bims-mibica 2022-02-27 papers

bims-mibica

Biomed News

on Mitochondrial bioenergetics in cancer

Issue of 2022‒02‒27
forty papers selected by
Kelsey Fisher-Wellman, East Carolina University

ATP Synthase K+- and H+-fluxes Drive ATP Synthesis and Enable Mitochondrial K+-"Uniporter" Function: II. Ion and ATP Synthase Flux Regulation.
Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance.
Redox-Based Strategy for Selectively Inducing Energy Crisis Inside Cancer Cells: An Example of Modifying Dietary Curcumin to Target Mitochondria.
Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas.
Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency.
Deciphering the Heterogeneity of Mitochondrial Functions During Hematopoietic Lineage Differentiation.
Genetic BACH1 deficiency alters mitochondrial function and increases NLRP3 inflammasome activation in mouse macrophages.
Over-Reduced State of Mitochondria as a Trigger of "β-Oxidation Shuttle" in Cancer Cells.
Intravenous nicotinamide riboside elevates mouse skeletal muscle NAD+ without impacting respiratory capacity or insulin sensitivity.
Cancer/Testis Antigen 55 is required for cancer cell proliferation and mitochondrial DNA maintenance.
Overexpression of SLC25A51 promotes hepatocellular carcinoma progression by driving aerobic glycolysis through activation of SIRT5.
Increased Drp1 promotes autophagy and ESCC progression by mtDNA stress mediated cGAS-STING pathway.
Iron supplementation is sufficient to rescue skeletal muscle mass and function in cancer cachexia.
Genome-wide CRISPR screen identifies synthetic lethality between DOCK1 inhibition and metformin in liver cancer.
Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia.
Mitochondria in tumour progression: a network of mtDNA variants in different types of cancer.
PPARγ/SOD2 Protects Against Mitochondrial ROS-Dependent Apoptosis via Inhibiting ATG4D-Mediated Mitophagy to Promote Pancreatic Cancer Proliferation.
Effects of Cell Density and Microenvironment on Stem Cell Mitochondria Transfer among Human Adipose-Derived Stem Cells and HEK293 Tumorigenic Cells.
IL-9/STAT3/fatty acid oxidation-mediated lipid peroxidation contributes to Tc9 cell longevity and enhanced antitumor activity.
The new mitochondrial uncoupler BAM15 induces ROS production for treatment of acute myeloid leukemia.
Mitochondrial Function Differences between Tumor Tissue of Human Metastatic and Premetastatic CRC.
Inhibition of LDHA suppresses cell proliferation and increases mitochondrial apoptosis via the JNK signaling pathway in cervical cancer cells.
Mitochondrial Transplantation for Organ Rescue.
Hemojuvelin deficiency promotes liver mitochondrial dysfunction and predisposes mice to hepatocellular carcinoma.
A functional screen with metformin identifies microRNAs that regulate metabolism in colorectal cancer cells.
Mitochondrial variant enrichment from high-throughput single-cell RNA sequencing resolves clonal populations.
T1121G Point Mutation in the Mitochondrial Gene COX1 Suppresses a Null Mutation in ATP23 Required for the Assembly of Yeast Mitochondrial ATP Synthase.
Knockdown of mitochondrial threonyl-tRNA synthetase 2 inhibits lung adenocarcinoma cell proliferation and induces apoptosis.
Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer.
Mechanisms of mitochondrial promoter recognition in humans and other mammalian species.
Mitochondrial COA7 is a heme-binding protein with disulfide reductase activity, which acts in the early stages of complex IV assembly.
Mitochondrial Transplantation Enhances Phagocytic Function and Decreases Lipid Accumulation in Foam Cell Macrophages.
Identification of Novel Mitochondrial Pyruvate Carrier Inhibitors by Homology Modeling and Pharmacophore-Based Virtual Screening.
Metabolic profiling of prostate cancer in skeletal microenvironments identifies G6PD as a key mediator of growth and survival.
Effective drug combinations in breast, colon and pancreatic cancer cells.
Fumarate inhibits PTEN to promote tumorigenesis and therapeutic resistance of type2 papillary renal cell carcinoma.
Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology.
Bcl-2 Family Members and the Mitochondrial Import Machineries: The Roads to Death.
Coenzyme Q10 and related quinones oxidize H2S to polysulfides and thiosulfate.
Phosphoproteomic profiling of T cell acute lymphoblastic leukemia reveals targetable kinases and combination treatment strategies.

Function (Oxf). 2022 ;3(2): zqac001

ATP Synthase K+- and H+-fluxes Drive ATP Synthesis and Enable Mitochondrial K+-"Uniporter" Function: II. Ion and ATP Synthase Flux Regulation.

Magdalena Juhaszova, Evgeny Kobrinsky, Dmitry B Zorov, H Bradley Nuss, Yael Yaniv, Kenneth W Fishbein, Rafael de Cabo, Lluis Montoliu, Sandra B Gabelli, Miguel A Aon, Sonia Cortassa, Steven J Sollott.

  We demonstrated that ATP synthase serves the functions of a primary mitochondrial K+ "uniporter," i.e., the primary way for K+ to enter mitochondria. This K+ entry is proportional to ATP synthesis, regulating matrix volume and energy supply-vs-demand matching. We show that ATP synthase can be upregulated by endogenous survival-related proteins via IF1. We identified a conserved BH3-like domain of IF1 which overlaps its "minimal inhibitory domain" that binds to the β-subunit of F1. Bcl-xL and Mcl-1 possess a BH3-binding-groove that can engage IF1 and exert effects, requiring this interaction, comparable to diazoxide to augment ATP synthase's H+ and K+ flux and ATP synthesis. Bcl-xL and Mcl-1, but not Bcl-2, serve as endogenous regulatory ligands of ATP synthase via interaction with IF1 at this BH3-like domain, to increase its chemo-mechanical efficiency, enabling its function as the recruitable mitochondrial KATP-channel that can limit ischemia-reperfusion injury. Using Bayesian phylogenetic analysis to examine potential bacterial IF1-progenitors, we found that IF1 is likely an ancient (∼2 Gya) Bcl-family member that evolved from primordial bacteria resident in eukaryotes, corresponding to their putative emergence as symbiotic mitochondria, and functioning to prevent their parasitic ATP consumption inside the host cell.

Keywords:  ATP synthase regulation; ATPase Inhibitory Factor-1 (IF₁); Bcl-2 family proteins; mitochondrial permeability transition pore; mitochondrial potassium transport; volume regulation

DOI:  https://doi.org/10.1093/function/zqac001
J Clin Invest. 2022 Feb 24. pii: e148852. [Epub ahead of print]

Brown adipose TRX2 deficiency activates mtDNA-NLRP3 to impair thermogenesis and protect against diet-induced insulin resistance.

Yanrui Huang, Jenny H Zhou, Haifeng Zhang, Alberto Canfrán-Duque, Abhishek K Singh, Rachel J Perry, Gerald Shulman, Carlos Fernandez-Hernando, Wang Min.

  Brown adipose tissue (BAT), a crucial heat-generating organ, regulate whole-body energy metabolism by mediating thermogenesis. BAT inflammation is implicated in the pathogenesis of mitochondrial dysfunction and impaired thermogenesis. However, the link between BAT inflammation and systematic metabolism remains unclear. Herein, we use mice with BAT deficiency of thioredoxin-2 (TRX2), a protein that scavenges mitochondrial reactive oxygen species (ROS), to evaluate the impact of BAT inflammation on metabolism and thermogenesis and its underlying mechanism. Our results describe that BAT-specific TRX2 ablation improves systematic metabolic performance via enhancing lipid uptake, which protects mice from diet-induced obesity, hypertriglyceridemia, and insulin resistance. TRX2 deficiency impairs adaptive thermogenesis by suppressing fatty acid oxidation. Mechanistically, loss of TRX2 induces excessive mitochondrial ROS, mitochondrial integrity disruption, and cytosolic release of mitochondrial DNA, which in turn activate aberrant innate immune responses in BAT, including the cGAS-STING and the NLRP3 inflammasome pathways. We identify NLRP3 as a key converging point, as its inhibition reverses both the thermogenesis defect and the metabolic benefits seen under nutrient overload in BAT-specific Trx2-deficient mice. In conclusion, we identify TRX2 as a critical hub integrating oxidative stress, inflammation, and lipid metabolism in BAT; uncovering an adaptive mechanism underlying the link between BAT inflammation and systematic metabolism.

Keywords:  Adipose tissue; Inflammation; Innate immunity; Metabolism; Mitochondria

DOI:  https://doi.org/10.1172/JCI148852
J Agric Food Chem. 2022 Feb 25.

Redox-Based Strategy for Selectively Inducing Energy Crisis Inside Cancer Cells: An Example of Modifying Dietary Curcumin to Target Mitochondria.

Ya-Long Zheng, Zhi-Shan Tu, Hong-Mei Cui, Shuai Yan, De-Chen Duan, Wei Tang, Fang Dai, Bo Zhou.

