bims-mibica 2023-09-03 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2023–09–03
forty-one papers selected by
Kelsey Fisher-Wellman, East Carolina University

Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes.
The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.
Inhibition of mitochondrial fusion via SIRT1/PDK2/PARL axis breaks mitochondrial metabolic plasticity and sensitizes cancer cells to glucose restriction therapy.
The malate-aspartate shuttle is important for de novo serine biosynthesis.
Spotlight on GOT2 in Cancer Metabolism.
Restoration of mitochondrial structure and function within Helicobacter pylori VacA intoxicated cells.
The transient character of mitochondrial uncoupling by the popular fungicide fluazinam is specific for liver.
Beyond the TCA cycle: new insights into mitochondrial calcium regulation of oxidative phosphorylation.
Structure and function of the human mitochondrial MRS2 channel.
Curcumin induces mitophagy by promoting mitochondrial succinate dehydrogenase activity and sensitizes human papillary thyroid carcinoma BCPAP cells to radioiodine treatment.
DHODH: A promising target in the treatment of T-Acute Lymphoblastic Leukemia.
Targeting aggressive B-cell lymphomas through pharmacological activation of the mitochondrial protease OMA1.
Complex I deficiency in m.3243A>G fibroblasts is alleviated by reducing NADH accumulation.
Biomimetic nanovesicle co-delivery system impairs energy metabolism for cancer treatment.
Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis.
Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems.
Synergism of small molecules targeting VDAC with sorafenib, regorafenib or lenvatinib on hepatocarcinoma cell proliferation and survival.
IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing.
Mitophagy-promoting agents and their ability to promote healthy-aging.
T cell differentiation drives the negative selection of pathogenic mitochondrial DNA variants.
Lycorine promotes IDH1 acetylation to induce mitochondrial dynamics imbalance in colorectal cancer cells.
Alternative oxidase causes cell type- and tissue-specific responses in mutator mice.
GPRC5C Drives Branched-Chain Amino Acid Metabolism in Leukemogenesis.
Single-cell transcriptomics reveals multiple chemoresistant properties in leukemic stem and progenitor cells in pediatric AML.
SUMOylation of yeast Pso2 enhances its translocation and accumulation in the mitochondria and suppresses methyl methanesulfonate-induced mitochondrial DNA damage.
Mitochondrial phospholipid metabolism in health and disease.
Formate promotes invasion and metastasis in reliance on lipid metabolism.
Cuproptosis related gene PDHB is identified as a biomarker inversely associated with the progression of clear cell renal cell carcinoma.
Impaired age-associated mitochondrial translation is mitigated by exercise and PGC-1α.
Triaging of ⍺-helical proteins to the mitochondrial outer membrane by distinct chaperone machinery based on substrate topology.
Mutational landscape of intestinal crypt cells after long-term in vivo exposure to high fat diet.
Mitochondrial double membrane fission: A mystery solved?
Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control.
The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function.
Mitochondrial Microproteins: Critical Regulators of Protein Import, Energy Production, Stress Response Pathways, and Programmed Cell Death.
Acrolein increases the concentration of intracellular Zn2⁺ by producing mitochondrial reactive oxygen species in A549 cells.
Mitochondrial superoxide dismutase Sod2 suppresses nuclear genome instability during oxidative stress.
Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response.
A Reversible Fluorescent Probe for In Situ Monitoring Redox Imbalance during Mitophagy.
A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.
Identification of an alternative triglyceride biosynthesis pathway.

Cell Metab. 2023 Aug 22. pii: S1550-4131(23)00289-9. [Epub ahead of print]

Preserved respiratory chain capacity and physiology in mice with profoundly reduced levels of mitochondrial respirasomes.

Dusanka Milenkovic, Jelena Misic, Johannes F Hevler, Thibaut Molinié, Injae Chung, Ilian Atanassov, Xinping Li, Roberta Filograna, Andrea Mesaros, Arnaud Mourier, Albert J R Heck, Judy Hirst, Nils-Göran Larsson.

  The mammalian respiratory chain complexes I, III2, and IV (CI, CIII2, and CIV) are critical for cellular bioenergetics and form a stable assembly, the respirasome (CI-CIII2-CIV), that is biochemically and structurally well documented. The role of the respirasome in bioenergetics and the regulation of metabolism is subject to intense debate and is difficult to study because the individual respiratory chain complexes coexist together with high levels of respirasomes. To critically investigate the in vivo role of the respirasome, we generated homozygous knockin mice that have normal levels of respiratory chain complexes but profoundly decreased levels of respirasomes. Surprisingly, the mutant mice are healthy, with preserved respiratory chain capacity and normal exercise performance. Our findings show that high levels of respirasomes are dispensable for maintaining bioenergetics and physiology in mice but raise questions about their alternate functions, such as those relating to the regulation of protein stability and prevention of age-associated protein aggregation.

Keywords:  OXPHOS; mitochondria; mitochondrial respirasomes; supercomplexes

DOI:  https://doi.org/10.1016/j.cmet.2023.07.015
bioRxiv. 2023 Aug 16. pii: 2023.08.15.553413. [Epub ahead of print]

The BCKDK inhibitor BT2 is a chemical uncoupler that lowers mitochondrial ROS production and de novo lipogenesis.

Aracely Acevedo, Anthony E Jones, Bezawit T Danna, Rory Turner, Katrina P Montales, Cristiane Benincá, Karen Reue, Orian S Shirihai, Linsey Stiles, Martina Wallace, Yibin Wang, Ambre M Bertholet, Ajit S Divakaruni.

Elevated levels of branched chain amino acids (BCAAs) and branched-chain α-ketoacids (BCKAs) are associated with cardiovascular and metabolic disease, but the molecular mechanisms underlying a putative causal relationship remain unclear. The branched-chain ketoacid dehydrogenase kinase (BCKDK) inhibitor BT2 is often used in preclinical models to increase BCAA oxidation and restore steady-state BCAA and BCKA levels. BT2 administration is protective in various rodent models of heart failure and metabolic disease, but confoundingly, targeted ablation of Bckdk in specific tissues does not reproduce the beneficial effects conferred by pharmacologic inhibition. Here we demonstrate that BT2, a lipophilic weak acid, can act as a mitochondrial uncoupler. Measurements of oxygen consumption, mitochondrial membrane potential, and patch-clamp electrophysiology show BT2 increases proton conductance across the mitochondrial inner membrane independently of its inhibitory effect on BCKDK. BT2 is roughly five-fold less potent than the prototypical uncoupler 2,4-dinitrophenol (DNP), and phenocopies DNP in lowering de novo lipogenesis and mitochondrial superoxide production. The data suggest the therapeutic efficacy of BT2 may be attributable to the well-documented effects of mitochondrial uncoupling in alleviating cardiovascular and metabolic disease.

DOI: https://doi.org/10.1101/2023.08.15.553413
Biomed Pharmacother. 2023 Aug 24. pii: S0753-3322(23)01133-2. [Epub ahead of print]166 115342

Inhibition of mitochondrial fusion via SIRT1/PDK2/PARL axis breaks mitochondrial metabolic plasticity and sensitizes cancer cells to glucose restriction therapy.

Yongjian Guo, Chengju Luo, Yuening Sun, Wenjing Guo, Ruitian Zhang, Xin Zhang, Xue Ke, Libin Wei.

  Mitochondria dynamically change their morphology via fusion and fission, a process called mitochondrial dynamics. Dysregulated mitochondrial dynamics respond rapidly to metabolic cues, and are linked to the initiation and progression of diverse human cancers. Metabolic adaptations significantly contribute to tumor development and escape from tissue homeostatic defenses. In this work, we identified oroxylin A (OA), a dual GLUT1/mitochondrial fusion inhibitor, which restricted glucose catabolism of hepatocellular carcinoma cells and simultaneously inhibited mitochondrial fusion by disturbing SIRT1/PDK2/PARL axis. Based the dual action of OA in metabolic regulation and mitochondrial dynamics, further results revealed that mitochondrial functional status and spare respiratory capacity (SRC) of cancer cells had a close correlation with mitochondrial metabolic plasticity, and played important roles in the susceptibility to cancer therapy aiming at glucose restriction. Cancer cells with healthy mitochondria and high SRC exhibit greater metabolic flexibility and higher resistance to GLUT1 inhibitors. This phenomenon is attributed to the fact that high SRC cells fuse mitochondria in response to glucose restriction, enhancing tolerance to energy deficiency, but undergo less mitochondrial oxidative stress compared to low SRC cells. Thus, inhibiting mitochondrial fusion breaks mitochondrial metabolic plasticity and increases cancer cell susceptibility to glucose restriction therapy. Collectively, these finding indicate that combining a GLUT1 inhibitor with a mitochondrial fusion inhibitor can work synergistically in cancer therapy and, more broadly, suggest that the incorporations of mitochondrial dynamics and metabolic regulation may become the targetable vulnerabilities bypassing the genotypic heterogeneity of multiple malignancies.

Keywords:  Glucose restriction; Mitochondrial fusion; Mitochondrial metabolic plasticity; Oroxylin A

DOI:  https://doi.org/10.1016/j.biopha.2023.115342
Cell Rep. 2023 Aug 29. pii: S2211-1247(23)01054-9. [Epub ahead of print]42(9): 113043

The malate-aspartate shuttle is important for de novo serine biosynthesis.

