AraC-resistant AML cells. Panobinostat treatment downregulated c-Myc and Bcl-xL and upregulated Bim, which enhanced the antileukemic activity of VEN + AZA against AraC-resistant AML cells. In addition, panobinostat alone and in combination with VEN + AZA suppressed oxidative phosphorylation and/or glycolysis in AraC-resistant AML cells. These findings support further development of panobinostat in combination with VEN + AZA for the treatment of AraC-resistant AML.

Keywords:  Acute myeloid leukemia; Azacitidine; Panobinostat; Venetoclax

DOI:  https://doi.org/10.1016/j.bcp.2024.116065
Nat Commun. 2024 Feb 17. 15(1): 1476

Cyclic peptides discriminate BCL-2 and its clinical mutants from BCL-XL by engaging a single-residue discrepancy.

Fengwei Li, Junjie Liu, Chao Liu, Ziyan Liu, Xiangda Peng, Yinyue Huang, Xiaoyu Chen, Xiangnan Sun, Sen Wang, Wei Chen, Dan Xiong, Xiaotong Diao, Sheng Wang, Jingjing Zhuang, Chuanliu Wu, Dalei Wu.

Overexpressed pro-survival B-cell lymphoma-2 (BCL-2) family proteins BCL-2 and BCL-XL can render tumor cells malignant. Leukemia drug venetoclax is currently the only approved selective BCL-2 inhibitor. However, its application has led to an emergence of resistant mutations, calling for drugs with an innovative mechanism of action. Herein we present cyclic peptides (CPs) with nanomolar-level binding affinities to BCL-2 or BCL-XL, and further reveal the structural and functional mechanisms of how these CPs target two proteins in a fashion that is remarkably different from traditional small-molecule inhibitors. In addition, these CPs can bind to the venetoclax-resistant clinical BCL-2 mutants with similar affinities as to the wild-type protein. Furthermore, we identify a single-residue discrepancy between BCL-2 D111 and BCL-XL A104 as a molecular "switch" that can differently engage CPs. Our study suggests that CPs may inhibit BCL-2 or BCL-XL by delicately modulating protein-protein interactions, potentially benefiting the development of next-generation therapeutics.

DOI: https://doi.org/10.1038/s41467-024-45848-1
Redox Biol. 2024 Feb 13. pii: S2213-2317(24)00063-6. [Epub ahead of print]71 103087

METTL17 coordinates ferroptosis and tumorigenesis by regulating mitochondrial translation in colorectal cancer.

Hao Li, Kailun Yu, Huilong Hu, Xiandan Zhang, Siyu Zeng, Jiawen Li, Xiaoning Dong, Xusheng Deng, Jianhui Zhang, Yongyou Zhang.

  Ferroptosis, an iron-dependent lipid peroxidation-induced form of regulated cell death, shows great promise as a cancer therapy strategy. Despite the critical role of mitochondria in ferroptosis regulation, the underlying mechanisms remain elusive. This study reveals that the mitochondrial protein METTL17 governs mitochondrial function in colorectal cancer (CRC) cells through epigenetic modulation. Bioinformatic analysis establishes that METTL17 expression positively correlates with ferroptosis resistance in cancer cells and is up-regulated in CRC. Depletion of METTL17 sensitizes CRC cells to ferroptosis, impairs cell proliferation, migration, invasion, xenograft tumor growth, and AOM/DSS-induced CRC tumorigenesis. Furthermore, suppression of METTL17 disrupts mitochondrial function, energy metabolism, and enhances intracellular and mitochondrial lipid peroxidation and ROS levels during ferroptotic stress. Mechanistically, METTL17 inhibition significantly reduces mitochondrial RNA methylation, including m4C, m5C, m3C, m7G, and m6A, leading to impaired translation of mitochondrial protein-coding genes. Additionally, the interacting proteins associated with METTL17 are essential for mitochondrial gene expression, and their knockdown sensitizes CRC cells to ferroptosis and inhibits cell proliferation. Notably, combined targeting of METTL17 and ferroptosis in a therapeutic approach effectively suppresses CRC xenograft growth in vivo. This study uncovers the METTL17-mediated defense mechanism for cell survival and ferroptosis in mitochondria, highlighting METTL17 as a potential therapeutic target for CRC.