  Reprograming of energy metabolism is a major hallmark of cancer, but its effective intervention is still a challenging task due to metabolic heterogeneity and plasticity of cancer cells. Herein, we report a general redox-based strategy for meeting the challenge. The strategy was exemplified by a dietary curcumin analogue (MitoCur-1) that was designed to target mitochondria (MitoCur-1). By virtue of its electrophilic and mitochondrial-targeting properties, MitoCur-1 generated reactive oxygen species (ROS) more effectively and selectively in HepG2 cells than in L02 cells via the inhibition of mitochondrial antioxidative thioredoxin reductase 2 (TrxR2). The ROS generation preferentially mediated the energy crisis of HepG2 cells in a dual-inhibition fashion against both mitochondrial and glycolytic metabolisms, which could hit the metabolic plasticity of HepG2 cells. The ROS-dependent energy crisis also allowed its preferential killing of HepG2 cells (IC50 = 1.4 μM) over L02 cells (IC50 = 9.1 μM), via induction of cell-cycle arrest, apoptosis and autophagic death, and its high antitumor efficacy in vivo, in nude mice bearing HepG2 tumors (15 mg/kg). These results highlight that inhibiting mitochondrial TrxR2 to produce ROS by electrophiles is a promising redox-based strategy for the effective intervention of cancer cell energy metabolic reprograming.

Keywords:  curcumin; metabolic reprograming; mitochondria; reactive oxygen species; thioredoxin reductase

DOI:  https://doi.org/10.1021/acs.jafc.1c07690
Cancer Metab. 2022 Feb 22. 10(1): 6

Combined inhibition of HMGCoA reductase and mitochondrial complex I induces tumor regression of BRAF inhibitor-resistant melanomas.

Evelyn de Groot, Sruthy Varghese, Lin Tan, Barbara Knighton, Mary Sobieski, Nghi Nguyen, Yong Sung Park, Reid Powell, Philip L Lorenzi, Bin Zheng, Clifford Stephan, Y N Vashisht Gopal.

  BACKGROUND: Primary and posttreatment resistance to BRAFV600 mutation-targeting inhibitors leads to disease relapse in a majority of melanoma patients. In many instances, this resistance is promoted by upregulation of mitochondrial oxidative phosphorylation (OxPhos) in melanoma cells. We recently showed that a novel electron transport chain (ETC) complex I inhibitor, IACS-010759 (IACS), abolished OxPhos and significantly inhibited tumor growth of high-OxPhos, BRAF inhibitor (BRAFi)-resistant human melanomas. However, the inhibition was not uniform across different high OxPhos melanomas, and combination with BRAFi did not improve efficacy.METHODS: We performed a high-throughput unbiased combinatorial drug screen of clinically relevant small molecules to identify the most potent combination agent with IACS for inhibiting the growth of high-OxPhos, BRAFi-resistant melanomas. We performed bioenergetics and carbon-13 metabolite tracing to delineate the metabolic basis of sensitization of melanomas to the combination treatment. We performed xenograft tumor growth studies and Reverse-Phase Protein Array (RPPA)-based functional proteomics analysis of tumors from mice fed with regular or high-fat diet to evaluate in vivo molecular basis of sensitization to the combination treatment.
RESULTS: A combinatorial drug screen and subsequent validation studies identified Atorvastatin (STN), a hydroxymethylglutaryl-coenzyme A reductase inhibitor (HMGCRi), as the most potent treatment combination with IACS to inhibit in vitro cell growth and induce tumor regression or stasis of some BRAFi-resistant melanomas. Bioenergetics analysis revealed a dependence on fatty acid metabolism in melanomas that responded to the combination treatment. RPPA analysis and carbon-13 tracing analysis in these melanoma cells showed that IACS treatment decreased metabolic fuel utilization for fatty acid metabolism, but increased substrate availability for activation of the mevalonate pathway by HMGCR, creating a dependence on this pathway. Functional proteomic analysis showed that IACS treatment inhibited MAPK but activated AKT pathway. Combination treatment with STN counteracted AKT activation.
CONCLUSIONS: STN and other clinically approved HMGCRi could be promising combinatorial agents for improving the efficacy of ETC inhibitors like IACS in BRAFi-resistant melanomas.

Keywords:  Fatty acid metabolism; HMGCoA reductase; Melanoma; Oxidative phosphorylation; Statin; Therapeutic resistance

DOI:  https://doi.org/10.1186/s40170-022-00281-0
Elife. 2022 02 21. pii: e72595. [Epub ahead of print]11

Paradoxical neuronal hyperexcitability in a mouse model of mitochondrial pyruvate import deficiency.

Andres De La Rossa, Marine H Laporte, Simone Astori, Thomas Marissal, Sylvie Montessuit, Preethi Sheshadri, Eva Ramos-Fernández, Pablo Mendez, Abbas Khani, Charles Quairiaux, Eric B Taylor, Jared Rutter, José Manuel Nunes, Alan Carleton, Michael R Duchen, Carmen Sandi, Jean-Claude Martinou.

  Neuronal excitation imposes a high demand of ATP in neurons. Most of the ATP derives primarily from pyruvate-mediated oxidative phosphorylation, a process that relies on import of pyruvate into mitochondria occuring exclusively via the mitochondrial pyruvate carrier (MPC). To investigate whether deficient oxidative phosphorylation impacts neuron excitability, we generated a mouse strain carrying a conditional deletion of MPC1, an essential subunit of the MPC, specifically in adult glutamatergic neurons. We found that, despite decreased levels of oxidative phosphorylation and decreased mitochondrial membrane potential in these excitatory neurons, mice were normal at rest. Surprisingly, in response to mild inhibition of GABA mediated synaptic activity, they rapidly developed severe seizures and died, whereas under similar conditions the behavior of control mice remained unchanged. We report that neurons with a deficient MPC were intrinsically hyperexcitable as a consequence of impaired calcium homeostasis, which reduced M-type potassium channel activity. Provision of ketone bodies restored energy status, calcium homeostasis and M-channel activity and attenuated seizures in animals fed a ketogenic diet. Our results provide an explanation for the seizures that frequently accompany a large number of neuropathologies, including cerebral ischemia and diverse mitochondriopathies, in which neurons experience an energy deficit.

Keywords:  calcium; kcnq kv.7 channel; ketogenic diet; metabolism; mitochondrial pyruvate carrier; mouse; neuronal excitability; neuroscience

DOI:  https://doi.org/10.7554/eLife.72595
Stem Cell Rev Rep. 2022 Feb 21.

Deciphering the Heterogeneity of Mitochondrial Functions During Hematopoietic Lineage Differentiation.

Haoyue Liang, Shuxu Dong, Weichao Fu, Sen Zhang, Wenying Yu, Fang Dong, Baolin He, Jinhong Wang, Yingdai Gao, Yuan Zhou, Yongxin Ru.

  BACKGROUND: The heterogeneity of mitochondrial function is an important feature of hematopoietic cell lineage differentiation, but its stage wise contribution is not adequately studied. To establish a model to compare the lineage differentiation of hematopoietic stem cells (HSCs), hematopoietic progenitor cells (HPCs), and differentiated blood cells, the mitochondrial mass (MM), mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and mitophagy level were analyzed.RESULTS AND DISCUSSION: HSCs had lower mitochondrial metabolic activity than committed progenitor populations, indicated by lower MM, MMP, and ROS and higher mitophagy. HPC1s shared more stem cell characteristics than HPC2s and committed progenitor populations in terms of mitochondrial number and function. The mitochondrial metabolism of mature blood cells had greater heterogeneity than hematopoietic stem and progenitor cells, with granulocytes being similar to monocytes. Moreover, HSCs exhibited heterogeneity in the selection of mitophagy-related PINK1/PARK2, BNIP3/NIX, and FUNDC1 pathways. Myeloid differentiation had greater morphological and functional heterogeneity of hematopoietic cells than lymphoid differentiation. Additionally, leukemia stem cells had higher aerobic metabolism and better stem cell function through elevated mitophagy than normal hematopoietic cells. ROS and MMP levels in differentiated leukemia cells were higher, but the level of mitophagy was lower than in differentiated hematopoietic cells.
CONCLUSION: This study provides a complete set of methods and basic reference values for the systematic study of the mitochondrial metabolic function of different types of hematopoietic cells under physiological and pathological conditions. The findings contribute to the future research of tumor and aging based on mitochondrial metabolism.

Keywords:  Hematopoietic cell; Lineage differentiation; Metabolic map; Mitochondrial function; Mitophagy

DOI:  https://doi.org/10.1007/s12015-022-10354-8
Redox Biol. 2022 Feb 10. pii: S2213-2317(22)00037-4. [Epub ahead of print]51 102265

Genetic BACH1 deficiency alters mitochondrial function and increases NLRP3 inflammasome activation in mouse macrophages.

Pooja Pradhan, Vijith Vijayan, Karsten Cirksena, Falk F R Buettner, Kazuhiko Igarashi, Roberto Motterlini, Roberta Foresti, Stephan Immenschuh.

  BTB-and-CNC homologue 1 (BACH1), a heme-regulated transcription factor, mediates innate immune responses via its functional role in macrophages. BACH1 has recently been shown to modulate mitochondrial metabolism in cancer cells. In the current study, we utilized a proteomics approach and demonstrate that genetic deletion of BACH1 in mouse macrophages is associated with decreased levels of various mitochondrial proteins, particularly mitochondrial complex I. Bioenergetic studies revealed alterations of mitochondrial energy metabolism in BACH1-/- macrophages with a shift towards increased glycolysis and decreased oxidative phosphorylation. Moreover, these cells exhibited enhanced mitochondrial membrane potential and generation of mitochondrial reactive oxygen species (mtROS) along with lower levels of mitophagy. Notably, a higher inducibility of NLRP3 inflammasome activation in response to ATP and nigericin following challenge with lipopolysaccharide (LPS) was observed in BACH1-deficient macrophages compared to wild-type cells. Mechanistically, pharmacological inhibition of mtROS markedly attenuated inflammasome activation. In addition, it is shown that inducible nitric oxide synthase and cyclooxygenase-2, both of which are markedly induced by LPS in macrophages, are directly implicated in BACH1-dependent regulation of NLRP3 inflammasome activation. Taken together, the current findings indicate that BACH1 is critical for immunomodulation of macrophages and may serve as a target for therapeutic approaches in inflammatory disorders.