Melissa H Broeks, Nils W F Meijer, Denise Westland, Marjolein Bosma, Johan Gerrits, Hannah M German, Jolita Ciapaite, Clara D M van Karnebeek, Ronald J A Wanders, Fried J T Zwartkruis, Nanda M Verhoeven-Duif, Judith J M Jans.

  The malate-aspartate shuttle (MAS) is a redox shuttle that transports reducing equivalents across the inner mitochondrial membrane while recycling cytosolic NADH to NAD+. We genetically disrupted each MAS component to generate a panel of MAS-deficient HEK293 cell lines in which we performed [U-13C]-glucose tracing. MAS-deficient cells have reduced serine biosynthesis, which strongly correlates with the lactate M+3/pyruvate M+3 ratio (reflective of the cytosolic NAD+/NADH ratio), consistent with the NAD+ dependency of phosphoglycerate dehydrogenase in the serine synthesis pathway. Among the MAS-deficient cells, those lacking malate dehydrogenase 1 (MDH1) show the most severe metabolic disruptions, whereas oxoglutarate-malate carrier (OGC)- and MDH2-deficient cells are less affected. Increasing the NAD+-regenerating capacity using pyruvate supplementation resolves most of the metabolic disturbances. Overall, we show that the MAS is important for de novo serine biosynthesis, implying that serine supplementation could be used as a therapeutic strategy for MAS defects and possibly other redox disorders.

Keywords:  CP: Metabolism; NADH shuttle; central carbon metabolism; glycolysis; isotope-tracer analysis; malate dehydrogenase; malate-aspartate shuttle; metabolomics; serine biosynthesis

DOI:  https://doi.org/10.1016/j.celrep.2023.113043
Onco Targets Ther. 2023 ;16 695-702

Spotlight on GOT2 in Cancer Metabolism.

Samuel A Kerk, Javier Garcia-Bermudez, Kivanc Birsoy, Mara H Sherman, Yatrik M Shah, Costas A Lyssiotis.

  GOT2 is at the nexus of several critical metabolic pathways in homeostatic cellular and dysregulated cancer metabolism. Despite this, recent work has emphasized the remarkable plasticity of cancer cells to employ compensatory pathways when GOT2 is inhibited. Here, we review the metabolic roles of GOT2, highlighting findings in both normal and cancer cells. We emphasize how cancer cells repurpose cell intrinsic metabolism and their flexibility when GOT2 is inhibited. We close by using this framework to discuss key considerations for future investigations into cancer metabolism.

Keywords:  mitochondria; nucleotides; pancreatic cancer; redox; transaminase; tumor microenvironment

DOI:  https://doi.org/10.2147/OTT.S382161
Adv Microbiol. 2023 Aug;13(8): 399-419

Restoration of mitochondrial structure and function within Helicobacter pylori VacA intoxicated cells.

Robin L Holland, Kristopher D Bosi, Ami Y Seeger, Steven R Blanke.

  The Helicobacter pylori vacuolating cytotoxin (VacA) is an intracellular, mitochondrial-targeting exotoxin that rapidly causes mitochondrial dysfunction and fragmentation. Although VacA targeting of mitochondria has been reported to alter overall cellular metabolism, there is little known about the consequences of extended exposure to the toxin. Here, we describe studies to address this gap in knowledge, which have revealed that mitochondrial dysfunction and fragmentation are followed by a time-dependent recovery of mitochondrial structure, mitochondrial transmembrane potential, and cellular ATP levels. Cells exposed to VacA also initially demonstrated a reduction in oxidative phosphorylation, as well as increase in compensatory aerobic glycolysis. These metabolic alterations were reversed in cells with limited toxin exposure, congruent with the recovery of mitochondrial transmembrane potential and the absence of cytochrome c release from the mitochondria. Taken together, these results are consistent with a model that mitochondrial structure and function are restored in VacA-intoxicated cells.

Keywords:  ATP; Helicobacter pylori; VacA; mitochondria; mitochondrial dynamics; mitochondrial dysfunction; mitochondrial fission; mitochondrial transmembrane potential; oxidative phosphorylation; vacuolating cytotoxin

DOI:  https://doi.org/10.4236/aim.2023.138026
Arch Biochem Biophys. 2023 Aug 29. pii: S0003-9861(23)00234-5. [Epub ahead of print] 109735

The transient character of mitochondrial uncoupling by the popular fungicide fluazinam is specific for liver.

Ljudmila S Khailova, Vladimir S Krasnov, Roman S Kirsanov, Lyudmila B Popova, Vadim N Tashlitsky, Elena A Kotova, Yuri N Antonenko.

  The popular fungicide fluazinam is known to exhibit an unusual cyclic pattern of the protonophoric uncoupling activity in isolated rat liver mitochondria (RLM), with membrane deenergization followed by spontaneous recoupling in the minute scale, which is associated with glutathione conjugation of fluazinam catalyzed by glutathione-S-transferase (GST). Here, we compare the fluazinam effect on RLM with that on rat kidney (RKM) and heart (RHM) mitochondria by monitoring three bioenergetic parameters: oxygen consumption rate, mitochondrial membrane potential and reduction of nucleotides. Only in RLM, the uncoupling activity of fluazinam was transient, i.e. disappeared in a few minutes, whereas in RKM and RHM it was stable in this time scale. We attribute this difference to the increased activity of mitochondrial GST in liver. We report data on the detection of glutathione-fluazinam conjugates by mass-spectrometry, thin layer chromatography and capillary electrophoresis after incubation of fluazinam with RLM but not with RKM, which supports the assumption of the tissue specificity of the conjugation.

Keywords:  Fluazinam; Fluazinam-glutathione conjugates; Membrane potential; Respiration rate; Tissue-specific mitochondrial uncoupler

DOI:  https://doi.org/10.1016/j.abb.2023.109735
Biochem Soc Trans. 2023 Aug 29. pii: BST20230012. [Epub ahead of print]

Beyond the TCA cycle: new insights into mitochondrial calcium regulation of oxidative phosphorylation.

Sandra H Lee, Hannah E Duron, Dipayan Chaudhuri.

  While mitochondria oxidative phosphorylation is broadly regulated, the impact of mitochondrial Ca2+ on substrate flux under both physiological and pathological conditions is increasingly being recognized. Under physiologic conditions, mitochondrial Ca2+ enters through the mitochondrial Ca2+ uniporter and boosts ATP production. However, maintaining Ca2+ homeostasis is crucial as too little Ca2+ inhibits adaptation to stress and Ca2+ overload can trigger cell death. In this review, we discuss new insights obtained over the past several years expanding the relationship between mitochondrial Ca2+ and oxidative phosphorylation, with most data obtained from heart, liver, or skeletal muscle. Two new themes are emerging. First, beyond boosting ATP synthesis, Ca2+ appears to be a critical determinant of fuel substrate choice between glucose and fatty acids. Second, Ca2+ exerts local effects on the electron transport chain indirectly, not via traditional allosteric mechanisms. These depend critically on the transporters involved, such as the uniporter or the Na+-Ca2+ exchanger. Alteration of these new relationships during disease can be either compensatory or harmful and suggest that targeting mitochondrial Ca2+ may be of therapeutic benefit during diseases featuring impairments in oxidative phosphorylation.

Keywords:  MCU; NCLX; electron transport chain; mitochondrial dysfunction; mitochondrial permeability transition pores; oxidative phosphorylation

DOI:  https://doi.org/10.1042/BST20230012
bioRxiv. 2023 Aug 15. pii: 2023.08.12.553106. [Epub ahead of print]

Structure and function of the human mitochondrial MRS2 channel.

Zhihui He, Yung-Chi Tu, Chen-Wei Tsai, Jonathan Mount, Jingying Zhang, Ming-Feng Tsai, Peng Yuan.

The human Mitochondrial RNA Splicing 2 protein (MRS2) has been implicated in Mg 2+ transport across mitochondrial inner membranes, thus playing an important role in Mg 2+ homeostasis critical for mitochondrial integrity and function. However, the molecular mechanisms underlying its fundamental channel properties such as ion selectivity and regulation remain unclear. Here, we present structural and functional investigation of MRS2. Cryo-electron microscopy structures in various ionic conditions reveal a pentameric channel architecture and the molecular basis of ion permeation and potential regulation mechanisms. Electrophysiological analyses demonstrate that MRS2 is a Ca 2+ -regulated, non-selective channel permeable to Mg 2+ , Ca 2+ , Na + and K + , which contrasts with its prokaryotic ortholog, CorA, operating as a Mg 2+ -gated Mg 2+ channel. Moreover, a conserved arginine ring within the pore of MRS2 functions to restrict cation movements, likely preventing the channel from collapsing the proton motive force that drives mitochondrial ATP synthesis. Together, our results provide a molecular framework for further understanding MRS2 in mitochondrial function and disease.

DOI: https://doi.org/10.1101/2023.08.12.553106
Toxicol In Vitro. 2023 Aug 25. pii: S0887-2333(23)00118-2. [Epub ahead of print]93 105669

Curcumin induces mitophagy by promoting mitochondrial succinate dehydrogenase activity and sensitizes human papillary thyroid carcinoma BCPAP cells to radioiodine treatment.

Li Zhang, Ling Qiu, Shichen Xu, Xian Cheng, Jing Wu, Yunping Wang, Wenjing Gao, Jiandong Bao, Huixin Yu.