Keywords:  Colorectal cancer (CRC); Ferroptosis; METTL17; Mitochondrial RNA methylation

DOI:  https://doi.org/10.1016/j.redox.2024.103087
Mol Oncol. 2024 Feb 20.

An arms-race against resistance: leukemic stem cells and lineage plasticity.

Alexander Waclawiczek, Aino-Maija Leppä, Simon Renders, Andreas Trumpp.

  Acute myeloid leukemia (AML) therapy is undergoing rapid development, but primary and acquired resistance to therapy complicates the prospect of a durable cure. Recent functional and single-cell multi-omics approaches have greatly expanded our knowledge of the diversity of lineage trajectories in AML settings. AML cells range from undifferentiated stem-like cells to more differentiated myeloid or megakaryocyte/erythroid cells. Current clinically relevant drugs predominantly target the myeloid progenitor lineage, while monocyte- or stem cell-like states can evade current AML treatment and may be targeted in the future with lineage-specific inhibitors. The extent of aberrant lineage plasticity upon therapeutic pressure in AML cells in conjunction with hijacking of normal differentiation pathways is still a poorly understood topic. Insights into the mechanisms of lineage plasticity of AML stem cells could identify both therapy-specific and cross-drug resistance pathways and reveal novel strategies to overcome them.

Keywords:  AML; LSC; lineage differentiation; plasticity; resistance; venetoclax

DOI:  https://doi.org/10.1002/1878-0261.13606
bioRxiv. 2024 Feb 11. pii: 2024.02.06.578742. [Epub ahead of print]

αKG-mediated carnitine synthesis promotes homologous recombination via histone acetylation.

Apoorva Uboveja, Zhentai Huang, Raquel Buj, Amandine Amalric, Hui Wang, Naveen Kumar Tangudu, Aidan R Cole, Emily Megill, Daniel Kantner, Adam Chatoff, Hafsah Ahmad, Mariola M Marcinkiewicz, Julie A Disharoon, Sarah Graff, Erika S Dahl, Nadine Hempel, Wayne Stallaert, Simone Sidoli, Benjamin G Bitler, David T Long, Nathaniel W Snyder, Katherine M Aird.

Homologous recombination (HR) deficiency enhances sensitivity to DNA damaging agents commonly used to treat cancer. In HR-proficient cancers, metabolic mechanisms driving response or resistance to DNA damaging agents remain unclear. Here we identified that depletion of alpha-ketoglutarate (αKG) sensitizes HR-proficient cells to DNA damaging agents by metabolic regulation of histone acetylation. αKG is required for the activity of αKG-dependent dioxygenases (αKGDDs), and prior work has shown that changes in αKGDD affect demethylases. Using a targeted CRISPR knockout library consisting of 64 αKGDDs, we discovered that Trimethyllysine Hydroxylase Epsilon (TMLHE), the first and rate-limiting enzyme in de novo carnitine synthesis, is necessary for proliferation of HR-proficient cells in the presence of DNA damaging agents. Unexpectedly, αKG-mediated TMLHE-dependent carnitine synthesis was required for histone acetylation, while histone methylation was affected but dispensable. The increase in histone acetylation via αKG-dependent carnitine synthesis promoted HR-mediated DNA repair through site- and substrate-specific histone acetylation. These data demonstrate for the first time that HR-proficiency is mediated through αKG directly influencing histone acetylation via carnitine synthesis and provide a metabolic avenue to induce HR-deficiency and sensitivity to DNA damaging agents.

DOI: https://doi.org/10.1101/2024.02.06.578742
Nat Metab. 2024 Feb 20.

Monocarboxylate transporters facilitate succinate uptake into brown adipocytes.

Anita Reddy, Sally Winther, Nhien Tran, Haopeng Xiao, Josefine Jakob, Ryan Garrity, Arianne Smith, Martha Ordonez, Dina Laznik-Bogoslavski, Jeffrey D Rothstein, Evanna L Mills, Edward T Chouchani.

