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The polar oxy-metabolome reveals the 4-hydroxymandelate CoQ10 synthesis pathway

Banh, Robert S; Kim, Esther S; Spillier, Quentin; Biancur, Douglas E; Yamamoto, Keisuke; Sohn, Albert S W; Shi, Guangbin; Jones, Drew R; Kimmelman, Alec C; Pacold, Michael E
Oxygen is critical for a multitude of metabolic processes that are essential for human life. Biological processes can be identified by treating cells with 18O2 or other isotopically labelled gases and systematically identifying biomolecules incorporating labeled atoms. Here we labelled cell lines of distinct tissue origins with 18O2 to identify the polar oxy-metabolome, defined as polar metabolites labelled with 18O under different physiological O2 tensions. The most highly 18O-labelled feature was 4-hydroxymandelate (4-HMA). We demonstrate that 4-HMA is produced by hydroxyphenylpyruvate dioxygenase-like (HPDL), a protein of previously unknown function in human cells. We identify 4-HMA as an intermediate involved in the biosynthesis of the coenzyme Q10 (CoQ10) headgroup in human cells. The connection of HPDL to CoQ10 biosynthesis provides crucial insights into the mechanisms underlying recently described neurological diseases related to HPDL deficiencies1-4 and cancers with HPDL overexpression5.
PMID: 34471290
ISSN: 1476-4687
CID: 4989322

Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition

Ngo, Bryan; Kim, Eugenie; Osorio-Vasquez, Victoria; Doll, Sophia; Bustraan, Sophia; Liang, Roger J; Luengo, Alba; Davidson, Shawn M; Ali, Ahmed; Ferraro, Gino B; Fischer, Grant M; Eskandari, Roozbeh; Kang, Diane S; Ni, Jing; Plasger, Ariana; Rajasekhar, Vinagolu K; Kastenhuber, Edward R; Bacha, Sarah; Sriram, Roshan K; Stein, Benjamin D; Bakhoum, Samuel F; Snuderl, Matija; Cotzia, Paolo; Healey, John H; Mainolfi, Nello; Suri, Vipin; Friedman, Adam; Manfredi, Mark; Sabatini, David M; Jones, Drew R; Yu, Min; Zhao, Jean J; Jain, Rakesh K; Keshari, Kayvan R; Davies, Michael A; Vander Heiden, Matthew G; Hernando, Eva; Mann, Matthias; Cantley, Lewis C; Pacold, Michael E
A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine-limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo, genetic suppression and pharmacological inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggests that PHGDH inhibitors may be useful in the treatment of brain metastasis.
PMID: 32571778
ISSN: 2159-8290
CID: 4492952

Addendum: Unravelling cysteine-deficiency-associated rapid weight loss

Varghese, Alan; Gusarov, Ivan; Gamallo-Lana, Begoña; Dolgonos, Daria; Mankan, Yatin; Shamovsky, Ilya; Phan, Mydia; Jones, Rebecca; Gomez-Jenkins, Maria; White, Eileen; Wang, Rui; Jones, Drew R; Papagiannakopoulos, Thales; Pacold, Michael E; Mar, Adam C; Littman, Dan R; Nudler, Evgeny
PMID: 40579778
ISSN: 1476-4687
CID: 5887242

Unravelling cysteine-deficiency-associated rapid weight loss

Varghese, Alan; Gusarov, Ivan; Gamallo-Lana, Begoña; Dolgonos, Daria; Mankan, Yatin; Shamovsky, Ilya; Phan, Mydia; Jones, Rebecca; Gomez-Jenkins, Maria; White, Eileen; Wang, Rui; Jones, Drew R; Papagiannakopoulos, Thales; Pacold, Michael E; Mar, Adam C; Littman, Dan R; Nudler, Evgeny
Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with the incidence surging globally1,2. Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, have been explored to combat this epidemic3-6. Here we investigated the impact of removing individual amino acids on the weight profiles of mice. We show that conditional cysteine restriction resulted in the most substantial weight loss when compared to essential amino acid restriction, amounting to 30% within 1 week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, partly explaining the phenotype7-9. Notably, we observed lower levels of tissue coenzyme A (CoA), which has been considered to be extremely stable10, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective tricarboxylic acid cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen-rich compounds and amino acids. In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism and stress signalling compared with other amino acid restrictions. These findings suggest strategies for addressing a range of metabolic diseases and the growing obesity crisis.
PMID: 40399674
ISSN: 1476-4687
CID: 5853222

DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy

Lin, Hsin-Pin; Petersen, Jennifer D; Gilsrud, Alexandra J; Madruga, Angelo; D'Silva, Theresa M; Huang, Xiaoping; Shammas, Mario K; Randolph, Nicholas P; Johnson, Kory R; Li, Yan; Jones, Drew R; Pacold, Michael E; Narendra, Derek P
Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy, but how muscle senses and adapts to mitochondrial dysfunction is not well understood. Here, we used diverse mouse models of mitochondrial myopathy to show that the signal for mitochondrial dysfunction originates within mitochondria. The mitochondrial proteins OMA1 and DELE1 sensed disruption of the inner mitochondrial membrane and, in response, activated the mitochondrial integrated stress response (mt-ISR) to increase the building blocks for protein synthesis. In the absence of the mt-ISR, protein synthesis in muscle was dysregulated causing protein misfolding, and mice with early-onset mitochondrial myopathy failed to grow and survive. The mt-ISR was similar following disruptions in mtDNA maintenance (Tfam knockout) and mitochondrial protein misfolding (CHCHD10 G58R and S59L knockin) but heterogenous among mitochondria-rich tissues, with broad gene expression changes observed in heart and skeletal muscle and limited changes observed in liver and brown adipose tissue. Taken together, our findings identify that the DELE1 mt-ISR mediates a similar response to diverse forms of mitochondrial stress and is critical for maintaining growth and survival in early-onset mitochondrial myopathy.
PMID: 39379554
ISSN: 1460-2075
CID: 5706012

Technologies for Decoding Cancer Metabolism with Spatial Resolution

Chen, Walter W; Pacold, Michael E; Sabatini, David M; Kanarek, Naama
It is increasingly appreciated that cancer cells adapt their metabolic pathways to support rapid growth and proliferation as well as survival, often even under the poor nutrient conditions that characterize some tumors. Cancer cells can also rewire their metabolism to circumvent chemotherapeutics that inhibit core metabolic pathways, such as nucleotide synthesis. A critical approach to the study of cancer metabolism is metabolite profiling (metabolomics), the set of technologies, usually based on mass spectrometry, that allow for the detection and quantification of metabolites in cancer cells and their environments. Metabolomics is a burgeoning field, driven by technological innovations in mass spectrometers, as well as novel approaches to isolate cells, subcellular compartments, and rare fluids, such as the interstitial fluid of tumors. Here, we discuss three emerging metabolomic technologies: spatial metabolomics, single-cell metabolomics, and organellar metabolomics. The use of these technologies along with more established profiling methods, like single-cell transcriptomics and proteomics, is likely to underlie new discoveries and questions in cancer research.
PMID: 39284668
ISSN: 2157-1422
CID: 5720142

Unraveling cysteine deficiency-associated rapid weight loss

Varghese, Alan; Gusarov, Ivan; Gamallo-Lana, Begoña; Dolgonos, Daria; Mankan, Yatin; Shamovsky, Ilya; Phan, Mydia; Jones, Rebecca; Gomez-Jenkins, Maria; White, Eileen; Wang, Rui; Jones, Drew; Papagiannakopoulos, Thales; Pacold, Michael E; Mar, Adam C; Littman, Dan R; Nudler, Evgeny
Forty percent of the US population and 1 in 6 individuals worldwide are obese, and the incidence of this disease is surging globally1,2. Various dietary interventions, including carbohydrate and fat restriction, and more recently amino acid restriction, have been explored to combat this epidemic3-6. We sought to investigate the impact of removing individual amino acids on the weight profiles of mice. Compared to essential amino acid restriction, induction of conditional cysteine restriction resulted in the most dramatic weight loss, amounting to 20% within 3 days and 30% within one week, which was readily reversed. This weight loss occurred despite the presence of substantial cysteine reserves stored in glutathione (GSH) across various tissues7. Further analysis demonstrated that the weight reduction primarily stemmed from an increase in the utilization of fat mass, while locomotion, circadian rhythm and histological appearance of multiple other tissues remained largely unaffected. Cysteine deficiency activated the integrated stress response (ISR) and NRF2-mediated oxidative stress response (OSR), which amplify each other, leading to the induction of GDF15 and FGF21, hormones associated with increased lipolysis, energy homeostasis and food aversion8-10. We additionally observed rapid tissue coenzyme A (CoA) depletion, resulting in energetically inefficient anaerobic glycolysis and TCA cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen rich compounds and amino acids. In summary, our investigation highlights that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism, and stress signaling compared to other amino acid restrictions. These findings may pave the way for innovative strategies for addressing a range of metabolic diseases and the growing obesity crisis.
PMCID:11312522
PMID: 39131293
ISSN: 2692-8205
CID: 5688592

DELE1 promotes translation-associated homeostasis, growth, and survival in mitochondrial myopathy

