bims-celmim 2024-04-21 papers

bims-celmim

Biomed News

on Cellular and mitochondrial metabolism

Issue of 2024‒04‒21
twenty-one papers selected by
Marc Segarra Mondejar

Transcriptional regulation and post-translational modifications in the glycolytic pathway for targeted cancer therapy.
ABCG2 and SLC1A5 functionally interact to rewire metabolism and confer a survival advantage to cancer cells under oxidative stress.
The intersection of frailty and metabolism.
Mitochondrial energy state controls AMPK-mediated foraging behavior in C. elegans.
Bisbiguanide analogs induce mitochondrial stress to inhibit lung cancer cell invasion.
ULK1-dependent phosphorylation of PKM2 antagonizes O-GlcNAcylation and regulates the Warburg effect in breast cancer.
Context-dependent roles for ubiquitous mitochondrial creatine kinase CKMT1 in breast cancer progression.
Deuterium metabolic imaging differentiates glioblastoma metabolic subtypes and detects early response to chemoradiotherapy.
Optical recordings of organellar membrane potentials and the components of membrane conductance in lysosomes.
Cross-link assisted spatial proteomics to map sub-organelle proteomes and membrane protein topologies.
High-resolution In-situ Structures of Mammalian Mitochondrial Respiratory Supercomplexes in Reaction within Native Mitochondria.
Accumulation of APP C-terminal fragments causes endolysosomal dysfunction through the dysregulation of late endosome to lysosome-ER contact sites.
Mitochondria function in cytoplasmic FeS protein biogenesis.
Exploring machine learning for untargeted metabolomics using molecular fingerprints.
Iron regulates the quiescence of naive CD4 T cells by controlling mitochondria and cellular metabolism.
Diet and Cancer Metabolism.
GPR1 and CMKLR1 control lipid metabolism to support development of clear cell renal cell carcinoma.
Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism.
The key role of altered tubule cell lipid metabolism in kidney disease development.
OMA1 clears traffic jam in TOM tunnel in mammals.
Protein feature engineering framework for AMPylation site prediction.

Acta Pharmacol Sin. 2024 Apr 15.

Transcriptional regulation and post-translational modifications in the glycolytic pathway for targeted cancer therapy.

Xuan Ni, Cheng-Piao Lu, Guo-Qiang Xu, Jing-Jing Ma.

  Cancer cells largely rely on aerobic glycolysis or the Warburg effect to generate essential biomolecules and energy for their rapid growth. The key modulators in glycolysis including glucose transporters and enzymes, e.g. hexokinase 2, enolase 1, pyruvate kinase M2, lactate dehydrogenase A, play indispensable roles in glucose uptake, glucose consumption, ATP generation, lactate production, etc. Transcriptional regulation and post-translational modifications (PTMs) of these critical modulators are important for signal transduction and metabolic reprogramming in the glycolytic pathway, which can provide energy advantages to cancer cell growth. In this review we recapitulate the recent advances in research on glycolytic modulators of cancer cells and analyze the strategies targeting these vital modulators including small-molecule inhibitors and microRNAs (miRNAs) for targeted cancer therapy. We focus on the regulation of the glycolytic pathway at the transcription level (e.g., hypoxia-inducible factor 1, c-MYC, p53, sine oculis homeobox homolog 1, N6-methyladenosine modification) and PTMs (including phosphorylation, methylation, acetylation, ubiquitination, etc.) of the key regulators in these processes. This review will provide a comprehensive understanding of the regulation of the key modulators in the glycolytic pathway and might shed light on the targeted cancer therapy at different molecular levels.

Keywords:  aerobic glycolysis; glycolytic modulators; post-translational modification; targeted cancer therapy; transcriptional regulation

DOI:  https://doi.org/10.1038/s41401-024-01264-1
J Biol Chem. 2024 Apr 17. pii: S0021-9258(24)01800-3. [Epub ahead of print] 107299

ABCG2 and SLC1A5 functionally interact to rewire metabolism and confer a survival advantage to cancer cells under oxidative stress.

Jia Shi, Kirk Pabon, Rui Ding, Kathleen W Scotto.