Keywords:  BACH1; Inflammation; Macrophages; Mitochondrial complex 1; Mitochondrial metabolism; NLRP3 inflammasome

DOI:  https://doi.org/10.1016/j.redox.2022.102265
Cancers (Basel). 2022 Feb 10. pii: 871. [Epub ahead of print]14(4):

Over-Reduced State of Mitochondria as a Trigger of "β-Oxidation Shuttle" in Cancer Cells.

Zhivko Zhelev, Akira Sumiyoshi, Ichio Aoki, Dessislava Lazarova, Tatyana Vlaykova, Tatsuya Higashi, Rumiana Bakalova.

  A considerable amount of data have accumulated in the last decade on the pronounced mitochondrial fatty acid oxidation (mFAO) in many types of cancer cells. As a result, mFAO was found to coexist with abnormally activated fatty acid synthesis (FAS) and the mevalonate pathway. Recent studies have demonstrated that overactivated mitochondrial β-oxidation may aggravate the impaired mitochondrial redox state and vice versa. Furthermore, the impaired redox state of cancerous mitochondria can ensure the continuous operation of β-oxidation by disconnecting it from the Krebs cycle and connecting it to the citrate-malate shuttle. This could create a new metabolic state/pathway in cancer cells, which we have called the "β-oxidation-citrate-malate shuttle", or "β-oxidation shuttle" for short, which forces them to proliferate. The calculation of the phosphate/oxygen ratio indicates that it is inefficient as an energy source and must consume significantly more oxygen per mole of ATP produced when combined with acetyl-CoA consuming pathways, such as the FAS and mevalonate pathways. The "β-oxidation shuttle" is an unconventional mFAO, a separate metabolic pathway that has not yet been explored as a source of energy, as well as a source of cataplerosis, leading to biomass accumulation, accelerated oxygen consumption, and, ultimately, a source of proliferation. The role of the "β-oxidation shuttle" and its contribution to redox-altered cancer metabolism provides a new direction for the development of future anticancer strategies. This may represent the metabolic "secret" of cancer underlying hypoxia and genomic instability.

Keywords:  cancer; metabolism; mitochondrial fatty acid oxidation; β-oxidation shuttle

DOI:  https://doi.org/10.3390/cancers14040871
iScience. 2022 Feb 18. 25(2): 103863

Intravenous nicotinamide riboside elevates mouse skeletal muscle NAD+ without impacting respiratory capacity or insulin sensitivity.

Mads V Damgaard, Thomas S Nielsen, Astrid L Basse, Sabina Chubanava, Kajetan Trost, Thomas Moritz, Ryan W Dellinger, Steen Larsen, Jonas T Treebak.

  In clinical trials, oral supplementation with nicotinamide riboside (NR) fails to increase muscle mitochondrial respiratory capacity and insulin sensitivity but also does not increase muscle NAD+ levels. This study tests the feasibility of chronically elevating skeletal muscle NAD+ in mice and investigates the putative effects on mitochondrial respiratory capacity, insulin sensitivity, and gene expression. Accordingly, to improve bioavailability to skeletal muscle, we developed an experimental model for administering NR repeatedly through a jugular vein catheter. Mice on a Western diet were treated with various combinations of NR, pterostilbene (PT), and voluntary wheel running, but the metabolic effects of NR and PT treatment were modest. We conclude that the chronic elevation of skeletal muscle NAD+ by the intravenous injection of NR is possible but does not affect muscle respiratory capacity or insulin sensitivity in either sedentary or physically active mice. Our data have implications for NAD+ precursor supplementation regimens.

Keywords:  Drugs; Molecular physiology; Transcriptomics

DOI:  https://doi.org/10.1016/j.isci.2022.103863
Mitochondrion. 2022 Feb 18. pii: S1567-7249(22)00012-5. [Epub ahead of print]

Cancer/Testis Antigen 55 is required for cancer cell proliferation and mitochondrial DNA maintenance.

Jade Aurrière, David Goudenege, Simone A Baechler, Shar-Yin N Huang, Naig Gueguen, Valerie Desquiret-Dumas, Floris Chabrun, Rodolphe Perrot, Arnaud Chevrollier, Majida Charif, Olivier Baris, Yves Pommier, Guy Lenaers, Salim Khiati.

  Cancer/Testis Antigens (CTAs) represent a group of proteins whose expression under physiological conditions is restricted to testis but activated in many human cancers. Also, it was observed that co-expression of multiple CTAs worsens the patient prognosis. Five CTAs were reported acting in mitochondria and we recently reported 147 transcripts encoded by 67 CTAs encoding for proteins potentially targeted to mitochondria. Among them, we identified the two isoforms encoded by CT55 for whom the function is poorly understood. First, we found that patients with tumors expressing wild-type CT55 are associated with poor survival. Moreover, CT55 silencing decreases dramatically cell proliferation. Second, to investigate the role of CT55 on mitochondria, we first show that CT55 is localized to both mitochondria and endoplasmic reticulum (ER) due to the presence of an ambiguous N-terminal targeting signal. Then, we show that CT55 silencing decreases mtDNA copy number and delays mtDNA recovery after an acute depletion. Moreover, demethylation of CT55 promotor increases its expression, which in turn increases mtDNA copy number. Finally, we measured the mtDNA copy number in NCI-60 cell lines and screened for genes whose expression is strongly correlated to mtDNA amount. We identified CT55 as the second highest correlated hit. Also, we show that compared to siRNA scrambled control (siCtrl) treatment, CT55 specific siRNA (siCT55) treatment down-regulates aerobic respiration, indicating that CT55 sustains mitochondrial respiration. Altogether, these data show for first time that CT55 acts on mtDNA copy number, modulates mitochondrial activity to sustain cancer cell proliferation.

Keywords:  CT55; NCI-60; cell proliferation; mitochondrial DNA

DOI:  https://doi.org/10.1016/j.mito.2022.02.005
Free Radic Biol Med. 2022 Feb 16. pii: S0891-5849(22)00067-3. [Epub ahead of print]182 11-22

Overexpression of SLC25A51 promotes hepatocellular carcinoma progression by driving aerobic glycolysis through activation of SIRT5.

Lu Bai, Zhao-Xu Yang, Peng-Fei Ma, Jian-Shan Liu, De-Sheng Wang, Heng-Chao Yu.

  Solute carrier family 25 member 20 (SLC25A51) is a newly identified mammalian mitochondrial NAD+ transporter. However, the clinicopathological and biological significance of SLC25A51 in human cancers, including hepatocellular carcinoma (HCC), remains unclear. The aim of this study was to define the role of SLC25A51 in HCC progression. Here we demonstrate that SLC25A51 is significantly overexpressed in human HCC specimens and cell lines, caused by, at least in partial, the decrease of miR-212-3p. SLC25A51 overexpression is positively correlated with the clinicopathological characteristics of vascular invasion and tumor diameter, as well as poor survival in patients with HCC. Knockdown of SLC25A51 attenuated, while overexpression of SLC25A51 enhanced the growth and metastasis of HCC cells both in vitro and in vivo. Mechanistically, glucose metabolism reprogramming from oxidative phosphorylation to glycolysis by activation of mitochondrial sirtuin 5 (SIRT5) was found to contribute to the promotion of growth and metastasis by SLC25A51 in HCC cells. Together, these findings reveal important roles of SLC25A51 in HCC tumorigenesis and suggest SLC25A51 as a promising prognostic marker and therapeutic target for treating HCC.

Keywords:  Glycolysis; Growth; HCC; Metastasis; SLC25A51

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.02.014
J Exp Clin Cancer Res. 2022 Feb 24. 41(1): 76

Increased Drp1 promotes autophagy and ESCC progression by mtDNA stress mediated cGAS-STING pathway.

Yujia Li, Hui Chen, Qi Yang, Lixin Wan, Jing Zhao, Yuanyuan Wu, Jiaxin Wang, Yating Yang, Menglan Niu, Hongliang Liu, Junqi Liu, Hushan Yang, Shaogui Wan, Yanming Wang, Dengke Bao.

  BACKGROUND: Mitochondrial dynamics homeostasis is important for cell metabolism, growth, proliferation, and immune responses. The critical GTPase for mitochondrial fission, Drp1 is frequently upregulated in many cancers and is closely implicated in tumorigenesis. However, the mechanism underling Drp1 to influence tumor progression is largely unknown, especially in esophageal squamous cell carcinoma (ESCC).METHODS: Immunohistochemistry was used to examine Drp1 and LC3B expression in tissues of ESCC patients. Autophagic vesicles were investigated by transmission electron microscopy. Fluorescent LC3B puncta and mitochondrial nucleoid were observed by fluorescent and confocal microscopy. Mitochondrial function was evaluated by mitochondrial membrane potential, ROS and ATP levels. Xenograft tumor model was performed in BALB/c nude mice to analyze the role of Drp1 on ESCC progression.
RESULTS: We found that Drp1 high expression is correlated with poor overall survival of ESCC patients. Drp1 overexpression promotes cell proliferation and xenograft ESCC tumor growth by triggering autophagy. Furthermore, we demonstrated that Drp1 overexpression disturbs mitochondrial function and subsequent induces mitochondrial DNA (mtDNA) released into the cytosol thereby inducing cytosolic mtDNA stress. Mechanistically, cytosolic mtDNA activates the cGAS-STING pathway and facilitates autophagy, which promotes ESCC cancer growth. Moreover, mtDNA digestion with DNase I and autophagy inhibition with chloroquine attenuates the cGAS-STING pathway activation and ESCC cancer growth.
CONCLUSIONS: Our finding reveals that Drp1 overexpression induces mitochondrial dysfunction and cytosolic mtDNA stress, which subsequently activates the cGAS-STING pathway, triggers autophagy and promotes ESCC progression.