Uptake of circulating succinate by brown adipose tissue (BAT) and beige fat elevates whole-body energy expenditure, counteracts obesity and antagonizes systemic tissue inflammation in mice. The plasma membrane transporters that facilitate succinate uptake in these adipocytes remain undefined. Here we elucidate a mechanism underlying succinate import into BAT via monocarboxylate transporters (MCTs). We show that succinate transport is strongly dependent on the proportion that is present in the monocarboxylate form. MCTs facilitate monocarboxylate succinate uptake, which is promoted by alkalinization of the cytosol driven by adrenoreceptor stimulation. In brown adipocytes, we show that MCT1 primarily facilitates succinate import. In male mice, we show that both acute pharmacological inhibition of MCT1 and congenital depletion of MCT1 decrease succinate uptake into BAT and consequent catabolism. In sum, we define a mechanism of succinate uptake in BAT that underlies its protective activity in mouse models of metabolic disease.

DOI: https://doi.org/10.1038/s42255-024-00981-5
Cell Death Dis. 2024 Feb 19. 15(2): 151

Fumarate induces LncRNA-MIR4435-2HG to regulate glutamine metabolism remodeling and promote the development of FH-deficient renal cell carcinoma.

Liangsong Zhu, Yilun Hong, Ziran Zhu, Jiwei Huang, Jianfeng Wang, Ge Li, Xiaoyu Wu, Yonghui Chen, Yunze Xu, Liang Zheng, Yiran Huang, Wen Kong, Wei Xue, Jin Zhang.

Fumarate hydratase (FH) deficient renal cell carcinoma (RCC) is a type of tumor with definite metabolic disorder, but the mechanism of metabolic remodeling is still unclear. LncRNA was reported to closely correlate with cancer metabolism, however the biological role of LncRNA in the development of progression of FH-deficent RCC was not well studied either. FH-deficient RCC samples were collected in my hospital and used for RNA-sequencing and Mass spectrometry analysis. FH-deficient RCC cell line UOK262 and control pFH cells were used for in vitro experiments, including proliferation assay, transwell assay, western-blot, mass spectrometry and so on. PDX mouse model was used for further drug inhibition experiments in vivo. In this study, we analyzed the profiles of LncRNA and mRNA in FH-deficienct RCC samples, and we found that the LncRNA-MIR4435-2GH was specifically highly expressed in FH-deficient RCC compared with ccRCC. In vitro experiments demonstrated that MIR4435-2HG was regulated by Fumarate through histone demethylation, and the deletion of this gene could inhibit glutamine metabolism. RNA-pulldown experiments showed that MIR4435-2HG specifically binds to STAT1, which can transcriptionally activate GLS1. GLS1 inhibitor CB-839 could significantly suppress tumor growth in PDX tumor models. This study analyzed the molecular mechanism of MIR4435-2HG in regulating metabolic remodeling of FH-deficient RCC in clinical samples, cells and animal models by combining transcriptional and metabolic methods. We found that that GLS1 was a therapeutic target for this tumor, and MIR4435-2HG can be used as a drug sensitivity marker.

DOI: https://doi.org/10.1038/s41419-024-06510-2
Biomedicines. 2024 Jan 28. pii: 305. [Epub ahead of print]12(2):

Mitophagy-Mediated Tumor Dormancy Protects Cancer Cells from Chemotherapy.

Yunqing Sun, Yang Chen, Zhenan Liu, Jingjing Wang, Junqiang Bai, Ruixue Du, Mingshu Long, Zhengjun Shang.

  Despite obvious tumor shrinkage, relapse after chemotherapy remains a main cause of cancer-related mortality, indicating that a subpopulation of cancer cells acquires chemoresistance and lingers after treatment. However, the mechanism involved in the emergence of chemoresistant cells remains largely unknown. Here, we demonstrate that the degradation of mitochondria via autophagy leads to a dormant state in a subpopulation of cancer cells and confers on them resistance to lethal cisplatin (DDP) exposure. The surviving DDP-resistant cells (hereafter, DRCs) have a lower metabolic rate but a stronger potential malignant potential. In the absence of DDP, these DRCs exhibit an ever-increasing self-renewal ability and heightened tumorigenicity. The combination of chloroquine and DDP exerts potent tumor-suppressive effects. In summary, our findings illuminate the mechanism between mitophagy and tumor dormancy and prove that targeting mitophagy might be a promising approach for overcoming chemoresistance in head and neck squamous cell carcinoma (HNSCC).