ABCG2, a member of the ABC transporter superfamily, is overexpressed in many human tumors and has long been studied for its ability to export a variety of chemotherapeutic agents, thereby conferring a multidrug resistance (MDR) phenotype. However, several studies have shown that ABCG2 can also confer an MDR-independent survival advantage to tumor cells exposed to stress. While investigating the mechanism by which ABCG2 enhances survival in stressful milieus, we have identified a physical and functional interaction between ABCG2 and SLC1A5, a member of the solute transporter superfamily and the primary transporter of glutamine in cancer cells. This interaction was accompanied by increased glutamine uptake, increased glutaminolysis and rewired cellular metabolism, as evidenced by an increase in key metabolic enzymes and alteration of glutamine-dependent metabolic pathways. Specifically, we observed an increase in glutamine metabolites shuttled to the TCA cycle, an increase in the synthesis of glutathione, accompanied by a decrease in basal levels of reactive oxygen species and a marked increase in cell survival in the face of oxidative stress. Notably, knockdown of SLC1A5 or depletion of exogenous glutamine diminished ABCG2-enhanced autophagy flux, further implicating this solute transporter in ABCG2-mediated cell survival. This is, to our knowledge, the first report of a functionally significant physical interaction between members of the two major transporter superfamilies. Moreover, these observations may underlie the protective role of ABCG2 in cancer cells under duress and suggest a novel role for ABCG2 in the regulation of metabolism in normal and diseased states.

DOI: https://doi.org/10.1016/j.jbc.2024.107299
Cell Metab. 2024 Apr 05. pii: S1550-4131(24)00091-3. [Epub ahead of print]

The intersection of frailty and metabolism.

Manish Mishra, Judy Wu, Alice E Kane, Susan E Howlett.

  On average, aging is associated with unfavorable changes in cellular metabolism, which are the processes involved in the storage and expenditure of energy. However, metabolic dysregulation may not occur to the same extent in all older individuals as people age at different rates. Those who are aging rapidly are at increased risk of adverse health outcomes and are said to be "frail." Here, we explore the links between frailty and metabolism, including metabolic contributors and consequences of frailty. We examine how metabolic diseases may modify the degree of frailty in old age and suggest that frailty may predispose toward metabolic disease. Metabolic interventions that can mitigate the degree of frailty in people are reviewed. New treatment strategies developed in animal models that are poised for translation to humans are also considered. We suggest that maintaining a youthful metabolism into older age may be protective against frailty.

Keywords:  frailty index; frailty phenotype; metabolic dysregulation; metabolic syndrome; mouse models; protein restriction

DOI:  https://doi.org/10.1016/j.cmet.2024.03.012
Sci Adv. 2024 Apr 19. 10(16): eadm8815

Mitochondrial energy state controls AMPK-mediated foraging behavior in C. elegans.

Anežka Vodičková, Annika Müller-Eigner, Chidozie N Okoye, Andrew P Bischer, Jacob Horn, Shon A Koren, Nada Ahmed Selim, Andrew P Wojtovich.

Organisms surveil and respond to their environment using behaviors entrained by metabolic cues that reflect food availability. Mitochondria act as metabolic hubs and at the center of mitochondrial energy production is the protonmotive force (PMF), an electrochemical gradient generated by metabolite consumption. The PMF serves as a central integrator of mitochondrial status, but its role in governing metabolic signaling is poorly understood. We used optogenetics to dissipate the PMF in Caenorhabditis elegans tissues to test its role in food-related behaviors. Our data demonstrate that PMF reduction in the intestine is sufficient to initiate locomotor responses to acute food deprivation. This behavioral adaptation requires the cellular energy regulator AMP-activated protein kinase (AMPK) in neurons, not in the intestine, and relies on mitochondrial dynamics and axonal trafficking. Our results highlight a role for intestinal PMF as an internal metabolic cue, and we identify a bottom-up signaling axis through which changes in the PMF trigger AMPK activity in neurons to promote foraging behavior.

DOI: https://doi.org/10.1126/sciadv.adm8815
iScience. 2024 Apr 19. 27(4): 109591

Bisbiguanide analogs induce mitochondrial stress to inhibit lung cancer cell invasion.

Christina M Knippler, Jamie L Arnst, Isaac E Robinson, Veronika Matsuk, Tala O Khatib, R Donald Harvey, Mala Shanmugam, Janna K Mouw, Haian Fu, Thota Ganesh, Adam I Marcus.

  Targeting cancer metabolism to limit cellular energy and metabolite production is an attractive therapeutic approach. Here, we developed analogs of the bisbiguanide, alexidine, to target lung cancer cell metabolism and assess a structure-activity relationship (SAR). The SAR led to the identification of two analogs, AX-4 and AX-7, that limit cell growth via G1/G0 cell-cycle arrest and are tolerated in vivo with favorable pharmacokinetics. Mechanistic evaluation revealed that AX-4 and AX-7 induce potent mitochondrial defects; mitochondrial cristae were deformed and the mitochondrial membrane potential was depolarized. Additionally, cell metabolism was rewired, as indicated by reduced oxygen consumption and mitochondrial ATP production, with an increase in extracellular lactate. Importantly, AX-4 and AX-7 impacted overall cell behavior, as these compounds reduced collective cell invasion. Taken together, our study establishes a class of bisbiguanides as effective mitochondria and cell invasion disrupters, and proposes bisbiguanides as promising approaches to limiting cancer metastasis.