  Thyroid cancer is one of the most common endocrine malignancies. Differentiated thyroid cancer (DTC) treatment is based on the ability of thyroid follicular cells to accumulate radioactive iodide (RAI). DTC generally has a good prognosis. However, tumor dedifferentiation or defect in certain cell death mechanism occurs in a subset of DTC patients, leading to RAI resistance. Therefore, developing novel therapeutic approaches that enhance RAI sensitivity are still warranted. We found that curcumin, an active ingredient in turmeric with anti-cancer properties, rapidly accumulated in the mitochondria of thyroid cancer cells but not normal epithelial cells. Curcumin treatment triggered mitochondrial membrane depolarization, engulfment of mitochondria within autophagosomes and a robust decrease in mitochondrial mass and proteins, indicating that curcumin selectively induced mitophagy in thyroid cancer cells. In addition, curcumin-induced mitophagic cell death and its synergistic cytotoxic effect with radioiodine could be attenuated by autophagy inhibitor, 3-methyladenine (3-MA). Interestingly, the mechanism of mitophagy-inducing potential of curcumin was its unique mitochondria-targeting property, which induced a burst of SDH activity and excessive ROS production. Our data suggest that curcumin induces mitochondrial dysfunction and triggers lethal mitophagy, which synergizes with radioiodine to kill thyroid cancer cells.

Keywords:  Curcumin; Differentiated thyroid cancer; Mitophagy; Radioactive iodide therapy; Succinate dehydrogenase

DOI:  https://doi.org/10.1016/j.tiv.2023.105669
Blood Adv. 2023 Aug 30. pii: bloodadvances.2023010337. [Epub ahead of print]

DHODH: A promising target in the treatment of T-Acute Lymphoblastic Leukemia.

Amy N Sexauer, Gabriela Alexe, Karin Gustafsson, Elizabeth Zanetakos, Jelena Milosevic, Mary L Ayres, Varsha Gandhi, Yana Pikman, Kimberly Stegmaier, David Brian Sykes.

Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) have a poor prognosis with few therapeutic options. With the goal of identifying novel therapeutic targets, we used data from the Dependency Map project to identify DHODH (dihydroorotate dehydrogenase) as one of the top metabolic dependencies in T-ALL. DHODH catalyzes the fourth step of de novo pyrimidine nucleotide synthesis. Small molecule inhibition of DHODH rapidly leads to the depletion of intracellular pyrimidine pools and forces cells to rely on extracellular salvage. In the absence of sufficient salvage, this intracellular nucleotide starvation results in the inhibition of DNA and RNA synthesis, cell cycle arrest, and ultimately death. T lymphoblasts appear to be specifically and exquisitely sensitive to nucleotide starvation following DHODHi. We have confirmed this sensitivity in vitro as well as in vivo in three murine models of T ALL. We identified that certain subsets of T-ALL seem to have an increased reliance on oxidative phosphorylation when treated with DHODHi. Through a series of metabolic assays, we show that leukemia cells, in the setting of nucleotide starvation, have changes in their mitochondrial membrane potential and may be more highly dependent on alternative fuel sources. The effect on normal T cell development in young mice was also examined to show that DHODH inhibition does not permanent damage the developing thymus. These changes suggest a new metabolic vulnerability that may distinguish these cells from normal T-cells and other normal hematopoietic cells and offer an exploitable therapeutic opportunity. The availability of clinical-grade DHODH inhibitors currently in human clinical trials speaks to the potential for rapidly advancing this work into the clinic.

DOI: https://doi.org/10.1182/bloodadvances.2023010337
Mol Cancer Ther. 2023 Aug 30.

Targeting aggressive B-cell lymphomas through pharmacological activation of the mitochondrial protease OMA1.

Adrian Schwarzer, Matheus Oliveira, Marc-Jens Kleppa, Scott D Slattery, Andy Anantha, Alan Cooper, Mark Hannink, Axel Schambach, Anneke Doerrie, Alexey Kotylarov, Matthias Gaestel, Todd Hembrough, Jedd Levine, Michael Luther, Michael Stocum, Linsey Stiles, David M Weinstock, Marc Liesa, Matthew J Kostura.

DLBCL are aggressive, rapidly proliferating tumors that critically depend on the ATF4-mediated integrated stress response (ISR) to adapt to stress caused by uncontrolled growth, such as hypoxia, amino acid deprivation and accumulation of misfolded proteins. Here we show that ISR hyperactivation is a targetable liability in DLBCL. We describe a novel class of compounds represented by BTM-3528 and BTM-3566, that activate the ISR through the mitochondrial protease OMA1. Treatment of tumor cells with compound leads to OMA1-dependent cleavage of DELE1 and OPA1, mitochondrial fragmentation, activation of the eIF2α-kinase HRI, cell growth arrest and apoptosis. Activation of OMA1 by BTM-3528 and BTM-3566 is mechanistically distinct from inhibitors of mitochondrial electron transport, as the compounds induce OMA1 activity in the absence of acute changes in respiration. We further identify the mitochondrial protein FAM210B as a negative regulator of BTM-3528 and BTM-3566 activity. Overexpression of FAM210B prevents both OMA1 activation and apoptosis. Notably, FAM210B expression is nearly absent in healthy germinal-center B-lymphocytes and in derived B-cell malignancies, revealing a fundamental molecular vulnerability which is targeted by BTM compounds. Both compounds induce rapid apoptosis across diverse DLBCL lines derived from activated B-cell, germinal center B-cell, and MYC-rearranged lymphomas. Once-daily oral dosing of BTM-3566 resulted in complete regression of xenografted human DLBCL SU-DHL-10 cells and complete regression in 6 of 9 DLBCL patient-derived xenografts. BTM-3566 represents a first- of-its kind approach of selectively hyperactivating the mitochondrial ISR for treating DLBCL.

DOI: https://doi.org/10.1158/1535-7163.MCT-22-0718
Front Physiol. 2023 ;14 1164287

Complex I deficiency in m.3243A>G fibroblasts is alleviated by reducing NADH accumulation.

Tongling Liufu, Haiyan Yu, Jiaxi Yu, Meng Yu, Yue Tian, Yichun Ou, Jianwen Deng, Guogang Xing, Zhaoxia Wang.

  Introduction: Mitochondrial disease is a spectrum of debilitating disorders caused by mutations in the mitochondrial DNA (mtDNA) or nuclear DNA that compromises the respiratory chain. Mitochondrial 3243A>G (m.3243 A>G) is the most common mutation showing great heterogeneity in phenotype. Previous studies have indicated that NADH: ubiquinone oxidoreductase (complex I) deficiency accompanied by a decreased nicotinamide adenine dinucleotide (NAD+)/reduced NAD+ (NADH) ratio may play a pivotal role in the pathogenesis of m.3243A>G mutation. Methods: To evaluate the potential effects of strategies targeting the imbalanced NAD+/NADH ratio in m.3243A>G mutation, we treated fibroblasts derived from patients with the m.3243 A>G mutation using nicotinamide riboside (NR) or mitochondria-targeted H2O-forming NADH oxidase (mitoLbNOX). Results: M.3243 A>G fibroblasts showed a significant reduction in complex I core subunit 6, complex I enzymatic activity, complex I-dependent oxygen consumption rate (OCR), and adenosine triphosphate (ATP) production compared to the controls. The NAD+/NADH ratio was also significantly reduced in m.3243 A>G fibroblasts, and, using fluorescence lifetime imaging microscopy, we also found that the NADH level was elevated in m.3243 A>G fibroblasts. After NR treatment, the NAD+/NADH ratio, complex I-dependent OCR, and ATP levels increased, whereas NADH levels remained unchanged. More excitingly, after treatment with mitoLbNOX, the NAD+/NADH ratio, complex I-independent OCR, and ATP levels increased more pronouncedly compared with the NR treatment group, accompanied by significantly reduced NADH levels. Discussion: The present study suggests that compared with repletion of NAD+ alone, the combination of this therapeutic modality with alleviation of NADH overload may amplify the treatment effect of restoring NAD+/NADH balance in m.3243A>G fibroblasts.

Keywords:  NADH; complex I; m.3243 A>G; mitoLbNOX; mitochondrial disease; nr

DOI:  https://doi.org/10.3389/fphys.2023.1164287
J Nanobiotechnology. 2023 Aug 26. 21(1): 299

Biomimetic nanovesicle co-delivery system impairs energy metabolism for cancer treatment.

Yongmei Zhao, Yan Zhu, Kai Ding, Shanshan Li, Tianqing Liu.

  Metabolic reprogramming in cancer cells plays a crucial role in cancer development, metastasis and invasion. Cancer cells have a unique metabolism profile that could switch between glycolysis and oxidative phosphorylation (OXPHOS) in order to satisfy a higher proliferative rate and enable survival in tumor microenvironment. Although dietary-based cancer starvation therapy has shown some positive outcomes for cancer treatment, it is difficult for patients to persist for a long time due to the adverse effects. Here in this study, we developed a specific M1 macrophage-derived membrane-based drug delivery system for breast cancer treatment. Both metformin and 3-Bromopyruvate were loaded into the engineered cell membrane-based biomimetic carriers (Met-3BP-Lip@M1) for the shutdown of energy metabolism in cancer cells via simultaneous inhibition of both glycolysis and oxygen consumption. The in vitro studies showed that Met-3BP-Lip@M1 had excellent cancer cell uptake and enhanced cancer cell apoptosis via cell cycle arrest. Our results also demonstrated that this novel biomimetic nanomedicine-based cancer starvation therapy synergistically improved the therapeutic efficiency against breast cancer cells by blocking energy metabolic pathways, which resulted in a significant reduction of cancer cell proliferation, 3D tumor spheroid growth as well as in vivo tumor growth.