Keywords:  Autophagy; Drp1; Esophageal Squamous Cell Carcinoma; Mitochondrial DNA stress; cGAS-STING signaling pathway

DOI:  https://doi.org/10.1186/s13046-022-02262-z
EMBO Rep. 2022 Feb 24. e53746

Iron supplementation is sufficient to rescue skeletal muscle mass and function in cancer cachexia.

Elisabeth Wyart, Myriam Y Hsu, Roberta Sartori, Erica Mina, Valentina Rausch, Elisa S Pierobon, Mariarosa Mezzanotte, Camilla Pezzini, Laure B Bindels, Andrea Lauria, Fabio Penna, Emilio Hirsch, Miriam Martini, Massimiliano Mazzone, Antonella Roetto, Simonetta Geninatti Crich, Hans Prenen, Marco Sandri, Alessio Menga, Paolo E Porporato.

  Cachexia is a wasting syndrome characterized by devastating skeletal muscle atrophy that dramatically increases mortality in various diseases, most notably in cancer patients with a penetrance of up to 80%. Knowledge regarding the mechanism of cancer-induced cachexia remains very scarce, making cachexia an unmet medical need. In this study, we discovered strong alterations of iron metabolism in the skeletal muscle of both cancer patients and tumor-bearing mice, characterized by decreased iron availability in mitochondria. We found that modulation of iron levels directly influences myotube size in vitro and muscle mass in otherwise healthy mice. Furthermore, iron supplementation was sufficient to preserve both muscle function and mass, prolong survival in tumor-bearing mice, and even rescues strength in human subjects within an unexpectedly short time frame. Importantly, iron supplementation refuels mitochondrial oxidative metabolism and energy production. Overall, our findings provide new mechanistic insights in cancer-induced skeletal muscle wasting, and support targeting iron metabolism as a potential therapeutic option for muscle wasting diseases.

Keywords:  cachexia; iron; metabolism; mitochondria; muscle

DOI:  https://doi.org/10.15252/embr.202153746
Protein Cell. 2022 Feb 26.

Genome-wide CRISPR screen identifies synthetic lethality between DOCK1 inhibition and metformin in liver cancer.

Junru Feng, Hui Lu, Wenhao Ma, Wenjing Tian, Zhuan Lu, Hongying Yang, Yongping Cai, Pengfei Cai, Yuchen Sun, Zilong Zhou, Jiaqian Feng, Jiazhong Deng, Ying Shu, Kun Qu, Weidong Jia, Ping Gao, Huafeng Zhang.

  Metformin is currently a strong candidate anti-tumor agent in multiple cancers. However, its anti-tumor effectiveness varies among different cancers or subpopulations, potentially due to tumor heterogeneity. It thus remains unclear which hepatocellular carcinoma (HCC) patient subpopulation(s) can benefit from metformin treatment. Here, through a genome-wide CRISPR-Cas9-based knockout screen, we find that DOCK1 levels determine the anti-tumor effects of metformin and that DOCK1 is a synthetic lethal target of metformin in HCC. Mechanistically, metformin promotes DOCK1 phosphorylation, which activates RAC1 to facilitate cell survival, leading to metformin resistance. The DOCK1-selective inhibitor, TBOPP, potentiates anti-tumor activity by metformin in vitro in liver cancer cell lines and patient-derived HCC organoids, and in vivo in xenografted liver cancer cells and immunocompetent mouse liver cancer models. Notably, metformin improves overall survival of HCC patients with low DOCK1 levels but not among patients with high DOCK1 expression. This study shows that metformin effectiveness depends on DOCK1 levels and that combining metformin with DOCK1 inhibition may provide a promising personalized therapeutic strategy for metformin-resistant HCC patients.

Keywords:  CRISPR screen; DOCK1; hepatocellular carcinoma; metformin; small GTPase

DOI:  https://doi.org/10.1007/s13238-022-00906-6
Signal Transduct Target Ther. 2022 02 21. 7(1): 51

Activation of RAS/MAPK pathway confers MCL-1 mediated acquired resistance to BCL-2 inhibitor venetoclax in acute myeloid leukemia.

Qi Zhang, Bridget Riley-Gillis, Lina Han, Yanan Jia, Alessia Lodi, Haijiao Zhang, Saravanan Ganesan, Rongqing Pan, Sergej N Konoplev, Shannon R Sweeney, Jeremy A Ryan, Yulia Jitkova, Kenneth Dunner, Shaun E Grosskurth, Priyanka Vijay, Sujana Ghosh, Charles Lu, Wencai Ma, Stephen Kurtz, Vivian R Ruvolo, Helen Ma, Connie C Weng, Cassandra L Ramage, Natalia Baran, Ce Shi, Tianyu Cai, Richard Eric Davis, Venkata L Battula, Yingchang Mi, Jing Wang, Courtney D DiNardo, Michael Andreeff, Jeffery W Tyner, Aaron Schimmer, Anthony Letai, Rose Ann Padua, Carlos E Bueso-Ramos, Stefano Tiziani, Joel Leverson, Relja Popovic, Marina Konopleva.

Despite high initial response rates, acute myeloid leukemia (AML) treated with the BCL-2-selective inhibitor venetoclax (VEN) alone or in combinations commonly acquires resistance. We performed gene/protein expression, metabolomic and methylation analyses of isogenic AML cell lines sensitive or resistant to VEN, and identified the activation of RAS/MAPK pathway, leading to increased stability and higher levels of MCL-1 protein, as a major acquired mechanism of VEN resistance. MCL-1 sustained survival and maintained mitochondrial respiration in VEN-RE cells, which had impaired electron transport chain (ETC) complex II activity, and MCL-1 silencing or pharmacologic inhibition restored VEN sensitivity. In support of the importance of RAS/MAPK activation, we found by single-cell DNA sequencing rapid clonal selection of RAS-mutated clones in AML patients treated with VEN-containing regimens. In summary, these findings establish RAS/MAPK/MCL-1 and mitochondrial fitness as key survival mechanisms of VEN-RE AML and provide the rationale for combinatorial strategies effectively targeting these pathways.

DOI: https://doi.org/10.1038/s41392-021-00870-3
BMC Genom Data. 2022 Feb 18. 23(1): 16

Mitochondria in tumour progression: a network of mtDNA variants in different types of cancer.

Giovanna C Cavalcante, Ândrea Ribeiro-Dos-Santos, Gilderlanio S de Araújo.

  BACKGROUND: Mitochondrial participation in tumorigenesis and metastasis has been studied for many years, but several aspects of this mechanism remain unclear, such as the association of mitochondrial DNA (mtDNA) with different cancers. Here, based on two independent datasets, we modelled an mtDNA mutation-cancer network by systematic integrative analysis including 37 cancer types to identify the mitochondrial variants found in common among them.RESULTS: Our network showed mtDNA associations between gastric cancer and other cancer types, particularly kidney, liver, and prostate cancers, which is suggestive of a potential role of such variants in the metastatic processes among these cancer types. A graph-based interactive web tool was made available at www2.lghm.ufpa.br/mtdna. We also highlighted that most shared variants were in the MT-ND4, MT-ND5 and D-loop, and that some of these variants were nonsynonymous, indicating a special importance of these variants and regions regarding cancer progression, involving genomic and epigenomic alterations.
CONCLUSIONS: This study reinforces the importance of studying mtDNA in cancer and offers new perspectives on the potential involvement of different mitochondrial variants in cancer development and metastasis.

Keywords:  Cancer; Genetic overlap; Interactive variant networks; Mitochondrial genome; Oxidative stress

DOI:  https://doi.org/10.1186/s12863-022-01032-2
Front Cell Dev Biol. 2021 ;9 745554

PPARγ/SOD2 Protects Against Mitochondrial ROS-Dependent Apoptosis via Inhibiting ATG4D-Mediated Mitophagy to Promote Pancreatic Cancer Proliferation.

Shuang Nie, Zhao Shi, Mengyue Shi, Hongzhen Li, Xuetian Qian, Chunyan Peng, Xiwei Ding, Shu Zhang, Ying Lv, Lei Wang, Bo Kong, Xiaoping Zou, Shanshan Shen.

  Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive disease with poor prognosis. Our previous study found that peroxisome proliferator activated receptor gamma (PPARγ) was capable of enhancing glycolysis in PDAC cells. However, whether PPARγ could promote PDAC progression remains unclear. In our present study, PPARγ was positively associated with tumor size and poor prognosis in PDAC patients. Functional assays demonstrated that PPARγ could promote the proliferation of pancreatic cancer cells in vitro and in vivo. Additionally, flow cytometry results showed that PPARγ decreased mitochondrial reactive oxygen species (mitochondrial ROS) production, stabilized mitochondrial membrane potential (MMP) and inhibited cell apoptosis via up-regulating superoxide dismutase 2 (SOD2), followed by the inhibition of ATG4D-mediated mitophagy. Meanwhile, the activation of PPARγ might reduce pancreatic cancer cell stemness to improve PDAC chemosensitivity via down-regulating ATG4D. Thus, these results revealed that PPARγ/SOD2 might protect against mitochondrial ROS-dependent apoptosis via inhibiting ATG4D-mediated mitophagy to promote pancreatic cancer proliferation, further improving PDAC chemosensitivity.