Keywords:  Cancer; Cell biology; Cellular physiology

DOI:  https://doi.org/10.1016/j.isci.2024.109591
Oncogene. 2024 Apr 17.

ULK1-dependent phosphorylation of PKM2 antagonizes O-GlcNAcylation and regulates the Warburg effect in breast cancer.

Zibin Zhou, Xiyuan Zheng, Jianxin Zhao, Aiyun Yuan, Zhuan Lv, Guangcan Shao, Bin Peng, Meng-Qiu Dong, Quan Xu, Xingzhi Xu, Jing Li.

Pyruvate kinase M2 (PKM2) is a central metabolic enzyme driving the Warburg effect in tumor growth. Previous investigations have demonstrated that PKM2 is subject to O-linked β-N-acetylglucosamine (O-GlcNAc) modification, which is a nutrient-sensitive post-translational modification. Here we found that unc-51 like autophagy activating kinase 1 (ULK1), a glucose-sensitive kinase, interacts with PKM2 and phosphorylates PKM2 at Ser333. Ser333 phosphorylation antagonizes PKM2 O-GlcNAcylation, promotes its tetramer formation and enzymatic activity, and decreases its nuclear localization. As PKM2 is known to have a nuclear role in regulating c-Myc, we also show that PKM2-S333 phosphorylation inhibits c-Myc expression. By downregulating glucose consumption and lactate production, PKM2 pS333 attenuates the Warburg effect. Through mouse xenograft assays, we demonstrate that the phospho-deficient PKM2-S333A mutant promotes tumor growth in vivo. In conclusion, we identified a ULK1-PKM2-c-Myc axis in inhibiting breast cancer, and a glucose-sensitive phosphorylation of PKM2 in modulating the Warburg effect.

DOI: https://doi.org/10.1038/s41388-024-03035-y
Cell Rep. 2024 Apr 12. pii: S2211-1247(24)00449-2. [Epub ahead of print]43(4): 114121

Context-dependent roles for ubiquitous mitochondrial creatine kinase CKMT1 in breast cancer progression.

Vinay Ayyappan, Nicole M Jenkinson, Caitlin M Tressler, Zheqiong Tan, Menglin Cheng, Xinyi Elaine Shen, Alejandro Guerrero, Kanchan Sonkar, Ruoqing Cai, Oluwatobi Adelaja, Sujayita Roy, Alan Meeker, Pedram Argani, Kristine Glunde.

  Metabolic reprogramming is a hallmark of cancer, enabling cancer cells to rapidly proliferate, invade, and metastasize. We show that creatine levels in metastatic breast cancer cell lines and secondary metastatic tumors are driven by the ubiquitous mitochondrial creatine kinase (CKMT1). We discover that, while CKMT1 is highly expressed in primary tumors and promotes cell viability, it is downregulated in metastasis. We further show that CKMT1 downregulation, as seen in breast cancer metastasis, drives up mitochondrial reactive oxygen species (ROS) levels. CKMT1 downregulation contributes to the migratory and invasive potential of cells by ROS-induced upregulation of adhesion and degradative factors, which can be reversed by antioxidant treatment. Our study thus reconciles conflicting evidence about the roles of metabolites in the creatine metabolic pathway in breast cancer progression and reveals that tight, context-dependent regulation of CKMT1 expression facilitates cell viability, cell migration, and cell invasion, which are hallmarks of metastatic spread.

Keywords:  CKMT1; CP: Cancer; CP: Metabolism; breast cancer; creatine; metabolism; metastasis; reactive oxygen species

DOI:  https://doi.org/10.1016/j.celrep.2024.114121
Cancer Res. 2024 Apr 18.

Deuterium metabolic imaging differentiates glioblastoma metabolic subtypes and detects early response to chemoradiotherapy.

Jacob Chen Ming Low, Jianbo Cao, Friederike Hesse, Alan J Wright, Anastasia Tsyben, Islam Alshamleh, Richard Mair, Kevin M Brindle.