Lin, Hsin-Pin; Petersen, Jennifer D; Gilsrud, Alexandra J; Madruga, Angelo; D'Silva, Theresa M; Huang, Xiaoping; Shammas, Mario K; Randolph, Nicholas P; Li, Yan; Jones, Drew R; Pacold, Michael E; Narendra, Derek P
Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy. Here, we identified that diverse mitochondrial myopathy models elicit a protective mitochondrial integrated stress response (mt-ISR), mediated by OMA1-DELE1 signaling. The response was similar following disruptions in mtDNA maintenance, from knockout of Tfam, and mitochondrial protein unfolding, from disease-causing mutations in CHCHD10 (G58R and S59L). The preponderance of the response was directed at upregulating pathways for aminoacyl-tRNA biosynthesis, the intermediates for protein synthesis, and was similar in heart and skeletal muscle but more limited in brown adipose challenged with cold stress. Strikingly, models with early DELE1 mt-ISR activation failed to grow and survive to adulthood in the absence of Dele1, accounting for some but not all of OMA1's protection. Notably, the DELE1 mt-ISR did not slow net protein synthesis in stressed striated muscle, but instead prevented loss of translation-associated proteostasis in muscle fibers. Together our findings identify that the DELE1 mt-ISR mediates a stereotyped response to diverse forms of mitochondrial stress and is particularly critical for maintaining growth and survival in early-onset mitochondrial myopathy.
PMCID:10962736
PMID: 38529505
ISSN: 2692-8205
CID: 5688582

Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities

Karz, Alcida; Dimitrova, Maya; Kleffman, Kevin; Alvarez-Breckenridge, Christopher; Atkins, Michael B; Boire, Adrienne; Bosenberg, Marcus; Brastianos, Priscilla; Cahill, Daniel P; Chen, Qing; Ferguson, Sherise; Forsyth, Peter; Glitza Oliva, Isabella C; Goldberg, Sarah B; Holmen, Sheri L; Knisely, Jonathan P S; Merlino, Glenn; Nguyen, Don X; Pacold, Michael E; Perez-Guijarro, Eva; Smalley, Keiran S M; Tawbi, Hussein A; Wen, Patrick Y; Davies, Michael A; Kluger, Harriet M; Mehnert, Janice M; Hernando, Eva
Brain metastases are the most common brain malignancy. This review discusses the studies presented at the third annual meeting of the Melanoma Research Foundation in the context of other recent reports on the biology and treatment of melanoma brain metastases (MBM). Although symptomatic MBM patients were historically excluded from immunotherapy trials, efforts from clinicians and patient advocates have resulted in more inclusive and even dedicated clinical trials for MBM patients. The results of checkpoint inhibitor trials were discussed in conversation with current standards of care for MBM patients, including steroids, radiotherapy and targeted therapy. Advances in the basic scientific understanding of melanoma brain metastases, including the role of astrocytes and metabolic adaptations to the brain microenvironment are exposing new vulnerabilities which could be exploited for therapeutic purposes. Technical advances including single cell omics and multiplex imaging are expanding our understanding of the MBM ecosystem and its response to therapy. This unprecedented level of spatial and temporal resolution is expected to dramatically advance the field in coming years and render novel treatment approaches that might improve the MBM patient outcomes.
PMID: 35912544
ISSN: 1755-148x
CID: 5287832

Reversal of cancer gene expression identifies repurposed drugs for diffuse intrinsic pontine glioma

Zhao, Guisheng; Newbury, Patrick; Ishi, Yukitomo; Chekalin, Eugene; Zeng, Billy; Glicksberg, Benjamin S; Wen, Anita; Paithankar, Shreya; Sasaki, Takahiro; Suri, Amreena; Nazarian, Javad; Pacold, Michael E; Brat, Daniel J; Nicolaides, Theodore; Chen, Bin; Hashizume, Rintaro
Diffuse intrinsic pontine glioma (DIPG) is an aggressive incurable brainstem tumor that targets young children. Complete resection is not possible, and chemotherapy and radiotherapy are currently only palliative. This study aimed to identify potential therapeutic agents using a computational pipeline to perform an in silico screen for novel drugs. We then tested the identified drugs against a panel of patient-derived DIPG cell lines. Using a systematic computational approach with publicly available databases of gene signature in DIPG patients and cancer cell lines treated with a library of clinically available drugs, we identified drug hits with the ability to reverse a DIPG gene signature to one that matches normal tissue background. The biological and molecular effects of drug treatment was analyzed by cell viability assay and RNA sequence. In vivo DIPG mouse model survival studies were also conducted. As a result, two of three identified drugs showed potency against the DIPG cell lines Triptolide and mycophenolate mofetil (MMF) demonstrated significant inhibition of cell viability in DIPG cell lines. Guanosine rescued reduced cell viability induced by MMF. In vivo, MMF treatment significantly inhibited tumor growth in subcutaneous xenograft mice models. In conclusion, we identified clinically available drugs with the ability to reverse DIPG gene signatures and anti-DIPG activity in vitro and in vivo. This novel approach can repurpose drugs and significantly decrease the cost and time normally required in drug discovery.
PMCID:9590174
PMID: 36274161
ISSN: 2051-5960
CID: 5352632