Keywords:  ATG4D; PPARγ; SOD2; mitophagy; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.3389/fcell.2021.745554
Int J Mol Sci. 2022 Feb 11. pii: 2003. [Epub ahead of print]23(4):

Effects of Cell Density and Microenvironment on Stem Cell Mitochondria Transfer among Human Adipose-Derived Stem Cells and HEK293 Tumorigenic Cells.

Shalise A Burch, Carlos Luna Lopez.

  Stem cells (SC) are largely known for their potential to restore damaged tissue through various known mechanisms. Among these mechanisms is their ability to transfer healthy mitochondria to injured cells to rescue them. This mitochondrial transfer plays a critical role in the healing process. To determine the optimal parameters for inducing mitochondrial transfer between cells, we assessed mitochondrial transfer as a function of seeding density and in two-dimensional (2D) and semi three-dimensional (2.5D) culture models. Since mitochondrial transfer can occur through direct contact or secretion, the 2.5D culture model utilizes collagen to provide cells with a more physiologically relevant extracellular matrix and offers a more realistic representation of cell attachment and movement. Results demonstrate the dependence of mitochondrial transfer on cell density and the distance between donor and recipient cell. Furthermore, the differences found between the transfer of mitochondria in 2D and 2.5D microenvironments suggest an optimal mode of mitochondria transport. Using these parameters, we explored the effects on mitochondrial transfer between SCs and tumorigenic cells. HEK293 (HEK) is an immortalized cell line derived from human embryonic kidney cells which grow rapidly and form tumors in culture. Consequently, HEKs have been deemed tumorigenic and are widely used in cancer research. We observed mitochondrial transfer from SCs to HEK cells at significantly higher transfer rates when compared to a SC-SC co-culture system. Interestingly, our results also revealed an increase in the migratory ability of HEK cells when cultured with SCs. As more researchers find co-localization of stem cells and tumors in the human body, these results could be used to better understand their biological relationship and lead to enhanced therapeutic applications.

Keywords:  HEK293; adipose-derived stem cells; cancer; microenvironment; mitochondria; mitochondria transfer; tumor cells; tumorigenic cells

DOI:  https://doi.org/10.3390/ijms23042003
J Clin Invest. 2022 Feb 22. pii: e153247. [Epub ahead of print]

IL-9/STAT3/fatty acid oxidation-mediated lipid peroxidation contributes to Tc9 cell longevity and enhanced antitumor activity.

Liuling Xiao, Xingzhe Ma, Lingqun Ye, Pan Su, Wei Xiong, Enguang Bi, Qiang Wang, Miao Xian, Maojie Yang, Jianfei Qian, Qing Yi.

  CD8+ T cell longevity regulated by metabolic activity plays important roles in cancer immunotherapy. Although in vitro polarized, transferred IL-9-secreting CD8+ Tc9 cells exert greater persistence and antitumor efficacy than Tc1/CTL cells, the underlying mechanism remains unclear. Here, we show that tumor-infiltrating Tc9 cells display significantly lower lipid peroxidation than Tc1 cells in several mouse models, which is strongly correlated with their persistence. Using RNA-sequence and functional validation, we found that Tc9 cells exhibited unique lipid metabolic programs. Tc9 cell-derived IL-9 activated STAT3, upregulated fatty acid oxidation and mitochondrial activity, and rendered Tc9 cells with reduced lipid peroxidation and resistant to tumor or ROS induced ferroptosis in TME. IL-9 signal deficiency, inhibiting STAT3 or fatty acid oxidation increased lipid peroxidation and ferroptosis of Tc9 cells, resulting in impaired longevity and antitumor ability. Similarly, human Tc9 cells also possessed lower lipid peroxidation than Tc1 cells and tumor-infiltrating CD8+ T cells expressed lower IL-9 and higher lipid peroxidation- and ferroptosis-related genes than circulating CD8+ T cells in melanoma patients. This study indicates that lipid peroxidation regulates Tc9-cell longevity and antitumor effects via IL-9-STAT3-fatty acid oxidation pathway and regulating T-cell lipid peroxidation can be used to enhance T-cell based immunotherapy in human cancer.

Keywords:  Cancer immunotherapy; Fatty acid oxidation; Immunology; Metabolism; T cells

DOI:  https://doi.org/10.1172/JCI153247
Biochem Pharmacol. 2022 Feb 19. pii: S0006-2952(22)00042-9. [Epub ahead of print] 114948

The new mitochondrial uncoupler BAM15 induces ROS production for treatment of acute myeloid leukemia.

Zhen Xing Gao, Ze Long Cui, Min Ran Zhou, Yue Fu, Fen Liu, Lu Zhang, Sai Ma, Chun Yan Chen.

  Acute myeloid leukemia (AML) is a malignant proliferative disease of myeloid hematopoietic origin and cannot be treated appropriately at present. This is due to the fact that leukemia cells are not sensitive to some of the traditional chemotherapy drugs. Or some chemotherapeutic drugs are too toxic to normal cells, affecting their wide clinical application. In this study, we identified BAM15 as a novel mitochondrial uncoupling agent by screening a library of small molecule compounds that inhibit AML cell activity. BAM15 significantly inhibited proliferation and promoted apoptosis in AML cells while at the same time being less cytotoxic to normal cells. The mechanism may be related to the disturbance of the ROS production balance. In vivo investigations revealed that BAM15 effectively suppressed AML progression and prolonged the survival time of mice. In addition, we found that BAM15 can be used in combination with cytarabine to enhance its anti-cancer activity and inhibit the activity of primary cells in AML. Therefore, we identified BAM15 as a potential drug candidate for the treatment of AML.

Keywords:  BAM15; ROS; apoptosis; leukemia; primary cells; proliferation

DOI:  https://doi.org/10.1016/j.bcp.2022.114948
Biology (Basel). 2022 Feb 11. pii: 293. [Epub ahead of print]11(2):

Mitochondrial Function Differences between Tumor Tissue of Human Metastatic and Premetastatic CRC.

Reyniel Hernández-López, Margalida Torrens-Mas, Daniel G Pons, Maria M Company, Esther Falcó, Teresa Fernández, Javier M Ibarra de la Rosa, Pilar Roca, Jordi Oliver, Jorge Sastre-Serra.

  Most colorectal cancer (CRC) patients die as a consequence of metastasis. Mitochondrial dysfunction could enhance cancer development and metastatic progression. We aimed to evaluate the adaptations associated with mitochondrial function in tumor tissues from stages III and IV of human CRC and whether they could ultimately be used as a therapeutic target in metastatic colorectal cancer (mCRC). We analyzed the protein levels by Western blotting and the enzymatic activities of proteins involved in mitochondrial function, as well as the amount of mitochondrial DNA (mtDNA), by real-time PCR, analyzing samples of non-tumor adjacent tissue and tumor tissue from stages III and IV CRC patients without radio- or chemotherapy treatment prior to surgery. Our data indicate that the tumor tissue of pre-metastatic stage III CRC exhibited an oxidant metabolic profile very similar to the samples of non-tumor adjacent tissue of both stages. Notable differences in the protein expression levels of ATPase, IDH2, LDHA, and SIRT1, as well as mtDNA amount, were detected between the samples of non-tumor adjacent tissue and tumor tissue from metastatic CRC patients. These findings suggest a shift in the oxidative metabolic profile that takes place in the tumor tissue once the metastatic stage has been reached. Tumor tissue oxidative metabolism contributes to promote and maintain the metastatic phenotype, with evidence of mitochondrial function impairment in stage IV tumor tissue.

Keywords:  OXPHOS; colorectal cancer; metastatic cancer; mitochondrial function; mtDNA

DOI:  https://doi.org/10.3390/biology11020293
Oncol Rep. 2022 Apr;pii: 77. [Epub ahead of print]47(4):

Inhibition of LDHA suppresses cell proliferation and increases mitochondrial apoptosis via the JNK signaling pathway in cervical cancer cells.

Wenjing Zhang, Cui Wang, Xiaomei Hu, Yanzhen Lian, Caili Ding, Liang Ming.

  The Warburg effect or aerobic glycolysis is a hallmark of cancer. Lactate dehydrogenase (LDH), which catalyzes conversion of pyruvate into lactate, serves a critical role during Warburg effect. LDH A chain (LDHA), a member of the LDH family, is upregulated in multiple types of cancer and serves a vital role in tumor growth and progression. However, its expression and function in cervical cancer has not been characterized. The present study evaluated LDHA expression in The Cancer Genome Atlas database and found that LDHA was upregulated in cervical cancer compared with normal tissue. To clarify the role of LDHA in cervical cancer HeLa and SiHa cells, lentiviral shRNA was used to stably knockdown LDHA and oxamate, a small‑molecule inhibitor of LDHA, was used to inhibit the activity of LDHA. Glucose uptake assay, lactate production measurement and ATP detection assay demonstrated LDHA inhibition notably decreased glucose consumption, lactate production and ATP levels in both HeLa and SiHa cells. Furthermore, the effect of LDHA inhibition on cell proliferation, cell cycle and apoptosis was investigated by MTT, BrdU incorporation, colony formation assay, flow cytometry and western blotting; LDHA knockdown or oxamate treatment led to decreased cell proliferation and increased apoptosis. Inhibition of LDHA induced G2/M cell cycle arrest and activated the mitochondrial apoptosis pathway. Mechanistically, the JNK signaling pathway was key for LDHA inhibition‑mediated cell cycle arrest and apoptosis. Collectively, these results indicated that LDHA was involved in cervical cancer pathogenesis and may be a promising therapeutic target for treatment.