Metabolic subtypes of glioblastoma have different prognoses and responses to treatment. Deuterium metabolic imaging with 2H-labeled substrates is a potential approach to stratify patients into metabolic subtypes for targeted treatment. Here, we used 2H magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) measurements of [6,6'-2H2]glucose metabolism to identify metabolic subtypes and their responses to chemoradiotherapy in patient-derived glioblastoma xenografts in vivo. The metabolism of patient-derived cells was first characterized in vitro by measuring the oxygen consumption rate, a marker of mitochondrial TCA cycle activity, as well as the extracellular acidification rate and 2H-labeled lactate production from [6,6'-2H2]glucose, which are markers of glycolytic activity. Two cell lines representative of a glycolytic subtype and two representative of a mitochondrial subtype were identified. 2H MRS and MRSI measurements showed similar concentrations of 2H-labeled glucose from [6,6'-2H2]glucose in all four tumor models when implanted orthotopically in mice. The glycolytic subtypes showed higher concentrations of 2H-labeled lactate than the mitochondrial subtypes and normal-appearing brain tissue, whereas the mitochondrial subtypes showed more glutamate/glutamine labeling, a surrogate for TCA cycle activity, than the glycolytic subtypes and normal-appearing brain tissue. The response of the tumors to chemoradiation could be detected within 24 hours of treatment completion, with the mitochondrial subtypes showing a decrease in both 2H-labeled glutamate/glutamine and lactate concentrations and glycolytic tumors showing a decrease in 2H-labeled lactate concentration. This technique has the potential to be used clinically for treatment selection and early detection of treatment response.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2552
J Physiol. 2024 Apr;602(8): 1637-1654

Optical recordings of organellar membrane potentials and the components of membrane conductance in lysosomes.

Cristian Castillo-Velasquez, Ella Matamala, Diego Becerra, Patricio Orio, Sebastian E Brauchi.

  The eukaryotic cell is highly compartmentalized with organelles. Owing to their function in transporting metabolites, metabolic intermediates and byproducts of metabolic activity, organelles are important players in the orchestration of cellular function. Recent advances in optical methods for interrogating the different aspects of organellar activity promise to revolutionize our ability to dissect cellular processes with unprecedented detail. The transport activity of organelles is usually coupled to the transport of charged species; therefore, it is not only associated with the metabolic landscape but also entangled with membrane potentials. In this context, the targeted expression of fluorescent probes for interrogating organellar membrane potential (Ψorg) emerges as a powerful approach, offering less-invasive conditions and technical simplicity to interrogate cellular signalling and metabolism. Different research groups have made remarkable progress in adapting a variety of optical methods for measuring and monitoring Ψorg. These approaches include using potentiometric dyes, genetically encoded voltage indicators, hybrid fluorescence resonance energy transfer sensors and photoinduced electron transfer systems. These studies have provided consistent values for the resting potential of single-membrane organelles, such as lysosomes, the Golgi and the endoplasmic reticulum. We can foresee the use of dynamic measurements of Ψorg to study fundamental problems in organellar physiology that are linked to serious cellular disorders. Here, we present an overview of the available techniques, a survey of the resting membrane potential of internal membranes and, finally, an open-source mathematical model useful to interpret and interrogate membrane-bound structures of small volume by using the lysosome as an example.

Keywords:  Golgi; hybrid voltage sensor; lysosome; model; optical; organelle; reticulum; voltage

DOI:  https://doi.org/10.1113/JP283825
Nat Commun. 2024 Apr 17. 15(1): 3290

Cross-link assisted spatial proteomics to map sub-organelle proteomes and membrane protein topologies.

Ying Zhu, Kerem Can Akkaya, Julia Ruta, Nanako Yokoyama, Cong Wang, Max Ruwolt, Diogo Borges Lima, Martin Lehmann, Fan Liu.

The functions of cellular organelles and sub-compartments depend on their protein content, which can be characterized by spatial proteomics approaches. However, many spatial proteomics methods are limited in their ability to resolve organellar sub-compartments, profile multiple sub-compartments in parallel, and/or characterize membrane-associated proteomes. Here, we develop a cross-link assisted spatial proteomics (CLASP) strategy that addresses these shortcomings. Using human mitochondria as a model system, we show that CLASP can elucidate spatial proteomes of all mitochondrial sub-compartments and provide topological insight into the mitochondrial membrane proteome. Biochemical and imaging-based follow-up studies confirm that CLASP allows discovering mitochondria-associated proteins and revising previous protein sub-compartment localization and membrane topology data. We also validate the CLASP concept in synaptic vesicles, demonstrating its applicability to different sub-cellular compartments. This study extends the scope of cross-linking mass spectrometry beyond protein structure and interaction analysis towards spatial proteomics, and establishes a method for concomitant profiling of sub-organelle and membrane proteomes.