Keywords:  3-Bromopyruvate; Biomimetic nanomedicines; Cancer therapy; Energy metabolism; M1 macrophage; Metformin

DOI:  https://doi.org/10.1186/s12951-023-02061-4
Nat Metab. 2023 Aug 31.

Adipocytes reprogram cancer cell metabolism by diverting glucose towards glycerol-3-phosphate thereby promoting metastasis.

Abir Mukherjee, Divya Bezwada, Francesco Greco, Malu Zandbergen, Tong Shen, Chun-Yi Chiang, Medine Tasdemir, Johannes Fahrmann, Dmitry Grapov, Michael R La Frano, Hieu S Vu, Brandon Faubert, John W Newman, Liam A McDonnell, Luigi Nezi, Oliver Fiehn, Ralph J DeBerardinis, Ernst Lengyel.

In the tumor microenvironment, adipocytes function as an alternate fuel source for cancer cells. However, whether adipocytes influence macromolecular biosynthesis in cancer cells is unknown. Here we systematically characterized the bidirectional interaction between primary human adipocytes and ovarian cancer (OvCa) cells using multi-platform metabolomics, imaging mass spectrometry, isotope tracing and gene expression analysis. We report that, in OvCa cells co-cultured with adipocytes and in metastatic tumors, a part of the glucose from glycolysis is utilized for the biosynthesis of glycerol-3-phosphate (G3P). Normoxic HIF1α protein regulates the altered flow of glucose-derived carbons in cancer cells, resulting in increased glycerophospholipids and triacylglycerol synthesis. The knockdown of HIF1α or G3P acyltransferase 3 (a regulatory enzyme of glycerophospholipid synthesis) reduced metastasis in xenograft models of OvCa. In summary, we show that, in an adipose-rich tumor microenvironment, cancer cells generate G3P as a precursor for critical membrane and signaling components, thereby promoting metastasis. Targeting biosynthetic processes specific to adipose-rich tumor microenvironments might be an effective strategy against metastasis.

DOI: https://doi.org/10.1038/s42255-023-00879-8
Nat Aging. 2023 Aug 31.

Induction of mitochondrial recycling reverts age-associated decline of the hematopoietic and immune systems.

Mukul Girotra, Yi-Hsuan Chiang, Melanie Charmoy, Pierpaolo Ginefra, Helen Carrasco Hope, Charles Bataclan, Yi-Ru Yu, Frederica Schyrr, Fabien Franco, Hartmut Geiger, Stephane Cherix, Ping-Chih Ho, Olaia Naveiras, Johan Auwerx, Werner Held, Nicola Vannini.

Aging compromises hematopoietic and immune system functions, making older adults especially susceptible to hematopoietic failure, infections and tumor development, and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward the myeloid lineage (myeloid bias)1,2. These processes are accompanied by an aberrant accumulation of mitochondria in HSCs3. The administration of the mitochondrial modulator urolithin A corrects mitochondrial function in HSCs and completely restores the blood reconstitution capability of 'old' HSCs. Moreover, urolithin A-supplemented food restores lymphoid compartments, boosts HSC function and improves the immune response against viral infection in old mice. Altogether our results demonstrate that boosting mitochondrial recycling reverts the aging phenotype in the hematopoietic and immune systems.

DOI: https://doi.org/10.1038/s43587-023-00473-3
Eur J Pharmacol. 2023 Aug 29. pii: S0014-2999(23)00546-0. [Epub ahead of print] 176034

Synergism of small molecules targeting VDAC with sorafenib, regorafenib or lenvatinib on hepatocarcinoma cell proliferation and survival.

C Ventura, M Junco, F X Santiago Valtierra, M Gooz, Y Zhiwei, D M Townsend, P M Woster, E N Maldonado.

  Voltage dependent anion channels (VDAC) in the outer mitochondrial membrane regulate the influx of metabolites that sustain mitochondrial metabolism and the efflux of ATP to the cytosol. Free tubulin and NADH close VDAC. The small molecules X1 and SC18 open VDAC and modulate mitochondrial metabolism. X1 antagonizes the inhibitory effect of tubulin on VDAC. SC18 occupies an NADH-binding pocket in the inner wall of all VDAC isoforms. Here, we hypothesized that X1 and SC18 have a synergistic effect with sorafenib, regorafenib or lenvatinib to arrest proliferation and induce death in hepatocarcinoma cells. We used colony formation assays to determine cell proliferation, and a combination of calcein/propidium iodide, and trypan blue exclusion to assess cell death in the well differentiated Huh7 and the poorly differentiated SNU-449 cells. Synergism was assessed using the Chou-Talalay method. The inhibitory effect of X1, SC18, sorafenib, regorafenib and lenvatinib was concentration and time dependent. IC50 values calculated from the inhibition of clonogenic capacity were lower than those determined from cell survival. At IC50s that inhibited cell proliferation, SC18 arrested cells in G0/G1. SC18 at 0.25-2 IC50s had a synergistic effect with sorafenib on inhibiting clonogenicity in Huh7 and SNU-449 cells, and with regorafenib or lenvatinib in SNU-449 cells. X1 or SC18 also had synergistic effects with sorafenib on promoting cell death at 0.5-2 IC50s for SC18 in Huh7 and SNU-449 cells. These results suggest that small molecules targeting VDAC represent a potential new class of drugs to treat liver cancer.

Keywords:  Hepatocarcinoma; Regorafenib; Sorafenib; Synergism; VDAC; X1-SC18

DOI:  https://doi.org/10.1016/j.ejphar.2023.176034
NAR Cancer. 2023 Sep;5(3): zcad046

IQGAP1 mediates the communication between the nucleus and the mitochondria via NDUFS4 alternative splicing.

Vasiliki Papadaki, Zoi Erpapazoglou, Maria Kokkori, Malgorzata Ewa Rogalska, Myrto Potiri, Andrada Birladeanu, Eleni N Tsakiri, Hassan Ashktorab, Duane T Smoot, Katerina Papanikolopoulou, Martina Samiotaki, Panagiota Kafasla.

Constant communication between mitochondria and nucleus ensures cellular homeostasis and adaptation to mitochondrial stress. Anterograde regulatory pathways involving a large number of nuclear-encoded proteins control mitochondrial biogenesis and functions. Such functions are deregulated in cancer cells, resulting in proliferative advantages, aggressive disease and therapeutic resistance. Transcriptional networks controlling the nuclear-encoded mitochondrial genes are known, however alternative splicing (AS) regulation has not been implicated in this communication. Here, we show that IQGAP1, a scaffold protein regulating AS of distinct gene subsets in gastric cancer cells, participates in AS regulation that strongly affects mitochondrial respiration. Combined proteomic and RNA-seq analyses of IQGAP1KO and parental cells show that IQGAP1KO alters an AS event of the mitochondrial respiratory chain complex I (CI) subunit NDUFS4 and downregulates a subset of CI subunits. In IQGAP1KO cells, CI intermediates accumulate, resembling assembly deficiencies observed in patients with Leigh syndrome bearing NDUFS4 mutations. Mitochondrial CI activity is significantly lower in KO compared to parental cells, while exogenous expression of IQGAP1 reverses mitochondrial defects of IQGAP1KO cells. Our work sheds light to a novel facet of IQGAP1 in mitochondrial quality control that involves fine-tuning of CI activity through AS regulation in gastric cancer cells relying highly on mitochondrial respiration.

DOI: https://doi.org/10.1093/narcan/zcad046
Biochem Soc Trans. 2023 Aug 31. pii: BST20221363. [Epub ahead of print]

Mitophagy-promoting agents and their ability to promote healthy-aging.

Vijigisha Srivastava, Einav Gross.

  The removal of damaged mitochondrial components through a process called mitochondrial autophagy (mitophagy) is essential for the proper function of the mitochondrial network. Hence, mitophagy is vital for the health of all aerobic animals, including humans. Unfortunately, mitophagy declines with age. Many age-associated diseases, including Alzheimer's and Parkinson's, are characterized by the accumulation of damaged mitochondria and oxidative damage. Therefore, activating the mitophagy process with small molecules is an emerging strategy for treating multiple aging diseases. Recent studies have identified natural and synthetic compounds that promote mitophagy and lifespan. This article aims to summarize the existing knowledge about these substances. For readers' convenience, the knowledge is presented in a table that indicates the chemical data of each substance and its effect on lifespan. The impact on healthspan and the molecular mechanism is reported if known. The article explores the potential of utilizing a combination of mitophagy-inducing drugs within a therapeutic framework and addresses the associated challenges of this strategy. Finally, we discuss the process that balances mitophagy, i.e. mitochondrial biogenesis. In this process, new mitochondrial components are generated to replace the ones cleared by mitophagy. Furthermore, some mitophagy-inducing substances activate biogenesis (e.g. resveratrol and metformin). Finally, we discuss the possibility of combining mitophagy and biogenesis enhancers for future treatment. In conclusion, this article provides an up-to-date source of information about natural and synthetic substances that activate mitophagy and, hopefully, stimulates new hypotheses and studies that promote healthy human aging worldwide.