Keywords:  HNSCC; chemotherapy; dormancy; mitophagy

DOI:  https://doi.org/10.3390/biomedicines12020305
Elife. 2024 Feb 23. pii: RP90024. [Epub ahead of print]12

An engineered biosensor enables dynamic aspartate measurements in living cells.

Kristian Davidsen, Jonathan S Marvin, Abhi Aggarwal, Timothy A Brown, Lucas B Sullivan.

  Intracellular levels of the amino acid aspartate are responsive to changes in metabolism in mammalian cells and can correspondingly alter cell function, highlighting the need for robust tools to measure aspartate abundance. However, comprehensive understanding of aspartate metabolism has been limited by the throughput, cost, and static nature of the mass spectrometry (MS)-based measurements that are typically employed to measure aspartate levels. To address these issues, we have developed a green fluorescent protein (GFP)-based sensor of aspartate (jAspSnFR3), where the fluorescence intensity corresponds to aspartate concentration. As a purified protein, the sensor has a 20-fold increase in fluorescence upon aspartate saturation, with dose-dependent fluorescence changes covering a physiologically relevant aspartate concentration range and no significant off target binding. Expressed in mammalian cell lines, sensor intensity correlated with aspartate levels measured by MS and could resolve temporal changes in intracellular aspartate from genetic, pharmacological, and nutritional manipulations. These data demonstrate the utility of jAspSnFR3 and highlight the opportunities it provides for temporally resolved and high-throughput applications of variables that affect aspartate levels.

Keywords:  aspartate; biochemistry; biosensor; cell biology; chemical biology; glutamine; human; metabolism; mitochondria; protein engineering

DOI:  https://doi.org/10.7554/eLife.90024
Clin Lymphoma Myeloma Leuk. 2024 Jan 18. pii: S2152-2650(24)00036-3. [Epub ahead of print]

Venetoclax and Cobimetinib in Relapsed/Refractory AML: A Phase 1b Trial.

Marina Y Konopleva, Monique Dail, Naval G Daver, Jacqueline S Garcia, Brian A Jonas, Karen W L Yee, Kevin R Kelly, Norbert Vey, Sarit Assouline, Gail J Roboz, Stefania Paolini, Daniel A Pollyea, Agostino Tafuri, Joseph M Brandwein, Arnaud Pigneux, Bayard L Powell, Pierre Fenaux, Rebecca L Olin, Giuseppe Visani, Giovanni Martinelli, Maika Onishi, Jue Wang, Weize Huang, Diana Dunshee, Habib Hamidi, Marion G Ott, Wan-Jen Hong, Michael Andreeff.

   BACKGROUND: Therapies for relapsed/refractory acute myeloid leukemia remain limited and outcomes poor, especially amongst patients who are ineligible for cytotoxic chemotherapy or targeted therapies.
PATIENTS AND METHODS: This phase 1b trial evaluated venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, plus cobimetinib, a MEK1/2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia, ineligible for cytotoxic chemotherapy. Two-dimensional dose-escalation was performed for venetoclax dosed daily, and for cobimetinib dosed on days 1-21 of each 28-day cycle.
RESULTS: Thirty patients (median [range] age: 71.5 years [60-84]) received venetoclax-cobimetinib. The most common adverse events (AEs; in ≥40.0% of patients) were diarrhea (80.0%), nausea (60.0%), vomiting (40.0%), febrile neutropenia (40.0%), and fatigue (40.0%). Overall, 66.7% and 23.3% of patients experienced AEs leading to dose modification/interruption or treatment withdrawal, respectively. The composite complete remission (CRc) rate (complete remission [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery) was 15.6%; antileukemic response rate (CRc + morphologic leukemia-free state/partial remission) was 18.8%. For the recommended phase 2 dose (venetoclax: 600 mg; cobimetinib: 40 mg), CRc and antileukemic response rates were both 12.5%. Failure to achieve an antileukemic response was associated with elevated baseline phosphorylated ERK and MCL-1 levels, but not BCL-xL. Baseline mutations in ≥1 signaling gene or TP53 were noted in nonresponders and emerged on treatment. Pharmacodynamic biomarkers revealed inconsistent, transient inhibition of the mitogen-activated protein kinase (MAPK) pathway.
CONCLUSION: Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations.