DOI: https://doi.org/10.1038/s41467-024-47569-x
bioRxiv. 2024 Apr 03. pii: 2024.04.02.587796. [Epub ahead of print]

High-resolution In-situ Structures of Mammalian Mitochondrial Respiratory Supercomplexes in Reaction within Native Mitochondria.

Wan Zheng, Pengxin Chai, Jiapeng Zhu, Kai Zhang.

Mitochondria play a pivotal role in ATP energy production through oxidative phosphorylation, which occurs within the inner membrane via a series of respiratory complexes. Despite extensive in-vitro structural studies, revealing the atomic details of their molecular mechanisms in physiological states remains a major challenge, primarily because of the loss of the native environment during purification. Here, we directly image porcine mitochondria using an in-situ cryo-electron microscopy approach. This enables us to determine the structures of various high-order assemblies of respiratory supercomplexes in their native states, achieving up to 1.8-Å local resolution. We identify four major supercomplex organizations: I1III2IV1, I1III2IV2, I2III2IV2, and I2III4IV2, which can potentially expand into higher-order arrays on the inner membranes. The formation of these diverse supercomplexes is largely contributed by 'protein-lipids-protein' interactions, which in turn dramatically impact the local geometry of the surrounding membranes. Our in-situ structures also capture numerous reactive intermediates within these respiratory supercomplexes, shedding light on the dynamic processes of the ubiquinone/ubiquinol exchange mechanism in complex I and the Q-cycle in complex III. By comparing supercomplex structures from mitochondria treated under distinct conditions, we elucidate how conformational changes and ligand binding states interplay between complexes I and III in response to environmental redox alterations. Our approach, by preserving the native membrane environment, enables structural studies of mitochondrial respiratory supercomplexes in reaction at high resolution across multiple scales, spanning from atomic-level details to the broader subcellular context.

DOI: https://doi.org/10.1101/2024.04.02.587796
Dev Cell. 2024 Apr 12. pii: S1534-5807(24)00199-0. [Epub ahead of print]

Accumulation of APP C-terminal fragments causes endolysosomal dysfunction through the dysregulation of late endosome to lysosome-ER contact sites.

Marine Bretou, Ragna Sannerud, Abril Escamilla-Ayala, Tom Leroy, Céline Vrancx, Zoë P Van Acker, Anika Perdok, Wendy Vermeire, Inge Vorsters, Sophie Van Keymolen, Michelle Maxson, Benjamin Pavie, Keimpe Wierda, Eeva-Liisa Eskelinen, Wim Annaert.

  Neuronal endosomal and lysosomal abnormalities are among the early changes observed in Alzheimer's disease (AD) before plaques appear. However, it is unclear whether distinct endolysosomal defects are temporally organized and how altered γ-secretase function or amyloid precursor protein (APP) metabolism contribute to these changes. Inhibiting γ-secretase chronically, in mouse embryonic fibroblast and hippocampal neurons, led to a gradual endolysosomal collapse initiated by decreased lysosomal calcium and increased cholesterol, causing downstream defects in endosomal recycling and maturation. This endolysosomal demise is γ-secretase dependent, requires membrane-tethered APP cytoplasmic domains, and is rescued by APP depletion. APP C-terminal fragments (CTFs) localized to late endosome/lysosome-endoplasmic reticulum contacts; an excess of APP-CTFs herein reduced lysosomal Ca2+ refilling from the endoplasmic reticulum, promoting cholesterol accretion. Tonic regulation by APP-CTFs provides a mechanistic explanation for their cellular toxicity: failure to timely degrade APP-CTFs sustains downstream signaling, instigating lysosomal dyshomeostasis, as observed in prodromal AD. This is the opposite of substrates such as Notch, which require intramembrane proteolysis to initiate signaling.

Keywords:  APP proteolysis; APP-CTF; endolysosomal homeostasis; late endosome/lysosome-endoplasmic reticulum contact sites; lysosomal Ca(2+); presenilins; primary hippocampal neurons; γ-secretase; γ-secretase inhibitor

DOI:  https://doi.org/10.1016/j.devcel.2024.03.030
Biochim Biophys Acta Mol Cell Res. 2024 Apr 17. pii: S0167-4889(24)00076-4. [Epub ahead of print] 119733

Mitochondria function in cytoplasmic FeS protein biogenesis.

Andrew Dancis, Ashutosh K Pandey, Debkumar Pain.