Keywords:  aging; lifespan; mitochondria; mitochondrial autophagy; mitochondrial biogenesis; mitophagy

DOI:  https://doi.org/10.1042/BST20221363
Life Sci Alliance. 2023 Nov;pii: e202302271. [Epub ahead of print]6(11):

T cell differentiation drives the negative selection of pathogenic mitochondrial DNA variants.

Imogen G Franklin, Paul Milne, Jordan Childs, Róisín M Boggan, Isabel Barrow, Conor Lawless, Gráinne S Gorman, Yi Shiau Ng, Matthew Collin, Oliver M Russell, Sarah J Pickett.

Pathogenic mitochondrial DNA (mtDNA) single-nucleotide variants are a common cause of adult mitochondrial disease. Levels of some variants decrease with age in blood. Given differing division rates, longevity, and energetic requirements within haematopoietic lineages, we hypothesised that cell-type-specific metabolic requirements drive this decline. We coupled cell-sorting with mtDNA sequencing to investigate mtDNA variant levels within progenitor, myeloid, and lymphoid lineages from 26 individuals harbouring one of two pathogenic mtDNA variants (m.3243A>G and m.8344A>G). For both variants, cells of the T cell lineage show an enhanced decline. High-throughput single-cell analysis revealed that decline is driven by increasing proportions of cells that have cleared the variant, following a hierarchy that follows the current orthodoxy of T cell differentiation and maturation. Furthermore, patients with pathogenic mtDNA variants have a lower proportion of T cells than controls, indicating a key role for mitochondrial function in T cell homeostasis. This work identifies the ability of T cell subtypes to selectively purify their mitochondrial genomes, and identifies pathogenic mtDNA variants as a new means to track blood cell differentiation status.

DOI: https://doi.org/10.26508/lsa.202302271
Cancer Lett. 2023 Aug 28. pii: S0304-3835(23)00315-4. [Epub ahead of print] 216364

Lycorine promotes IDH1 acetylation to induce mitochondrial dynamics imbalance in colorectal cancer cells.

Fang-Fang Zhuo, Ling Li, Ting-Ting Liu, Xiao-Min Liang, Zhuo Yang, Yong-Zhe Zheng, Qian-Wei Luo, Jia-Hong Lu, Dan Liu, Ke-Wu Zeng, Peng-Fei Tu.

  Isocitrate dehydrogenase (IDH) 1 and 2, as essential enzymes in energy metabolism, contribute to the survival and drug resistance of a variety of solid tumors, especially for colorectal cancer (CRC). However, the underlying molecular mechanism still remains unclear. In this study, IDH1 was identified as a crucial cellular target of a natural-derived anti-CRC small molecule lycorine, using the unbiased thermal proteome profiling (TPP) strategy. We found that lycorine directly targeted a unique C-terminal domain of IDH1, and disrupted IDH1 interaction with deacetylase sirtuin 1 (SIRT1), thereby significantly promoting IDH1 acetylation modification. Then, lycorine noticeably triggered oxidative stress in CRC cells to cause mitochondrial membranes injury, and subsequently facilitated mitochondrial fission. Specific knockdown of IDH1 or SIRT1 markedly aggrieved lycorine-mediated oxidative stress and mitochondrial fragmentation in CRC cells. Furthermore, the combination of lycorine and sirtuins blocker nicotinamide (NAM) exhibited a synergic therapeutic effect in CRC cells. Collectively, our results reveal that IDH1 may serve as a promising therapeutic target for CRC via pharmacologically driving oxidative stress-dependent mitochondrial dynamics imbalance.

Keywords:  Colorectal cancer; Isocitrate dehydrogenase (IDH); Lycorine; Mitochondrial dynamics; Oxidative stress; Sirtuin 1

DOI:  https://doi.org/10.1016/j.canlet.2023.216364
Life Sci Alliance. 2023 Nov;pii: e202302036. [Epub ahead of print]6(11):

Alternative oxidase causes cell type- and tissue-specific responses in mutator mice.

Lilli Ikonen, Sini Pirnes-Karhu, Swagat Pradhan, Howard T Jacobs, Marten Szibor, Anu Suomalainen.

Energetic insufficiency, excess production of reactive oxygen species (ROS), and aberrant signaling partially account for the diverse pathology of mitochondrial diseases. Whether interventions affecting ROS, a regulator of stem cell pools, could modify somatic stem cell homeostasis remains unknown. Previous data from mitochondrial DNA mutator mice showed that increased ROS leads to oxidative damage in erythroid progenitors, causing lifespan-limiting anemia. Also unclear is how ROS-targeted interventions affect terminally differentiated tissues. Here, we set out to test in mitochondrial DNA mutator mice how ubiquitous expression of the Ciona intestinalis alternative oxidase (AOX), which attenuates ROS production, affects murine stem cell pools. We found that AOX does not affect neural stem cells but delays the progression of mutator-driven anemia. Furthermore, when combined with the mutator, AOX potentiates mitochondrial stress and inflammatory responses in skeletal muscle. These differential cell type-specific findings demonstrate that AOX expression is not a global panacea for curing mitochondrial dysfunction. ROS attenuation must be carefully studied regarding specific underlying defects before AOX can be safely used in therapy.

DOI: https://doi.org/10.26508/lsa.202302036
Blood Adv. 2023 Aug 28. pii: bloodadvances.2023010460. [Epub ahead of print]

GPRC5C Drives Branched-Chain Amino Acid Metabolism in Leukemogenesis.

Yu Wei Zhang, Talia Velasco-Hernandez, Julian Mess, Maria-Eleni Lalioti, Mari Carmen Romero-Mulero, Nadine Obier, Nikolaos Karantzelis, Jasmin Rettkowski, Katharina Schönberger, Noémie Karabacz, Karin Jäcklein, Tatsuya Morishima, Juan Luis Trincado, Paola Romecin, Alba Martinez-Moreno, Hitoshi Takizawa, Khalid Shoumariyeh, Simon Renders, Robert Zeiser, Heike L Pahl, François Béliveau, Josée Hébert, Bernhard Lehnertz, Guy Sauvageau, Pablo Menendez, Nina Cabezas-Wallscheid.

Leukemia stem cells (LSCs) share numerous features with healthy hematopoietic stem cells (HSCs). G-protein coupled receptor family C group 5 member C (GPRC5C) is a regulator of HSC dormancy. However, GPRC5C functionality in acute myeloid leukemia (AML) is yet to be determined. Within patient AML cohorts, high GPRC5C levels correlated with poorer survival. Ectopic Gprc5c expression increased AML aggression through activation of NF-κB, which resulted in an altered metabolic state with increased levels of intracellular branched-chain amino acids (BCAAs). This onco-metabolic profile was reversed upon loss of Gprc5c, which also abrogated the leukemia-initiating potential. Targeting the BCAA transporter SLC7A5 with JPH203 inhibited oxidative phosphorylation and elicited strong anti-leukemia effects, specifically in mouse and patient AML samples while sparing healthy bone marrow (BM) cells. This anti-leukemia effect was strengthened in the presence of venetoclax and azacitidine. Our results indicate that the GPRC5C-NF-κB-SLC7A5-BCAAs axis is a therapeutic target that can compromise leukemia stem cell function in AML.

DOI: https://doi.org/10.1182/bloodadvances.2023010460
Genome Biol. 2023 Aug 31. 24(1): 199

Single-cell transcriptomics reveals multiple chemoresistant properties in leukemic stem and progenitor cells in pediatric AML.

Yongping Zhang, Shuting Jiang, Fuhong He, Yuanyuan Tian, Haiyang Hu, Li Gao, Lin Zhang, Aili Chen, Yixin Hu, Liyan Fan, Chun Yang, Bi Zhou, Dan Liu, Zihan Zhou, Yanxun Su, Lei Qin, Yi Wang, Hailong He, Jun Lu, Peifang Xiao, Shaoyan Hu, Qian-Fei Wang.

   BACKGROUND: Cancer patients can achieve dramatic responses to chemotherapy yet retain resistant tumor cells, which ultimately results in relapse. Although xenograft model studies have identified several cellular and molecular features that are associated with chemoresistance in acute myeloid leukemia (AML), to what extent AML patients exhibit these properties remains largely unknown.
RESULTS: We apply single-cell RNA sequencing to paired pre- and post-chemotherapy whole bone marrow samples obtained from 13 pediatric AML patients who had achieved disease remission, and distinguish AML clusters from normal cells based on their unique transcriptomic profiles. Approximately 50% of leukemic stem and progenitor populations actively express leukemia stem cell (LSC) and oxidative phosphorylation (OXPHOS) signatures, respectively. These clusters have a higher chance of tolerating therapy and exhibit an enhanced metabolic program in response to treatment. Interestingly, the transmembrane receptor CD69 is highly expressed in chemoresistant hematopoietic stem cell (HSC)-like populations (named the CD69+ HSC-like subpopulation). Furthermore, overexpression of CD69 results in suppression of the mTOR signaling pathway and promotion of cell quiescence and adhesion in vitro. Finally, the presence of CD69+ HSC-like cells is associated with unfavorable genetic mutations, the persistence of residual tumor cells in chemotherapy, and poor outcomes in independent pediatric and adult public AML cohorts.
CONCLUSIONS: Our analysis reveals leukemia stem cell and OXPHOS as two major chemoresistant features in human AML patients. CD69 may serve as a potential biomarker in defining a subpopulation of chemoresistant leukemia stem cells. These findings have important implications for targeting residual chemo-surviving AML cells.