Keywords:  B-cell lymphoma-2; Biomarker; Mitogen-activated protein kinase pathway; Targeted therapy

DOI:  https://doi.org/10.1016/j.clml.2024.01.007
Cancers (Basel). 2024 Feb 08. pii: 713. [Epub ahead of print]16(4):

Fumarate Hydratase Enhances the Therapeutic Effect of PD-1 Antibody in Colorectal Cancer by Regulating PCSK9.

Le Qin, Liang Shi, Yu Wang, Haixin Yu, Zhouyuan Du, Mian Chen, Yuxuan Cai, Yinghao Cao, Shenghe Deng, Jun Wang, Denglong Cheng, Yixin Heng, Jiaxin Xu, Kailin Cai, Ke Wu.

  Despite the notable achievements of programmed death 1 (PD-1) antibodies in treating various cancers, the overall efficacy remains limited in the majority of colorectal cancer (CRC) cases. Metabolism reprogramming of tumors inhibits the tricarboxylic acid (TCA) cycle, leading to down-regulation of fumarate hydratase (FH), which is related to poor prognosis in CRC patients. By establishing a tumor-bearing mouse model of CRC with Fh1 expression deficiency, we confirmed that the therapeutic effect of PD-1 antibodies alone was suboptimal in mice with low Fh1 expression, which was improved by combination with a protein invertase subtilisin/kexin 9 (PCSK9) inhibitor. Mechanistically, FH binds to Ras-related nucleoprotein (RAN), which inhibits the nuclear import of the PCSK9 transcription factor SREBF1/2, thus reducing the expression of PCSK9. This leads to increased clonal expansion of CD8+ T cells while the number of Tregs remains unchanged, and the expression of PD-L1 does not change significantly, thus enhancing the immunotherapy response. On the contrary, the expression of PCSK9 increased in CRC cells with low FH expression, which antagonized the effects of immunotherapy. Overall, CRC patients with low FH expression may benefit from combinatorial therapy with PD-1 antibodies and PCSK9 inhibitors to enhance the curative effect.

Keywords:  colorectal cancer; fumarate hydratase; immunotherapy; programmed cell death 1; protein invertase subtilisin/kexin 9 type

DOI:  https://doi.org/10.3390/cancers16040713
Sci Adv. 2024 Feb 23. 10(8): eadk3663

HSP90 inhibition suppresses tumor glycolytic flux to potentiate the therapeutic efficacy of radiotherapy for head and neck cancer.

Fanghui Chen, Chris Tang, Fan Yang, Asari Ekpenyong, Richard Qin, Jin Xie, Fatemeh Momen-Heravi, Nabil F Saba, Yong Teng.

Glycolytic metabolism may account for antitumor immunity failure. Pyruvate kinase M2 (PKM2) and platelet phosphofructokinase (PFKP), two key enzymes involved in the glycolytic pathway, are hyperactivated in head and neck squamous cell carcinoma (HNSCC). Using ganetespib as a drug model for heat shock protein 90 (HSP90) inhibition and combining results from clinical trials and animal treatment, we demonstrated that HSP90 inhibition leads to a blockade of glycolytic flux in HNSCC cells by simultaneously suppressing PKM2 and PFKP at both the transcriptional and posttranslational levels. Down-regulation of tumor glycolysis facilitates tumor infiltration of cytotoxic T cells via suppression of glycolysis-dependent interleukin-8 signaling. The addition of ganetespib to radiation attenuates radiation-induced up-regulation of PKM2 and PFKP and potentiates T cell-mediated antitumor immunity, resulting in a more potent antitumor effect than either treatment alone, providing a molecular basis for exploring the combination of HSP90 inhibitors with radiotherapy to improve outcomes for patients with HNSCC.