  Iron‑sulfur (FeS) clusters are cofactors of numerous proteins involved in various essential functions including cellular respiration, protein translation, DNA synthesis and repair, ribosome maturation, anti-viral responses, and isopropylmalate isomerase activity. Novel FeS cluster proteins are still being discovered due to the widespread use of cryogenic electron microscopy (cryo-EM) and elegant genetic screens targeted at protein discovery. A complex sequence of biochemical reactions mediated by a conserved machinery controls biosynthesis of FeS clusters. In eukaryotes, a remarkable epistasis has been observed: the mitochondrial machinery, termed ISC (Iron-Sulfur Cluster), lies upstream of the cytoplasmic machinery, termed CIA (Cytoplasmic Iron‑sulfur protein Assembly). The basis for this arrangement is the production of a hitherto uncharacterized intermediate, termed X-S or (FeS)int, produced in mitochondria by the ISC machinery, exported by the mitochondrial ABC transporter Atm1 (ABC7 in humans), and then utilized by the CIA machinery for the cytoplasmic/nuclear FeS cluster assembly. Genetic and biochemical findings supporting this sequence of events are herein presented. New structural views of the Atm1 transport phases are reviewed. The key compartmental roles of glutathione in cellular FeS cluster biogenesis are highlighted. Finally, data are presented showing that every one of the ten core components of the mitochondrial ISC machinery and Atm1, when mutated or depleted, displays similar phenotypes: mitochondrial and cytoplasmic FeS clusters are both rendered deficient, consistent with the epistasis noted above.

Keywords:  (FeS)(int); Atm1; Cytoplasm; FeS cluster trafficking; FeS proteins; Glutaredoxin; Glutathione; Mitochondria; X-S

DOI:  https://doi.org/10.1016/j.bbamcr.2024.119733
Comput Methods Programs Biomed. 2024 Apr 08. pii: S0169-2607(24)00159-7. [Epub ahead of print]250 108163

Exploring machine learning for untargeted metabolomics using molecular fingerprints.

Christel Sirocchi, Federica Biancucci, Matteo Donati, Alessandro Bogliolo, Mauro Magnani, Michele Menotta, Sara Montagna.

  BACKGROUND: Metabolomics, the study of substrates and products of cellular metabolism, offers valuable insights into an organism's state under specific conditions and has the potential to revolutionise preventive healthcare and pharmaceutical research. However, analysing large metabolomics datasets remains challenging, with available methods relying on limited and incompletely annotated metabolic pathways.METHODS: This study, inspired by well-established methods in drug discovery, employs machine learning on metabolite fingerprints to explore the relationship of their structure with responses in experimental conditions beyond known pathways, shedding light on metabolic processes. It evaluates fingerprinting effectiveness in representing metabolites, addressing challenges like class imbalance, data sparsity, high dimensionality, duplicate structural encoding, and interpretable features. Feature importance analysis is then applied to reveal key chemical configurations affecting classification, identifying related metabolite groups.
RESULTS: The approach is tested on two datasets: one on Ataxia Telangiectasia and another on endothelial cells under low oxygen. Machine learning on molecular fingerprints predicts metabolite responses effectively, and feature importance analysis aligns with known metabolic pathways, unveiling new affected metabolite groups for further study.
CONCLUSION: In conclusion, the presented approach leverages the strengths of drug discovery to address critical issues in metabolomics research and aims to bridge the gap between these two disciplines. This work lays the foundation for future research in this direction, possibly exploring alternative structural encodings and machine learning models.

Keywords:  Ataxia telangiectasia; Machine learning; Mass spectrometry; Molecular fingerprinting; Untargeted metabolomics

DOI:  https://doi.org/10.1016/j.cmpb.2024.108163
Proc Natl Acad Sci U S A. 2024 Apr 23. 121(17): e2318420121

Iron regulates the quiescence of naive CD4 T cells by controlling mitochondria and cellular metabolism.

Ajay Kumar, Chenxian Ye, Afia Nkansah, Thomas Decoville, Garrett M Fogo, Peter Sajjakulnukit, Mack B Reynolds, Li Zhang, Osbourne Quaye, Young-Ah Seo, Thomas H Sanderson, Costas A Lyssiotis, Cheong-Hee Chang.