Keywords:  AML; CD69; Chemotherapy resistance; HSC-like; Leukemia stem cell; Oxidative phosphorylation; Residual tumor cell; Single-cell RNA sequencing

DOI:  https://doi.org/10.1186/s13059-023-03031-7
Mol Microbiol. 2023 Aug 30.

SUMOylation of yeast Pso2 enhances its translocation and accumulation in the mitochondria and suppresses methyl methanesulfonate-induced mitochondrial DNA damage.

Shravanahalli C Somashekara, Kshitiza M Dhyani, Manoj Thakur, Kalappa Muniyappa.

  Saccharomyces cerevisiae Pso2/SNM1 is essential for DNA interstrand crosslink (ICL) repair; however, its mechanism of action remains incompletely understood. While recent work has revealed that Pso2/Snm1 is dual-localized in the nucleus and mitochondria, it remains unclear whether cell-intrinsic and -extrinsic factors regulate its subcellular localization and function. Herein, we show that Pso2 undergoes ubiquitination and phosphorylation, but not SUMOylation, in unstressed cells. Unexpectedly, we found that methyl methanesulfonate (MMS), rather than ICL-forming agents, induced robust SUMOylation of Pso2 on two conserved residues, K97 and K575, and that SUMOylation markedly increased its abundance in the mitochondria. Reciprocally, SUMOylation had no discernible impact on Pso2 translocation to the nucleus, despite the presence of steady-state levels of SUMOylated Pso2 across the cell cycle. Furthermore, substitution of the invariant residues K97 and K575 by arginine in the Pso2 SUMO consensus motifs severely impaired SUMOylation and abolished its translocation to the mitochondria of MMS-treated wild type cells, but not in unstressed cells. We demonstrate that whilst Siz1 and Siz2 SUMO E3 ligases catalyze Pso2 SUMOylation, the former plays a dominant role. Notably, we found that the phenotypic characteristics of the SUMOylation-defective mutant Pso2K97R/K575R closely mirrored those observed in the Pso2Δ petite mutant. Additionally, leveraging next-generation sequencing analysis, we demonstrate that Pso2 mitigates MMS-induced damage to mitochondrial DNA (mtDNA). Viewed together, our work offers previously unknown insights into the link between genotoxic stress-induced SUMOylation of Pso2 and its preferential targeting to the mitochondria, as well as its role in attenuating MMS-induced mtDNA damage.

Keywords:  ICL repair; Pso2; SUMOylation; mitochondrial localization; mtDNA repair

DOI:  https://doi.org/10.1111/mmi.15145
J Cell Sci. 2023 Sep 01. pii: jcs260857. [Epub ahead of print]136(17):

Mitochondrial phospholipid metabolism in health and disease.

Alaumy Joshi, Travis H Richard, Vishal M Gohil.

  Studies of rare human genetic disorders of mitochondrial phospholipid metabolism have highlighted the crucial role that membrane phospholipids play in mitochondrial bioenergetics and human health. The phospholipid composition of mitochondrial membranes is highly conserved from yeast to humans, with each class of phospholipid performing a specific function in the assembly and activity of various mitochondrial membrane proteins, including the oxidative phosphorylation complexes. Recent studies have uncovered novel roles of cardiolipin and phosphatidylethanolamine, two crucial mitochondrial phospholipids, in organismal physiology. Studies on inter-organellar and intramitochondrial phospholipid transport have significantly advanced our understanding of the mechanisms that maintain mitochondrial phospholipid homeostasis. Here, we discuss these recent advances in the function and transport of mitochondrial phospholipids while describing their biochemical and biophysical properties and biosynthetic pathways. Additionally, we highlight the roles of mitochondrial phospholipids in human health by describing the various genetic diseases caused by disruptions in their biosynthesis and discuss advances in therapeutic strategies for Barth syndrome, the best-studied disorder of mitochondrial phospholipid metabolism.

Keywords:  Barth syndrome; Cardiolipin; Membranes; Mitochondria; Phosphatidylethanolamine; Phospholipids

DOI:  https://doi.org/10.1242/jcs.260857
Cell Rep. 2023 Aug 30. pii: S2211-1247(23)01045-8. [Epub ahead of print]42(9): 113034

Formate promotes invasion and metastasis in reliance on lipid metabolism.

Catherine Delbrouck, Nicole Kiweler, Oleg Chen, Vitaly I Pozdeev, Lara Haase, Laura Neises, Anaïs Oudin, Aymeric Fouquier d'Hérouël, Ruolin Shen, Lisa Schlicker, Rashi Halder, Antoine Lesur, Anne Schuster, Nadja I Lorenz, Christian Jaeger, Maureen Feucherolles, Gilles Frache, Martyna Szpakowska, Andy Chevigne, Michael W Ronellenfitsch, Etienne Moussay, Marie Piraud, Alexander Skupin, Almut Schulze, Simone P Niclou, Elisabeth Letellier, Johannes Meiser.

  Metabolic rewiring is essential for cancer onset and progression. We previously showed that one-carbon metabolism-dependent formate production often exceeds the anabolic demand of cancer cells, resulting in formate overflow. Furthermore, we showed that increased extracellular formate concentrations promote the in vitro invasiveness of glioblastoma cells. Here, we substantiate these initial observations with ex vivo and in vivo experiments. We also show that exposure to exogeneous formate can prime cancer cells toward a pro-invasive phenotype leading to increased metastasis formation in vivo. Our results suggest that the increased local formate concentration within the tumor microenvironment can be one factor to promote metastases. Additionally, we describe a mechanistic interplay between formate-dependent increased invasiveness and adaptations of lipid metabolism and matrix metalloproteinase activity. Our findings consolidate the role of formate as pro-invasive metabolite and warrant further research to better understand the interplay between formate and lipid metabolism.

Keywords:  CP: Cancer; CP: Metabolism; cancer metastasis; formate overflow; invasion; one-carbon metabolism

DOI:  https://doi.org/10.1016/j.celrep.2023.113034
BMC Cancer. 2023 Aug 28. 23(1): 804

Cuproptosis related gene PDHB is identified as a biomarker inversely associated with the progression of clear cell renal cell carcinoma.

Hu Wang, Zhan Yang, Xingyu He, Fengran Guo, Hao Sun, Sen Xu, Chao Xu, Zhu Wang, Hongzhuang Wen, Zhihai Teng, Yaxuan Wang, Zhenwei Han.

   BACKGROUND: Cuproptosis is a newly discovered programmed cell death dependent on mitochondrial respiratory disorder induced by copper overload. Pyruvate dehydrogenase E1 subunit beta (PDHB) is one of the cuproptosis genesand is a nuclear-encoded pyruvate dehydrogenase, which catalyzes the conversion of pyruvate to acetyl coenzyme A. However, the mechanism of PDHB in clear cell renal cell carcinoma (ccRCC) remains unclear.
METHODS: We used data from TCGA and GEO to assess the expression of PDHB in normal and tumor tissues. We further analyzed the relationship between PDHB and somatic mutations and immune infiltration. Finally, we preliminarily explored the impact of PDHB on ccRCC.
RESULTS: The expression level of PDHB was lower in tumor tissue compared with normal tissue. Meanwhile, the expression level of PDHB was also lower in high-grade tumors than low-grade tumors. PDHB is positively correlated with prognosis in ccRCC. Furthermore, PDHB may be associated with decreased risk of VHL, PBRM1 and KDM5C mutations. In 786-O cells, copper chloride could promote the expression of cuproptosis genes (DLAT, PDHB and FDX1) and inhibit cell growth. Last but not least, we found that PDHB could inhibit the proliferation and migration of ccRCC cells.
CONCLUSION: Our results demonstrated that PDHB could inhibit the proliferation, migration and invasion in ccRCC cells, which might be a prognostic predictor of ccRCC. Targeting this molecular might provide a new therapeutic strategy for patients with advanced ccRCC.

Keywords:  Clear cell renal cell carcinoma; Cuproptosis; PDHB; Tumor immune microenvironment

DOI:  https://doi.org/10.1186/s12885-023-11324-0
Proc Natl Acad Sci U S A. 2023 Sep 05. 120(36): e2302360120

Impaired age-associated mitochondrial translation is mitigated by exercise and PGC-1α.

Laura M de Smalen, Anastasiya Börsch, Aurel B Leuchtmann, Jonathan F Gill, Danilo Ritz, Mihaela Zavolan, Christoph Handschin.

  Sarcopenia, the age-related loss of skeletal muscle mass and function, can dramatically impinge on quality of life and mortality. While mitochondrial dysfunction and imbalanced proteostasis are recognized as hallmarks of sarcopenia, the regulatory and functional link between these processes is underappreciated and unresolved. We therefore investigated how mitochondrial proteostasis, a crucial process that coordinates the expression of nuclear- and mitochondrial-encoded mitochondrial proteins with supercomplex formation and respiratory activity, is affected in skeletal muscle aging. Intriguingly, a robust mitochondrial translation impairment was observed in sarcopenic muscle, which is regulated by the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) with the estrogen-related receptor α (ERRα). Exercise, a potent inducer of PGC-1α activity, rectifies age-related reduction in mitochondrial translation, in conjunction with quality control pathways. These results highlight the importance of mitochondrial proteostasis in muscle aging, and elucidate regulatory interactions that underlie the powerful benefits of physical activity in this context.