Keywords:  Warburg effect; apoptosis; cell proliferation; cervical cancer; lactate dehydrogenase A chain

DOI:  https://doi.org/10.3892/or.2022.8288
Mitochondrion. 2022 Feb 22. pii: S1567-7249(22)00020-4. [Epub ahead of print]

Mitochondrial Transplantation for Organ Rescue.

James D McCully, Pedro J Del Nido, Sitaram M Emani.

  Mitochondrial transplantation involves the replacement or augmentation of native mitochondria damaged, by ischemia, with viable, respiration-competent mitochondria isolated from non-ischemic tissue obtained from the patient's own body. The uptake and cellular functional integration of the transplanted mitochondria appears to occur in all cell types. Efficacy and safety have been demonstrated in cell culture, isolated perfused organ, in vivo large animal studies and in a first-human clinical study. Herein, we review our findings and provide insight for use in the treatment of organ ischemia- reperfusion injury.

Keywords:  Cardiac; Ischemia; Mitochondria; Reperfusion

DOI:  https://doi.org/10.1016/j.mito.2022.02.007
Commun Biol. 2022 02 22. 5(1): 153

Hemojuvelin deficiency promotes liver mitochondrial dysfunction and predisposes mice to hepatocellular carcinoma.

Abdolamir Allameh, Nico Hüttmann, Edouard Charlebois, Angeliki Katsarou, Wen Gu, Konstantinos Gkouvatsos, Elisa Pasini, Mamatha Bhat, Zoran Minic, Maxim Berezovski, Maria Guido, Carine Fillebeen, Kostas Pantopoulos.

Hemojuvelin (HJV) enhances signaling to the iron hormone hepcidin and its deficiency causes iron overload, a risk factor for hepatocellular carcinoma (HCC). We utilized Hjv-/- mice to dissect mechanisms for hepatocarcinogenesis. We show that suboptimal treatment with diethylnitrosamine (DEN) triggers HCC only in Hjv-/- but not wt mice. Liver proteomics data were obtained by mass spectrometry. Hierarchical clustering analysis revealed that Hjv deficiency and DEN elicit similar liver proteomic responses, including induction of mitochondrial proteins. Dietary iron overload of wt mice does not recapitulate the liver proteomic phenotype of Hjv-/- animals, which is only partially corrected by iron depletion. Consistent with these data, primary Hjv-/- hepatocytes exhibit mitochondrial hyperactivity, while aged Hjv-/- mice develop spontaneous HCC. Moreover, low expression of HJV or hepcidin (HAMP) mRNAs predicts poor prognosis in HCC patients. We conclude that Hjv has a hepatoprotective function and its deficiency in mice promotes mitochondrial dysfunction and hepatocarcinogenesis.

DOI: https://doi.org/10.1038/s42003-022-03108-2
Sci Rep. 2022 02 21. 12(1): 2889

A functional screen with metformin identifies microRNAs that regulate metabolism in colorectal cancer cells.

Ayla Orang, Saira R Ali, Janni Petersen, Ross A McKinnon, Amanda L Aloia, Michael Z Michael.

Metformin inhibits oxidative phosphorylation and can be used to dissect metabolic pathways in colorectal cancer (CRC) cells. CRC cell proliferation is inhibited by metformin in a dose dependent manner. MicroRNAs that regulate metabolism could be identified by their ability to alter the effect of metformin on CRC cell proliferation. An unbiased high throughput functional screen of a synthetic micoRNA (miRNA) library was used to identify miRNAs that impact the metformin response in CRC cells. Experimental validation of selected hits identified miRNAs that sensitize CRC cells to metformin through modulation of proliferation, apoptosis, cell-cycle and direct metabolic disruption. Among eight metformin sensitizing miRNAs identified by functional screening, miR-676-3p had both pro-apoptotic and cell cycle arrest activity in combination with metformin, whereas other miRNAs (miR-18b-5p, miR-145-3p miR-376b-5p, and miR-718) resulted primarily in cell cycle arrest when combined with metformin. Investigation of the combined effect of miRNAs and metformin on CRC cell metabolism showed that miR-18b-5p, miR-145-3p, miR-376b-5p, miR-676-3p and miR-718 affected glycolysis only, while miR-1181 only regulated CRC respiration. MicroRNAs can sensitize CRC cells to the anti-proliferative effects of metformin. Identifying relevant miRNA targets may enable the design of innovative therapeutic strategies.

DOI: https://doi.org/10.1038/s41598-022-06587-9
Nat Biotechnol. 2022 Feb 24.

Mitochondrial variant enrichment from high-throughput single-cell RNA sequencing resolves clonal populations.

Tyler E Miller, Caleb A Lareau, Julia A Verga, Erica A K DePasquale, Vincent Liu, Daniel Ssozi, Katalin Sandor, Yajie Yin, Leif S Ludwig, Chadi A El Farran, Duncan M Morgan, Ansuman T Satpathy, Gabriel K Griffin, Andrew A Lane, J Christopher Love, Bradley E Bernstein, Vijay G Sankaran, Peter van Galen.

The combination of single-cell transcriptomics with mitochondrial DNA variant detection can be used to establish lineage relationships in primary human cells, but current methods are not scalable to interrogate complex tissues. Here, we combine common 3' single-cell RNA-sequencing protocols with mitochondrial transcriptome enrichment to increase coverage by more than 50-fold, enabling high-confidence mutation detection. The method successfully identifies skewed immune-cell expansions in primary human clonal hematopoiesis.

DOI: https://doi.org/10.1038/s41587-022-01210-8
Int J Mol Sci. 2022 Feb 19. pii: 2327. [Epub ahead of print]23(4):

T1121G Point Mutation in the Mitochondrial Gene COX1 Suppresses a Null Mutation in ATP23 Required for the Assembly of Yeast Mitochondrial ATP Synthase.

Guangying Yang, Tong Zhao, Shan Lu, Jun Weng, Xiaomei Zeng.

  Nuclear-encoded Atp23 was previously shown to have dual functions, including processing the yeast Atp6 precursor and assisting the assembly of yeast mitochondrial ATP synthase. However, it remains unknown whether there are genes functionally complementary to ATP23 to rescue atp23 null mutant. In the present paper, we screen and characterize three revertants of atp23 null mutant and reveal a T1121G point mutation in the mitochondrial gene COX1 coding sequence, which leads to Val374Gly mutation in Cox1, the suppressor in the revertants. This was verified further by the partial restoration of mitochondrial ATP synthase assembly in atp23 null mutant transformed with exogenous hybrid COX1 T1121G mutant plasmid. The predicted tertiary structure of the Cox1 p.Val374Gly mutation showed no obvious difference from wild-type Cox1. By further chase labeling with isotope [35S]-methionine, we found that the stability of Atp6 of ATP synthase increased in the revertants compared with the atp23 null mutant. Taking all the data together, we revealed that the T1121G point mutation of mitochondrial gene COX1 could partially restore the unassembly of mitochondrial ATP synthase in atp23 null mutant by increasing the stability of Atp6. Therefore, this study uncovers a gene that is partially functionally complementary to ATP23 to rescue ATP23 deficiency, broadening our understanding of the relationship between yeast the cytochrome c oxidase complex and mitochondrial ATP synthase complex.

Keywords:  ATP23; COX1; mitochondrial ATP synthase; point mutation; revertant; stability of Atp6

DOI:  https://doi.org/10.3390/ijms23042327
Bioengineered. 2022 Mar;13(3): 5190-5204

Knockdown of mitochondrial threonyl-tRNA synthetase 2 inhibits lung adenocarcinoma cell proliferation and induces apoptosis.

Hui Tian, Hao Yan, Yong Zhang, Qiaofen Fu, Chunyan Li, Juan He, Hui Li, Yong Zhou, Youguang Huang, Rongqing Li.

Lung cancer is a significant global burden. Aminoacyl-tRNA synthetases (aaRSs) can be reliably identified by the occurrence and improvement of tumors. Threonyl-tRNA synthetase (TARS) and mitochondrial threonyl-tRNA synthetase 2 (TARS2) are both aaRSs. Many studies have shown that TARS are involved in tumor angiogenesis and metastasis. However, TARS2 has not yet been reported in tumors. This study explored the role of TARS2 in the proliferation and apoptosis of lung adenocarcinoma (LUAD). TARS2 expression in lung adenocarcinoma and non-cancerous lung tissues was detected via immunohistochemistry. Cell proliferation was detected using MTS, clone formation, and EdU staining assays. Flow cytometry was used to detect cell cycle, mitochondria reactive oxygen species (mROS) production, and apoptosis. Mitochondrial membrane potential (MMP ΔΨm) was detected using JC-1 fluorescent probes. Cell cycle, apoptosis-related pathway, and mitochondrial DNA (mtDNA) -encoded protein expression was detected via Western blotting. Finally, the effect of TARS2 on tumor growth was examined using a xenotransplanted tumor model in nude mice. We found that TARS2 was highly expressed in lung adenocarcinoma tissues and associated with poor overall survival (OS). Mechanistic analysis showed that knockdown of TARS2 inhibited proliferation through the retinoblastoma protein (RB) pathway and promoted mROS-induced apoptosis. Knockdown of TARS2 inhibits tumor growth in a xenotransplanted tumor model. TARS2 plays an important role in LUAD cell proliferation and apoptosis and may be a new therapeutic target.

DOI: https://doi.org/10.1080/21655979.2022.2037368
Proc Natl Acad Sci U S A. 2022 Feb 22. pii: e2107266119. [Epub ahead of print]119(8):

Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer.