  In response to an immune challenge, naive T cells undergo a transition from a quiescent to an activated state acquiring the effector function. Concurrently, these T cells reprogram cellular metabolism, which is regulated by iron. We and others have shown that iron homeostasis controls proliferation and mitochondrial function, but the underlying mechanisms are poorly understood. Given that iron derived from heme makes up a large portion of the cellular iron pool, we investigated iron homeostasis in T cells using mice with a T cell-specific deletion of the heme exporter, FLVCR1 [referred to as knockout (KO)]. Our finding revealed that maintaining heme and iron homeostasis is essential to keep naive T cells in a quiescent state. KO naive CD4 T cells exhibited an iron-overloaded phenotype, with increased spontaneous proliferation and hyperactive mitochondria. This was evidenced by reduced IL-7R and IL-15R levels but increased CD5 and Nur77 expression. Upon activation, however, KO CD4 T cells have defects in proliferation, IL-2 production, and mitochondrial functions. Iron-overloaded CD4 T cells failed to induce mitochondrial iron and exhibited more fragmented mitochondria after activation, making them susceptible to ferroptosis. Iron overload also led to inefficient glycolysis and glutaminolysis but heightened activity in the hexosamine biosynthetic pathway. Overall, these findings highlight the essential role of iron in controlling mitochondrial function and cellular metabolism in naive CD4 T cells, critical for maintaining their quiescent state.

Keywords:  heme; iron; mitochondria; tonic signaling

DOI:  https://doi.org/10.1073/pnas.2318420121
Cold Spring Harb Perspect Med. 2024 Apr 15. pii: a041549. [Epub ahead of print]

Diet and Cancer Metabolism.

Jason W Locasale, Marcus D Goncalves, Maira Di Tano, Guillermo Burgos-Barragan.

Diet and exercise are modifiable lifestyle factors known to have a major influence on metabolism. Clinical practice addresses diseases of altered metabolism such as diabetes or hypertension by altering these factors. Despite enormous public interest, there are limited defined diet and exercise regimens for cancer patients. Nevertheless, the molecular basis of cancer has converged over the past 15 years on an essential role for altered metabolism in cancer. However, our understanding of the molecular mechanisms that underlie the impact of diet and exercise on cancer metabolism is in its very early stages. In this work, we propose conceptual frameworks for understanding the consequences of diet and exercise on cancer cell metabolism and tumor biology and also highlight recent developments. By advancing our mechanistic understanding, we also discuss actionable ways that such interventions could eventually reach the mainstay of both medical oncology and cancer control and prevention.

DOI: https://doi.org/10.1101/cshperspect.a041549
Cancer Res. 2024 Apr 19.

GPR1 and CMKLR1 control lipid metabolism to support development of clear cell renal cell carcinoma.

Dazhi Wang, Iqbal Mahmud, Vijay S Thakur, Sze Kiat Tan, Daniel G Isom, David B Lombard, Mark L Gonzalgo, Oleksandr N Kryvenko, Philip L Lorenzi, Vanina T Tcheuyap, James Brugarolas, Scott M Welford.

Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, is largely incurable in the metastatic setting. ccRCC is characterized by excessive lipid accumulation that protects cells from stress and promotes tumor growth, suggesting that the underlying regulators of lipid storage could represent potential therapeutic targets. Here, we evaluated the regulatory roles of GPR1 and CMKLR1, two G-protein coupled receptors of the pro-tumorigenic adipokine chemerin that is involved in ccRCC lipid metabolism. Both genetic and pharmacological suppression of either receptor suppressed lipid formation and induced multiple forms of cell death, including apoptosis, ferroptosis and autophagy, significantly impeding ccRCC growth in cell lines and patient derived xenograft (PDX) models. Comprehensive lipidomic and transcriptomic profiling of receptor competent and depleted cells revealed overlapping and unique signaling of the receptors granting control over triglyceride synthesis, ceramide production, and fatty acid saturation and class production. Mechanistically, the receptors both enforced suppression of the triglyceride lipase ATGL but also demonstrated distinct functions, such as the unique ability of CMKLR1 to control lipid uptake through regulation of SREBP1c and the CD36 scavenger receptor. Treating PDX models with the CMKLR1-targeting small molecule α-NETA led to a dramatic reduction of tumor growth, lipid storage, and clear cell morphology. Together, these findings provide mechanistic insight into lipid regulation in ccRCC and identify a targetable axis at the core of the histological definition of this tumor that could be exploited therapeutically.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2926
Nat Aging. 2024 Apr 16.

Small extracellular vesicles from young plasma reverse age-related functional declines by improving mitochondrial energy metabolism.

Xiaorui Chen, Yang Luo, Qing Zhu, Jingzi Zhang, Huan Huang, Yansheng Kan, Dian Li, Ming Xu, Shuohan Liu, Jianxiao Li, Jinmeng Pan, Li Zhang, Yan Guo, Binghao Wang, Guantong Qi, Zhen Zhou, Chen-Yu Zhang, Lei Fang, Yanbo Wang, Xi Chen.