Keywords:  aging; mitochondria; proteostasis; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1073/pnas.2302360120
bioRxiv. 2023 Aug 17. pii: 2023.08.16.553624. [Epub ahead of print]

Triaging of ⍺-helical proteins to the mitochondrial outer membrane by distinct chaperone machinery based on substrate topology.

Gayathri Muthukumar, Taylor A Stevens, Alison J Inglis, Theodore K Esantsi, Reuben A Saunders, Fabian Schulte, Rebecca M Voorhees, Alina Guna, Jonathan S Weissman.

Mitochondrial outer membrane ⍺-helical proteins play critical roles in mitochondrial-cytoplasmic communication, but the rules governing the targeting and insertion of these biophysically diverse substrates remain unknown. Here, we first defined the complement of required mammalian biogenesis machinery through genome-wide CRISPRi screens using topologically distinct membrane proteins. Systematic analysis of nine identified factors across 21 diverse ⍺-helical substrates reveals that these components are organized into distinct targeting pathways which act on substrates based on their topology. NAC is required for efficient targeting of polytopic proteins whereas signal-anchored proteins require TTC1, a novel cytosolic chaperone which physically engages substrates. Biochemical and mutational studies reveal that TTC1 employs a conserved TPR domain and a hydrophobic groove in its C-terminal domain to support substrate solubilization and insertion into mitochondria. Thus, targeting of diverse mitochondrial membrane proteins is achieved through topological triaging in the cytosol using principles with similarities to ER membrane protein biogenesis systems.

DOI: https://doi.org/10.1101/2023.08.16.553624
Sci Rep. 2023 08 26. 13(1): 13964

Mutational landscape of intestinal crypt cells after long-term in vivo exposure to high fat diet.

Mathilde Meyenberg, Anna Hakobyan, Nikolina Papac-Milicevic, Laura Göderle, Franziska L Langner, Mateo Markovic, Ji-Hyun Lee, Bon-Kyoung Koo, Georg A Busslinger, Israel Tojal da Silva, Christoph J Binder, Jörg Menche, Joanna I Loizou.

Obesity is a modifiable risk factor in cancer development, especially for gastrointestinal cancer. While the etiology of colorectal cancer is well characterized by the adenoma-carcinoma sequence, it remains unclear how obesity influences colorectal cancer development. Dietary components of a high fat diet along with obesity have been shown to modulate the cancer risk by perturbing the homeostasis of intestinal stem cells, yet how adiposity impacts the development of genomic instability has not been studied. Mutational signatures are a powerful way to understand how a complex biological response impacts genomic stability. We utilized a mouse model of diet-induced obesity to study the mutational landscape of intestinal crypt cells after a 48-week exposure to an experimental high fat diet in vivo. By clonally enriching single crypt derived cells in organoid culture and obtaining whole genome sequences, we analyzed and compared the mutational landscape of intestinal epithelial cells from normal diet and high fat diet mice. Single nucleotide substitution signatures and indel signatures present in our cohort are found equally active in both diet groups and reflect biological processes of normal aging, cellular replication, and oxidative stress induced during organoid culturing. Thus, we demonstrate that in the absence of activating mutations or chemical exposure, high fat diet alone is not sufficient to increase genomic instability.

DOI: https://doi.org/10.1038/s41598-023-41123-3
J Cell Biol. 2023 Oct 02. pii: e202308119. [Epub ahead of print]222(10):

Mitochondrial double membrane fission: A mystery solved?

Benedikt Westermann.

It has long been an unresolved question whether the division machineries that assemble on the mitochondrial surface cooperate with factors inside the organelle. Now, two studies by Connor et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202303147) and Fukuda et al. (2023. Mol. Cell.https://doi.org/10.1016/j.molcel.2023.04.022) have identified an intermembrane space protein that is crucial for mitochondrial double membrane division.

DOI: https://doi.org/10.1083/jcb.202308119
Cell Rep. 2023 Aug 30. pii: S2211-1247(23)01058-6. [Epub ahead of print]42(9): 113047

Molecular, metabolic, and functional CD4 T cell paralysis in the lymph node impedes tumor control.

Mengdi Guo, Diala Abd-Rabbo, Bruna C Bertol, Madeleine Carew, Sabelo Lukhele, Laura M Snell, Wenxi Xu, Giselle M Boukhaled, Heidi Elsaesser, Marie Jo Halaby, Naoto Hirano, Tracy L McGaha, David G Brooks.

  CD4 T cells are central effectors of anti-cancer immunity and immunotherapy, yet the regulation of CD4 tumor-specific T (TTS) cells is unclear. We demonstrate that CD4 TTS cells are quickly primed and begin to divide following tumor initiation. However, unlike CD8 TTS cells or exhaustion programming, CD4 TTS cell proliferation is rapidly frozen in place by a functional interplay of regulatory T cells and CTLA4. Together these mechanisms paralyze CD4 TTS cell differentiation, redirecting metabolic circuits, and reducing their accumulation in the tumor. The paralyzed state is actively maintained throughout cancer progression and CD4 TTS cells rapidly resume proliferation and functional differentiation when the suppressive constraints are alleviated. Overcoming their paralysis established long-term tumor control, demonstrating the importance of rapidly crippling CD4 TTS cells for tumor progression and their potential restoration as therapeutic targets.

Keywords:  CD4 T cell; CP: Immunology; CTLA4; T regulatory cell; cancer; dysfunction; exhaustion; immunotherapy; metabolism; transcriptomic signature; tumor immunology

DOI:  https://doi.org/10.1016/j.celrep.2023.113047
Cell Rep. 2023 Aug 24. pii: S2211-1247(23)01024-0. [Epub ahead of print]42(9): 113013

The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function.

Iosifina P Foskolou, Pedro P Cunha, Elena Sánchez-López, Eleanor A Minogue, Benoît P Nicolet, Aurélie Guislain, Christian Jorgensen, Sarantos Kostidis, Nordin D Zandhuis, Laura Barbieri, David Bargiela, Demitris Nathanael, Petros A Tyrakis, Asis Palazon, Martin Giera, Monika C Wolkers, Randall S Johnson.

  2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in cluster of differentiation (CD)8+ T cell biology, where we find they have highly divergent effects on proliferation, differentiation, and T cell function. We show here an analysis of structural determinants that likely underlie these differential effects on specific α-ketoglutarate (αKG)-dependent enzymes. Treatment of CD8+ T cells with exogenous S-2HG, but not R-2HG, increased CD8+ T cell fitness in vivo and enhanced anti-tumor activity. These data show that S-2HG and R-2HG should be considered as two distinct and important actors in the regulation of T cell function.

Keywords:  2-hydroxyglutarate; CD8+ T cell function; CD8+ T cell memory; CP: Immunology; adoptive cell transfer; oncometabolites

DOI:  https://doi.org/10.1016/j.celrep.2023.113013
Am J Physiol Cell Physiol. 2023 Aug 29.

Mitochondrial Microproteins: Critical Regulators of Protein Import, Energy Production, Stress Response Pathways, and Programmed Cell Death.

Michael L Kamradt, Catherine A Makarewich.

  Mitochondria rely upon the coordination of protein import, protein translation, and proper functioning of oxidative phosphorylation (OXPHOS) complexes I-V to sustain the activities of life for an organism. Each process is dependent upon the function of profoundly large protein complexes found in the mitochondria (TOMM complex, TIMM complex, OXPHOS complexes, mitoribosomes). These massive protein complexes, in some instances more than one megadalton, are built up from numerous protein subunits of varying sizes, including many proteins that are ≤100-150 amino acids. However, these small proteins, termed microproteins, not only act as cogs in large molecular machines; they also have important steps in inhibiting or promoting the intrinsic pathway of apoptosis, coordinate responses to cellular stress and even act as hormones. This review focuses on microproteins that occupy the mitochondria and are critical for its function. Although the microprotein field is relatively new, researchers have long recognized the existence of these mitochondrial proteins as critical components of virtually all aspects of mitochondrial biology. Thus, recent studies estimating that hundreds of new microproteins of unknown function exist and are missing from current genome annotations suggests that the mitochondrial "microproteome" is a rich area for future biological investigation.

Keywords:  cell stress; microproteins; mitochondria; mitochondrial protein import; oxidative phosphorylation

DOI:  https://doi.org/10.1152/ajpcell.00189.2023
Toxicol Ind Health. 2023 Aug 30. 7482337231198350

Acrolein increases the concentration of intracellular Zn2⁺ by producing mitochondrial reactive oxygen species in A549 cells.

Xueqi Liu, Wenwu Sun, Jianping Cao, Zhuang Ma.