DOI: https://doi.org/10.1126/sciadv.adk3663
Breast Cancer Res. 2024 Feb 19. 26(1): 29

Metabolic adaptation towards glycolysis supports resistance to neoadjuvant chemotherapy in early triple negative breast cancers.

Françoise Derouane, Manon Desgres, Camilla Moroni, Jérôme Ambroise, Martine Berlière, Mieke R Van Bockstal, Christine Galant, Cédric van Marcke, Marianela Vara-Messler, Stefan J Hutten, Jos Jonkers, Larissa Mourao, Colinda L G J Scheele, Francois P Duhoux, Cyril Corbet.

   BACKGROUND: Neoadjuvant chemotherapy (NAC) is the standard of care for patients with early-stage triple negative breast cancers (TNBC). However, more than half of TNBC patients do not achieve a pathological complete response (pCR) after NAC, and residual cancer burden (RCB) is associated with dismal long-term prognosis. Understanding the mechanisms underlying differential treatment outcomes is therefore critical to limit RCB and improve NAC efficiency.
METHODS: Human TNBC cell lines and patient-derived organoids were used in combination with real-time metabolic assays to evaluate the effect of NAC (paclitaxel and epirubicin) on tumor cell metabolism, in particular glycolysis. Diagnostic biopsies (pre-NAC) from patients with early TNBC were analyzed by bulk RNA-sequencing to evaluate the predictive value of a glycolysis-related gene signature.
RESULTS: Paclitaxel induced a consistent metabolic switch to glycolysis, correlated with a reduced mitochondrial oxidative metabolism, in TNBC cells. In pre-NAC diagnostic biopsies from TNBC patients, glycolysis was found to be upregulated in non-responders. Furthermore, glycolysis inhibition greatly improved response to NAC in TNBC organoid models.
CONCLUSIONS: Our study pinpoints a metabolic adaptation to glycolysis as a mechanism driving resistance to NAC in TNBC. Our data pave the way for the use of glycolysis-related genes as predictive biomarkers for NAC response, as well as the development of inhibitors to overcome this glycolysis-driven resistance to NAC in human TNBC patients.

Keywords:  Early triple negative breast cancer; Glycolysis; Metabolism; Neoadjuvant chemotherapy; Organoids; Therapy resistance

DOI:  https://doi.org/10.1186/s13058-024-01788-8
Int J Biol Sci. 2024 ;20(4): 1218-1237

S-Adenosylmethionine Negatively Regulates the Mitochondrial Respiratory Chain Repressor MCJ in the Liver.

Lucía Barbier-Torres, Jyoti Chhimwal, So Yeon Kim, Komal Ramani, Aaron Robinson, Heping Yang, Jenny Van Eyk, Suthat Liangpunsakul, Ekihiro Seki, José M Mato, Shelly C Lu.

  MCJ (Methylation-Controlled J protein), an endogenous repressor of the mitochondrial respiratory chain, is upregulated in multiple liver diseases but little is known about how it is regulated. S-adenosylmethionine (SAMe), the biological methyl donor, is frequently depleted in chronic liver diseases. Here, we show that SAMe negatively regulates MCJ in the liver. While deficiency in methionine adenosyltransferase alpha 1 (MATα1), enzyme that catalyzes SAMe biosynthesis, leads to hepatic MCJ upregulation, MAT1A overexpression and SAMe treatment reduced MCJ expression. We found that MCJ is methylated at lysine residues and that it interacts with MATα1 in liver mitochondria, likely to facilitate its methylation. Lastly, we observed that MCJ is upregulated in alcohol-associated liver disease, a condition characterized by reduced MAT1A expression and SAMe levels along with mitochondrial injury. MCJ silencing protected against alcohol-induced mitochondrial dysfunction and lipid accumulation. Our study demonstrates a new role of MATα1 and SAMe in reducing hepatic MCJ expression.

Keywords:  MATα1; MCJ; S-adenosylmethionine; alcohol-associated liver disease; mitochondrial dysfunction; protein methylation

DOI:  https://doi.org/10.7150/ijbs.90104