Recent investigations into heterochronic parabiosis have unveiled robust rejuvenating effects of young blood on aged tissues. However, the specific rejuvenating mechanisms remain incompletely elucidated. Here we demonstrate that small extracellular vesicles (sEVs) from the plasma of young mice counteract pre-existing aging at molecular, mitochondrial, cellular and physiological levels. Intravenous injection of young sEVs into aged mice extends their lifespan, mitigates senescent phenotypes and ameliorates age-associated functional declines in multiple tissues. Quantitative proteomic analyses identified substantial alterations in the proteomes of aged tissues after young sEV treatment, and these changes are closely associated with metabolic processes. Mechanistic investigations reveal that young sEVs stimulate PGC-1α expression in vitro and in vivo through their miRNA cargoes, thereby improving mitochondrial functions and mitigating mitochondrial deficits in aged tissues. Overall, this study demonstrates that young sEVs reverse degenerative changes and age-related dysfunction, at least in part, by stimulating PGC-1α expression and enhancing mitochondrial energy metabolism.

DOI: https://doi.org/10.1038/s43587-024-00612-4
Kidney Int. 2024 Apr 11. pii: S0085-2538(24)00252-7. [Epub ahead of print]

The key role of altered tubule cell lipid metabolism in kidney disease development.

Lauren E Lee, Tomohito Doke, Dhanunjay Mukhi, Katalin Susztak.

  Kidney epithelial cells have very high energy requirements, which are largely met by fatty acid oxidation. Complex changes in lipid metabolism are observed in patients with kidney disease. Defects in fatty acid oxidation and increased lipid uptake, especially in the context of hyperlipidemia and proteinuria, contribute to this excess lipid build-up and exacerbate kidney disease development. Recent studies have also highlighted the role of increased de novo lipogenesis in kidney fibrosis. The defect in fatty acid oxidation will cause energy starvation. Increased lipid uptake, synthesis and lower fatty acid oxidation can cause toxic lipid build-up, reactive oxygen species generation, and mitochondrial damage. Better understanding of these metabolic processes may open new treatment avenues for kidney diseases by targeting lipid metabolism.

Keywords:  Acute kidney injury (AKI); chronic kidney disease (CKD); de novo lipogenesis; fatty acid oxidation; lipid; metabolism

DOI:  https://doi.org/10.1016/j.kint.2024.02.025
J Cell Biol. 2024 May 06. pii: e202403190. [Epub ahead of print]223(5):

OMA1 clears traffic jam in TOM tunnel in mammals.

Shiori Sekine, Yusuke Sekine.

Using an engineered mitochondrial clogger, Krakowczyk et al. (https://doi.org/10.1083/jcb.202306051) identified the OMA1 protease as a critical component that eliminates import failure at the TOM translocase in mammalian cells, providing a novel quality control mechanism that is distinct from those described in yeast.

DOI: https://doi.org/10.1083/jcb.202403190
Sci Rep. 2024 04 15. 14(1): 8695

Protein feature engineering framework for AMPylation site prediction.

Hardik Prabhu, Hrushikesh Bhosale, Aamod Sane, Renu Dhadwal, Vigneshwar Ramakrishnan, Jayaraman Valadi.

AMPylation is a biologically significant yet understudied post-translational modification where an adenosine monophosphate (AMP) group is added to Tyrosine and Threonine residues primarily. While recent work has illuminated the prevalence and functional impacts of AMPylation, experimental identification of AMPylation sites remains challenging. Computational prediction techniques provide a faster alternative approach. The predictive performance of machine learning models is highly dependent on the features used to represent the raw amino acid sequences. In this work, we introduce a novel feature extraction pipeline to encode the key properties relevant to AMPylation site prediction. We utilize a recently published dataset of curated AMPylation sites to develop our feature generation framework. We demonstrate the utility of our extracted features by training various machine learning classifiers, on various numerical representations of the raw sequences extracted with the help of our framework. Tenfold cross-validation is used to evaluate the model's capability to distinguish between AMPylated and non-AMPylated sites. The top-performing set of features extracted achieved MCC score of 0.58, Accuracy of 0.8, AUC-ROC of 0.85 and F1 score of 0.73. Further, we elucidate the behaviour of the model on the set of features consisting of monogram and bigram counts for various representations using SHapley Additive exPlanations.

DOI: https://doi.org/10.1038/s41598-024-58450-8