Zuen Ren, Huizhi Liang, Phillip M Galbo, Malindrie Dharmaratne, Ameya S Kulkarni, Atefeh Taherian Fard, Marie Louise Aoun, Nuria Martinez-Lopez, Kimita Suyama, Outhiriaradjou Benard, Wei Zheng, Yang Liu, Joseph Albanese, Deyou Zheng, Jessica C Mar, Rajat Singh, Michael B Prystowsky, Larry Norton, Rachel B Hazan.

  In search of redox mechanisms in breast cancer, we uncovered a striking role for glutathione peroxidase 2 (GPx2) in oncogenic signaling and patient survival. GPx2 loss stimulates malignant progression due to reactive oxygen species/hypoxia inducible factor-α (HIF1α)/VEGFA (vascular endothelial growth factor A) signaling, causing poor perfusion and hypoxia, which were reversed by GPx2 reexpression or HIF1α inhibition. Ingenuity Pathway Analysis revealed a link between GPx2 loss, tumor angiogenesis, metabolic modulation, and HIF1α signaling. Single-cell RNA analysis and bioenergetic profiling revealed that GPx2 loss stimulated the Warburg effect in most tumor cell subpopulations, except for one cluster, which was capable of oxidative phosphorylation and glycolysis, as confirmed by coexpression of phosphorylated-AMPK and GLUT1. These findings underscore a unique role for redox signaling by GPx2 dysregulation in breast cancer, underlying tumor heterogeneity, leading to metabolic plasticity and malignant progression.

Keywords:  HIF1α; ROS signaling; breast cancer; glutathione peroxidase 2; metabolism

DOI:  https://doi.org/10.1073/pnas.2107266119
Nucleic Acids Res. 2022 Feb 22. pii: gkac103. [Epub ahead of print]

Mechanisms of mitochondrial promoter recognition in humans and other mammalian species.

Angelica Zamudio-Ochoa, Yaroslav I Morozov, Azadeh Sarfallah, Michael Anikin, Dmitry Temiakov.

Recognition of mammalian mitochondrial promoters requires the concerted action of mitochondrial RNA polymerase (mtRNAP) and transcription initiation factors TFAM and TFB2M. In this work, we found that transcript slippage results in heterogeneity of the human mitochondrial transcripts in vivo and in vitro. This allowed us to correctly interpret the RNAseq data, identify the bona fide transcription start sites (TSS), and assign mitochondrial promoters for > 50% of mammalian species and some other vertebrates. The divergent structure of the mammalian promoters reveals previously unappreciated aspects of mtDNA evolution. The correct assignment of TSS also enabled us to establish the precise register of the DNA in the initiation complex and permitted investigation of the sequence-specific protein-DNA interactions. We determined the molecular basis of promoter recognition by mtRNAP and TFB2M, which cooperatively recognize bases near TSS in a species-specific manner. Our findings reveal a role of mitochondrial transcription machinery in mitonuclear coevolution and speciation.

DOI: https://doi.org/10.1093/nar/gkac103
Proc Natl Acad Sci U S A. 2022 Mar 01. pii: e2110357119. [Epub ahead of print]119(9):

Mitochondrial COA7 is a heme-binding protein with disulfide reductase activity, which acts in the early stages of complex IV assembly.

Luke E Formosa, Shadi Maghool, Alice J Sharpe, Boris Reljic, Linden Muellner-Wong, David A Stroud, Michael T Ryan, Megan J Maher.

  Cytochrome c oxidase (COX) assembly factor 7 (COA7) is a metazoan-specific assembly factor, critical for the biogenesis of mitochondrial complex IV (cytochrome c oxidase). Although mutations in COA7 have been linked to complex IV assembly defects and neurological conditions such as peripheral neuropathy, ataxia, and leukoencephalopathy, the precise role COA7 plays in the biogenesis of complex IV is not known. Here, we show that loss of COA7 blocks complex IV assembly after the initial step where the COX1 module is built, progression from which requires the incorporation of copper and addition of the COX2 and COX3 modules. The crystal structure of COA7, determined to 2.4 Å resolution, reveals a banana-shaped molecule composed of five helix-turn-helix (α/α) repeats, tethered by disulfide bonds. COA7 interacts transiently with the copper metallochaperones SCO1 and SCO2 and catalyzes the reduction of disulfide bonds within these proteins, which are crucial for copper relay to COX2. COA7 binds heme with micromolar affinity, through axial ligation to the central iron atom by histidine and methionine residues. We therefore propose that COA7 is a heme-binding disulfide reductase for regenerating the copper relay system that underpins complex IV assembly.

Keywords:  COA7; X-ray crystallography; cytochrome c oxidase; heme; mitochondria

DOI:  https://doi.org/10.1073/pnas.2110357119
Biomedicines. 2022 Jan 30. pii: 329. [Epub ahead of print]10(2):

Mitochondrial Transplantation Enhances Phagocytic Function and Decreases Lipid Accumulation in Foam Cell Macrophages.

Soraya Játiva, Priscila Calle, Selene Torrico, Ángeles Muñoz, Miriam García, Ivet Martinez, Anna Sola, Georgina Hotter.

  Macrophages have mechanisms for eliminating cholesterol from cells. If excess cholesterol is not eliminated from the macrophages, then transformation into a foam cell may occur. Foam cells are a hallmark of the atherosclerotic lesions that contribute to the development and rupture of atherosclerotic plaques. Several in vitro and in vivo studies have shown changes in the macrophage phenotype and improved phagocytosis after the acquisition of functional mitochondria. However, the effect of mitochondrial transplantation on promoting phagocytosis and phenotypic changes in lipid-loaded macrophages leading to foam cells has not been studied. We aimed to prove that the transplantation of healthy mitochondria to highly cholesterol-loaded macrophages induces macrophage phagocytosis and reduces the macrophage shift towards foam cells. For this purpose, using a murine macrophage cell line, RAW264.7, we determined if mitochondria transplantation to 7-ketocholesterol (7-KC)-loaded macrophages reduced lipid accumulation and modified their phagocytic function. We evidenced that mitochondrial transplantation to 7-KC-loaded macrophages reestablished phagocytosis and reduced lipid content. In addition, CPT1a expression and anti-inflammatory cytokines were restored after mitochondrial transplantation. We have developed a potential therapeutic approach to restore foam cell functionality.

Keywords:  7-ketocholesterol; CPT1a; foam cell; inflammation; macrophage; phagocytosis

DOI:  https://doi.org/10.3390/biomedicines10020329
Biomedicines. 2022 Feb 02. pii: 365. [Epub ahead of print]10(2):

Identification of Novel Mitochondrial Pyruvate Carrier Inhibitors by Homology Modeling and Pharmacophore-Based Virtual Screening.

Lamees Hegazy, Lauren E Gill, Kelly D Pyles, Christopher Kaiho, Sophia Kchouk, Brian N Finck, Kyle S McCommis, Bahaa Elgendy.

  The mitochondrial pyruvate carrier (MPC) is an inner-mitochondrial membrane protein complex that has emerged as a drug target for treating a variety of human conditions. A heterodimer of two proteins, MPC1 and MPC2, comprises the functional MPC complex in higher organisms; however, the structure of this complex, including the critical residues that mediate binding of pyruvate and inhibitors, remain to be determined. Using homology modeling, we identified a putative substrate-binding cavity in the MPC dimer. Three amino acid residues (Phe66 (MPC1) and Asn100 and Lys49 (MPC2)) were validated by mutagenesis experiments to be important for substrate and inhibitor binding. Using this information, we developed a pharmacophore model and then performed a virtual screen of a chemical library. We identified five new non-indole MPC inhibitors, four with IC50 values in the nanomolar range that were up to 7-fold more potent than the canonical inhibitor UK-5099. These novel compounds possess drug-like properties and complied with Lipinski's Rule of Five. They are predicted to have good aqueous solubility, oral bioavailability, and metabolic stability. Collectively, these studies provide important information about the structure-function relationships of the MPC complex and for future drug discovery efforts targeting the MPC.

Keywords:  homology modeling; mitochondrial pyruvate carrier; mutagenesis; pharmacophore modeling; virtual screening

DOI:  https://doi.org/10.3390/biomedicines10020365
Sci Adv. 2022 Feb 25. 8(8): eabf9096

Metabolic profiling of prostate cancer in skeletal microenvironments identifies G6PD as a key mediator of growth and survival.

Jessica Whitburn, Srinivasa R Rao, Emma V Morris, Sho Tabata, Akiyoshi Hirayama, Tomoyoshi Soga, James R Edwards, Zeynep Kaya, Charlotte Palmer, Freddie C Hamdy, Claire M Edwards.

The spread of cancer to bone is invariably fatal, with complex cross-talk between tumor cells and the bone microenvironment responsible for driving disease progression. By combining in silico analysis of patient datasets with metabolomic profiling of prostate cancer cells cultured with bone cells, we demonstrate the changing energy requirements of prostate cancer cells in the bone microenvironment, identifying the pentose phosphate pathway (PPP) as elevated in prostate cancer bone metastasis, with increased expression of the PPP rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD) associated with a reduction in progression-free survival. Genetic and pharmacologic manipulation demonstrates that G6PD inhibition reduces prostate cancer growth and migration, associated with changes in cellular redox state and increased chemosensitivity. Genetic blockade of G6PD in vivo results in reduction of tumor growth within bone. In summary, we demonstrate the metabolic plasticity of prostate cancer cells in the bone microenvironment, identifying the PPP and G6PD as metabolic targets for the treatment of prostate cancer bone metastasis.