  Smoking or occupational exposure leads to low concentrations of acrolein on the surface of the airways. Acrolein is involved in the pathophysiological processes of various respiratory diseases. Reports showed that acrolein induced an increase in mitochondrial reactive oxygen species (mROS). Furthermore, exogenous H₂O₂ was found to increase intracellular Zn2⁺ concentration ([Zn2⁺]ᵢ). However, the specific impact of acrolein on changes in intracellular Zn2⁺ levels has not been fully investigated. Therefore, this study aimed to investigate the effects of acrolein on mROS and [Zn2⁺]ᵢ in A549 cells. We used Mito Tracker Red CM-H2Xros (MitoROS) and Fluozin-3 fluorescent probes to observe changes in mROS and intracellular Zn2⁺. The results revealed that acrolein increased [Zn2⁺]ᵢ in a time- and dose-dependent manner. Additionally, the production of mROS was observed in response to acrolein treatment. Subsequent experiments showed that the intracellular Zn2⁺ chelator TPEN could inhibit the acrolein-induced elevation of [Zn2⁺]ᵢ but did not affect the acrolein-induced mROS production. Conversely, the acrolein-induced elevation of mROS and [Zn2⁺]ᵢ were significantly decreased by the inhibitors of ROS formation (NaHSO₃, NAC). Furthermore, external oxygen free radicals increased both [Zn2⁺]ᵢ levels and mROS production. These results demonstrated that acrolein-induced elevation of [Zn2⁺]ᵢ in A549 cells was mediated by mROS generation, rather than through a pathway where [Zn2⁺]ᵢ elevation leads to mROS production.

Keywords:  Acrolein; intracellular Zn2⁺; mitochondrial ROS; oxidative stress; respiratory epithelial cells

DOI:  https://doi.org/10.1177/07482337231198350
Genetics. 2023 Aug 28. pii: iyad147. [Epub ahead of print]

Mitochondrial superoxide dismutase Sod2 suppresses nuclear genome instability during oxidative stress.

Sonia Vidushi Gupta, Lillian Campos, Kristina Hildegard Schmidt.

  Oxidative stress can damage DNA and thereby contribute to genome instability. To avoid an imbalance or overaccumulation of reactive oxygen species (ROS), cells are equipped with antioxidant enzymes that scavenge excess ROS. Cells lacking the RecQ-family DNA helicase Sgs1, which contributes to homology-dependent DNA break repair and chromosome stability, are known to accumulate ROS, but the origin and consequences of this oxidative stress phenotype are not fully understood. Here, we show that the sgs1 mutant exhibits elevated mitochondrial superoxide, increased mitochondrial mass, and accumulation of recombinogenic DNA lesions that can be suppressed by antioxidants. Increased mitochondrial mass in the sgs1Δ mutant is accompanied by increased mitochondrial branching, which was also inducible in wildtype cells by replication stress. Superoxide dismutase Sod2 genetically interacts with Sgs1 in the suppression of nuclear chromosomal rearrangements under paraquat-induced oxidative stress. PQ-induced chromosome rearrangements in the absence of Sod2 are promoted by Rad51 recombinase and the polymerase subunit Pol32. Finally, dependence of chromosomal rearrangements on the Rev1/Pol ζ mutasome suggests that under oxidative stress successful DNA synthesis during DNA break repair depends on translesion DNA synthesis.

Keywords:  Sgs1; Sod2; chromosome instability; homologous recombination; mitochondria; reactive oxygen species (ROS); translesion DNA synthesis

DOI:  https://doi.org/10.1093/genetics/iyad147
Mol Cell. 2023 Aug 24. pii: S1097-2765(23)00640-8. [Epub ahead of print]

Lysosomal cystine governs ferroptosis sensitivity in cancer via cysteine stress response.

Robert V Swanda, Quanquan Ji, Xincheng Wu, Jingyue Yan, Leiming Dong, Yuanhui Mao, Saori Uematsu, Yizhou Dong, Shu-Bing Qian.

  The amino acid cysteine and its oxidized dimeric form cystine are commonly believed to be synonymous in metabolic functions. Cyst(e)ine depletion not only induces amino acid response but also triggers ferroptosis, a non-apoptotic cell death. Here, we report that unlike general amino acid starvation, cyst(e)ine deprivation triggers ATF4 induction at the transcriptional level. Unexpectedly, it is the shortage of lysosomal cystine, but not the cytosolic cysteine, that elicits the adaptative ATF4 response. The lysosome-nucleus signaling pathway involves the aryl hydrocarbon receptor (AhR) that senses lysosomal cystine via the kynurenine pathway. A blockade of lysosomal cystine efflux attenuates ATF4 induction and sensitizes ferroptosis. To potentiate ferroptosis in cancer, we develop a synthetic mRNA reagent, CysRx, that converts cytosolic cysteine to lysosomal cystine. CysRx maximizes cancer cell ferroptosis and effectively suppresses tumor growth in vivo. Thus, intracellular nutrient reprogramming has the potential to induce selective ferroptosis in cancer without systematic starvation.

Keywords:  AhR; cancer therapy; cysteine; cystine; ferroptosis; lysosome; mRNA; nutrient stress

DOI:  https://doi.org/10.1016/j.molcel.2023.08.004
Anal Chem. 2023 Aug 29.

A Reversible Fluorescent Probe for In Situ Monitoring Redox Imbalance during Mitophagy.

Junbin Li, Lifei Song, Weiguo Hu, Qin Zuo, Roumei Li, Min Dai, Yibo Zhou, Zhihe Qing.

Mitophagy is the lysosome-dependent degradation of damaged and dysfunctional mitochondria, which is closely associated with H2O2-related redox imbalance and pathological processes. However, development of fast-responding and highly sensitive reversible fluorescent probes for monitoring of mitochondrial H2O2 dynamics is still lacking. Herein, we report a reversible fluorescent probe (M-HP) that enables real-time imaging of H2O2-related redox imbalance. In vitro studies demonstrated that M-HP had a rapid response and high sensitivity to the H2O2/GSH redox cycle, with a detection limit of 17 nM for H2O2. M-HP was applied to imaging of H2O2 fluctuation in living cells with excellent reversibility and mitochondrial targeting. M-HP reveals an increase in mitochondrial H2O2 under lipopolysaccharide stimulation and a decrease in H2O2 following the combined treatment with rapamycin. This suggests that the level of oxidative stress is significantly suppressed after the enhancement of mitophagy. The rationally designed M-HP offers a powerful tool for understanding redox imbalance during mitophagy.

DOI: https://doi.org/10.1021/acs.analchem.3c02717
Nat Metab. 2023 Aug 31.

A defect in mitochondrial fatty acid synthesis impairs iron metabolism and causes elevated ceramide levels.

Undiagnosed Diseases Network

In most eukaryotic cells, fatty acid synthesis (FAS) occurs in the cytoplasm and in mitochondria. However, the relative contribution of mitochondrial FAS (mtFAS) to the cellular lipidome is not well defined. Here we show that loss of function of Drosophila mitochondrial enoyl coenzyme A reductase (Mecr), which is the enzyme required for the last step of mtFAS, causes lethality, while neuronal loss of Mecr leads to progressive neurodegeneration. We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative phenotypes, indicating an interplay between ceramide and iron metabolism. Mutations in human MECR cause pediatric-onset neurodegeneration, and we show that human-derived fibroblasts display similar elevated ceramide levels and impaired iron homeostasis. In summary, this study identifies a role of mecr/MECR in ceramide and iron metabolism, providing a mechanistic link between mtFAS and neurodegeneration.

DOI: https://doi.org/10.1038/s42255-023-00873-0
Nature. 2023 Aug 30.

Identification of an alternative triglyceride biosynthesis pathway.

Gian-Luca McLelland, Marta Lopez-Osias, Cristy R C Verzijl, Brecht D Ellenbroek, Rafaela A Oliveira, Nicolaas J Boon, Marleen Dekker, Lisa G van den Hengel, Rahmen Ali, Hans Janssen, Ji-Ying Song, Paul Krimpenfort, Tim van Zutphen, Johan W Jonker, Thijn R Brummelkamp.

Triacylglycerols (TAGs) are the main source of stored energy in the body, providing an important substrate pool for mitochondrial beta-oxidation. Imbalances in the amount of TAGs are associated with obesity, cardiac disease and various other pathologies1,2. In humans, TAGs are synthesized from excess, coenzyme A-conjugated fatty acids by diacylglycerol O-acyltransferases (DGAT1 and DGAT2)3. In other organisms, this activity is complemented by additional enzymes4, but whether such alternative pathways exist in humans remains unknown. Here we disrupt the DGAT pathway in haploid human cells and use iterative genetics to reveal an unrelated TAG-synthesizing system composed of a protein we called DIESL (also known as TMEM68, an acyltransferase of previously unknown function) and its regulator TMX1. Mechanistically, TMX1 binds to and controls DIESL at the endoplasmic reticulum, and loss of TMX1 leads to the unconstrained formation of DIESL-dependent lipid droplets. DIESL is an autonomous TAG synthase, and expression of human DIESL in Escherichia coli endows this organism with the ability to synthesize TAG. Although both DIESL and the DGATs function as diacylglycerol acyltransferases, they contribute to the cellular TAG pool under specific conditions. Functionally, DIESL synthesizes TAG at the expense of membrane phospholipids and maintains mitochondrial function during periods of extracellular lipid starvation. In mice, DIESL deficiency impedes rapid postnatal growth and affects energy homeostasis during changes in nutrient availability. We have therefore identified an alternative TAG biosynthetic pathway driven by DIESL under potent control by TMX1.

DOI: https://doi.org/10.1038/s41586-023-06497-4