DOI: https://doi.org/10.1126/sciadv.abf9096
Nature. 2022 Feb 23.

Effective drug combinations in breast, colon and pancreatic cancer cells.

Patricia Jaaks, Elizabeth A Coker, Daniel J Vis, Olivia Edwards, Emma F Carpenter, Simonetta M Leto, Lisa Dwane, Francesco Sassi, Howard Lightfoot, Syd Barthorpe, Dieudonne van der Meer, Wanjuan Yang, Alexandra Beck, Tatiana Mironenko, Caitlin Hall, James Hall, Iman Mali, Laura Richardson, Charlotte Tolley, James Morris, Frances Thomas, Ermira Lleshi, Nanne Aben, Cyril H Benes, Andrea Bertotti, Livio Trusolino, Lodewyk Wessels, Mathew J Garnett.

Combinations of anti-cancer drugs can overcome resistance and provide new treatments1,2. The number of possible drug combinations vastly exceeds what could be tested clinically. Efforts to systematically identify active combinations and the tissues and molecular contexts in which they are most effective could accelerate the development of combination treatments. Here we evaluate the potency and efficacy of 2,025 clinically relevant two-drug combinations, generating a dataset encompassing 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines. We show that synergy between drugs is rare and highly context-dependent, and that combinations of targeted agents are most likely to be synergistic. We incorporate multi-omic molecular features to identify combination biomarkers and specify synergistic drug combinations and their active contexts, including in basal-like breast cancer, and microsatellite-stable or KRAS-mutant colon cancer. Our results show that irinotecan and CHEK1 inhibition have synergistic effects in microsatellite-stable or KRAS-TP53 double-mutant colon cancer cells, leading to apoptosis and suppression of tumour xenograft growth. This study identifies clinically relevant effective drug combinations in distinct molecular subpopulations and is a resource to guide rational efforts to develop combinatorial drug treatments.

DOI: https://doi.org/10.1038/s41586-022-04437-2
Mol Cell. 2022 Feb 16. pii: S1097-2765(22)00105-8. [Epub ahead of print]

Fumarate inhibits PTEN to promote tumorigenesis and therapeutic resistance of type2 papillary renal cell carcinoma.

Xin Ge, Mengdie Li, Jianxing Yin, Zhumei Shi, Yao Fu, Ningwei Zhao, Hongshan Chen, Longxiyu Meng, Xinjian Li, Zhibin Hu, Xiaozhi Zhao, Hongqian Guo, Xu Qian.

  Fumarate is an oncometabolite. However, the mechanism underlying fumarate-exerted tumorigenesis remains unclear. Here, utilizing human type2 papillary renal cell carcinoma (PRCC2) as a model, we show that fumarate accumulates in cells deficient in fumarate hydratase (FH) and inhibits PTEN to activate PI3K/AKT signaling. Mechanistically, fumarate directly reacts with PTEN at cysteine 211 (C211) to form S-(2-succino)-cysteine. Succinated C211 occludes tethering of PTEN with the cellular membrane, thereby diminishing its inhibitory effect on the PI3K/AKT pathway. Functionally, re-expressing wild-type FH or PTEN C211S phenocopies an AKT inhibitor in suppressing tumor growth and sensitizing PRCC2 to sunitinib. Analysis of clinical specimens indicates that PTEN C211 succination levels are positively correlated with AKT activation in PRCC2. Collectively, these findings elucidate a non-metabolic, oncogenic role of fumarate in PRCC2 via direct post-translational modification of PTEN and further reveal potential stratification strategies for patients with FH loss by combinatorial AKTi and sunitinib therapy.

Keywords:  FH deficiency; PI3K/AKT; PRCC2; PTEN; TKI resistance; fumarate; succination; therapeutic resistance; tumorigenesis; type-2 papillary renal cell carcinoma

DOI:  https://doi.org/10.1016/j.molcel.2022.01.029
Nat Rev Mol Cell Biol. 2022 Feb 21.

Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology.

Helmut Sies, Vsevolod V Belousov, Navdeep S Chandel, Michael J Davies, Dean P Jones, Giovanni E Mann, Michael P Murphy, Masayuki Yamamoto, Christine Winterbourn.

'Reactive oxygen species' (ROS) is a generic term that defines a wide variety of oxidant molecules with vastly different properties and biological functions that range from signalling to causing cell damage. Consequently, the description of oxidants needs to be chemically precise to translate research on their biological effects into therapeutic benefit in redox medicine. This Expert Recommendation article pinpoints key issues associated with identifying the physiological roles of oxidants, focusing on H2O2 and O2.-. The generic term ROS should not be used to describe specific molecular agents. We also advocate for greater precision in measurement of H2O2, O2.- and other oxidants, along with more specific identification of their signalling targets. Future work should also consider inter-organellar communication and the interactions of redox-sensitive signalling targets within organs and whole organisms, including the contribution of environmental exposures. To achieve these goals, development of tools that enable site-specific and real-time detection and quantification of individual oxidants in cells and model organisms are needed. We also stress that physiological O2 levels should be maintained in cell culture to better mimic in vivo redox reactions associated with specific cell types. Use of precise definitions and analytical tools will help harmonize research among the many scientific disciplines working on the common goal of understanding redox biology.

DOI: https://doi.org/10.1038/s41580-022-00456-z
Biomolecules. 2022 Jan 19. pii: 162. [Epub ahead of print]12(2):

Bcl-2 Family Members and the Mitochondrial Import Machineries: The Roads to Death.

Lisenn Lalier, François Vallette, Stéphen Manon.

  The localization of Bcl-2 family members at the mitochondrial outer membrane (MOM) is a crucial step in the implementation of apoptosis. We review evidence showing the role of the components of the mitochondrial import machineries (translocase of the outer membrane (TOM) and the sorting and assembly machinery (SAM)) in the mitochondrial localization of Bcl-2 family members and how these machineries regulate the function of pro- and anti-apoptotic proteins in resting cells and in cells committed into apoptosis.

Keywords:  apoptosis; bcl-2 family; mitochondrial import machineries

DOI:  https://doi.org/10.3390/biom12020162
Free Radic Biol Med. 2022 Feb 21. pii: S0891-5849(22)00072-7. [Epub ahead of print]

Coenzyme Q10 and related quinones oxidize H2S to polysulfides and thiosulfate.

Kenneth R Olson, Kasey Clear, Paul Derry, Yan Gao, Zhilin Ma, Gang Wu, Thomas Kent, Karl D Straub.

  In the canonical pathway for mitochondrial H2S oxidation electrons are transferred from sulfide:quinone oxidoreductase (SQR) to complex III via ubiquinone (CoQ10). We previously observed that a number of quinones directly oxidize H2S and we hypothesize that CoQ10 may have similar properties. Here we examine H2S oxidation by CoQ10 and more hydrophilic, truncated forms, CoQ1 and CoQ0, in buffer using H2S and polysulfide fluorophores (AzMC and SSP4), silver nanoparticles to measure thiosulfate (H2S2O3), mass spectrometry to identify polysulfides and O2-sensitive optodes to measure O2 consumption. We show that all three quinones concentration-dependently catalyze the oxidization of H2S to polysulfides and thiosulfate in buffer with the potency CoQ0>CoQ1>CoQ10 and that CoQ0 specifically oxidizes H2S to per-polysulfides, H2S2,3,4. These reactions consume and require oxygen and are augmented by addition of SOD suggesting that the quinones, not superoxide, oxidize H2S. Related quinones, MitoQ, menadione and idebenone, oxidize H2S in similar reactions. Exogenous CoQ0 decreases cellular H2S and increases polysulfides and thiosulfate production and this is also O2-dependent, suggesting that the quinone has similar effects on sulfur metabolism in cells. Collectively, these results suggest an additional endogenous mechanism for H2S metabolism and a potential therapeutic approach in H2S-related metabolic disorders.

Keywords:  Antioxidants; CoQ(10); Down syndrome; Reactive oxygen species; Reactive sulfur species

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.02.018
Nat Commun. 2022 Feb 25. 13(1): 1048

Phosphoproteomic profiling of T cell acute lymphoblastic leukemia reveals targetable kinases and combination treatment strategies.

Valentina Cordo', Mariska T Meijer, Rico Hagelaar, Richard R de Goeij-de Haas, Vera M Poort, Alex A Henneman, Sander R Piersma, Thang V Pham, Koichi Oshima, Adolfo A Ferrando, Guido J R Zaman, Connie R Jimenez, Jules P P Meijerink.

Protein kinase inhibitors are amongst the most successful cancer treatments, but targetable kinases activated by genomic abnormalities are rare in T cell acute lymphoblastic leukemia. Nevertheless, kinases can be activated in the absence of genetic defects. Thus, phosphoproteomics can provide information on pathway activation and signaling networks that offer opportunities for targeted therapy. Here, we describe a mass spectrometry-based global phosphoproteomic profiling of 11 T cell acute lymphoblastic leukemia cell lines to identify targetable kinases. We report a comprehensive dataset consisting of 21,000 phosphosites on 4,896 phosphoproteins, including 217 kinases. We identify active Src-family kinases signaling as well as active cyclin-dependent kinases. We validate putative targets for therapy ex vivo and identify potential combination treatments, such as the inhibition of the INSR/IGF-1R axis to increase the sensitivity to dasatinib treatment. Ex vivo validation of selected drug combinations using patient-derived xenografts provides a proof-of-concept for phosphoproteomics-guided design of personalized treatments.

DOI: https://doi.org/10.1038/s41467-022-28682-1