Bladder cancer (BLCA) mortality is higher in African American (AA) patients compared with European American (EA) patients, but the molecular mechanism underlying race-specific differences are unknown. To address this gap, we conducted comprehensive RNA-Seq, proteomics, and metabolomics analysis of BLCA tumors from AA and EA. Our findings reveal a distinct metabolic phenotype in AA BLCA characterized by elevated mitochondrial oxidative phosphorylation (OXPHOS), particularly through the activation of complex I. The results provide insight into the complex I activation–driven higher OXPHOS activity resulting in glutamine-mediated metabolic rewiring and increased disease progression, which was also confirmed by [U]13C-glutamine tracing. Mechanistic studies further demonstrate that knockdown of NDUFB8, one of the components of complex I in AA BLCA cells, resulted in reduced basal respiration, ATP production, GLS1 expression, and proliferation. Moreover, preclinical studies demonstrate the therapeutic potential of targeting complex I, as evidenced by decreased tumor growth in NDUFB8-depleted AA BLCA tumors. Additionally, genetic and pharmacological inhibition of GLS1 attenuated mitochondrial respiration rates and tumor growth potential in AA BLCA. Taken together, these findings provide insight into BLCA disparity for targeting GLS1-Complex I for future therapy.
Karthik Reddy Kami Reddy, Danthasinghe Waduge Badrajee Piyarathna, Jun Hyoung Park, Vasanta Putluri, Chandra Sekhar Amara, Abu Hena Mostafa Kamal, Jun Xu, Daniel Kraushaar, Shixia Huang, Sung Yun Jung, Livia S. Eberlin, Jabril R. Johnson, Rick A. Kittles, Leomar Y. Ballester, Krishna Parsawar, M. Minhaj Siddiqui, Jianjun Gao, Adriana Langer Gramer, Roni J. Bollag, Martha K. Terris, Yair Lotan, Chad J. Creighton, Seth P. Lerner, Arun Sreekumar, Benny Abraham Kaipparettu, Nagireddy Putluri
Our objective was to interrogate infant mesenchymal stem cell (MSC) lipid metabolism and gestational exposures that may contribute to child obesity risk. MSCs were cultured from term infants of mothers with obesity (n=16) or normal-weight (n=15). In MSCs undergoing myogenesis in vitro, we used lipidomics to distinguish phenotypes by unbiased cluster analysis and lipid challenge (24h excess fatty acid, 24hFA). We measured MSC AMP-activated protein kinase (AMPK) activity and fatty acid oxidation (FAO), and a composite index of maternal glucose, insulin, triglycerides, free fatty acids, tumor necrosis factor-α, high density lipoprotein- and total- cholesterol in fasting blood from mid- and late-gestation (~17, ~27wks). We measured child adiposity at birth (n=29), 4-6m (n=29), and 4-6y (n=13). Three MSC clusters were distinguished by triacylglycerol (TAG) stores, with greatest TAGs in Cluster-2. All Clusters increased acylcarnitines and TAGs with 24hFA, though Cluster-2 was more pronounced and corresponded to AMPK activation and FAO. Maternal metabolic markers predicted MSC Clusters and child adiposity at 4-6y (both highest in Cluster-3). Our data supports that MSC phenotypes are predicted by comprehensive maternal metabolic milieu exposures, independent of maternal BMI, and suggest utility as an at-birth predictor for child adiposity, though validation with larger longitudinal samples is warranted.
Lauren E. Gyllenhammer, Vincent Zaegel, Allison M. Duensing, Manoel Lixandrao, Dana Dabelea, Bryan C. Bergman, Kristen E. Boyle
The prevalence of chronic kidney diseases (CKD) varies by race due to genetic and environmental factors. The Glu504Lys polymorphism in aldehyde dehydrogenase 2 (ALDH2), commonly observed among East Asians, alters the enzyme's function in detoxifying alcohol-derived aldehydes, impacting kidney function. This study investigated the association between variations in ALDH2 levels within the kidney and the progression of kidney fibrosis. Our clinical data indicates that diminished ALDH2 levels are linked to worse CKD outcomes, with correlations between ALDH2 expression, estimated glomerular filtration rate, urinary levels of acrolein, an aldehyde metabolized by ALDH2, and fibrosis severity. In mouse models of unilateral ureteral obstruction and folic acid nephropathy, reduced ALDH2 levels and elevated acrolein were observed in kidneys, especially in ALDH2 Glu504Lys knock-in mice. Mechanistically, acrolein modifies pyruvate kinase M2, leading to its nuclear translocation and co-activation of HIF-1α, shifting cellular metabolism to glycolysis, disrupting mitochondrial function, contributing to tubular damage and the progression of kidney fibrosis. Enhancing ALDH2 expression through adeno-associated virus vectors reduces acrolein and mitigates fibrosis in both wild-type and Glu504Lys knock-in mice. These findings underscore the potential therapeutic significance of targeting the dynamic interaction between ALDH2 and acrolein in CKD.
Szu-yuan Li, Ming-Tsun Tsai, Yu-Ming Kuo, Hui-Min Yang, Zhen-Jie Tong, Hsiao-Wei Cheng, Chih-Ching Lin, Hsiang-Tsui Wang
The complexity of the mechanisms underlying non-alcoholic fatty liver disease (NAFLD) progression remains a significant challenge for the development of effective therapeutics. miRNAs have shown great promise as regulators of biological processes and as therapeutic targets for complex diseases. Here, we study the role of hepatic miR-33, an important regulator of lipid metabolism, during the progression of NAFLD and the development of hepatocellular carcinoma (HCC). We report that miR-33 is elevated in the livers of humans and mice with NAFLD and that its deletion in hepatocytes (miR-33 HKO) improves multiple aspects of the disease, including steatosis and inflammation, limiting the progression to non-alcoholic steatohepatitis (NASH), fibrosis and HCC. Mechanistically, hepatic miR-33 deletion reduces lipid synthesis and promotes mitochondrial fatty acid oxidation, reducing lipid burden. Additionally, absence of miR-33 alters the expression of several known miR-33 target genes involved in metabolism and results in improved mitochondrial function and reduced oxidative stress. The reduction in lipid accumulation and liver injury resulted in decreased YAP/TAZ pathway activation, which may be involved in the reduced HCC progression in HKO livers. Together, these results suggest suppressing hepatic miR-33 may be an effective therapeutic approach to temper the development of NAFLD, NASH, and HCC in obesity
Pablo Fernández-Tussy, Magdalena P. Cardelo, Hanming Zhang, Jonathan Sun, Nathan L. Price, Nabil E. Boutagy, Leigh Goedeke, Martí Cadena-Sandoval, Chrysovalantou E. Xirouchaki, Wendy A. Brown, Xiaoyong Yang, Oscar Pastor-Rojo, Rebecca A. Haeusler, Anton M. Bennett, Tony Tiganis, Yajaira Suárez, Carlos Fernández-Hernando
Fuel substrate switching between carbohydrates and fat is essential for maintaining metabolic homeostasis. During aerobic exercise, the predominant energy source gradually shifts from carbohydrates to fat. While it is well known that exercise mobilizes fat storage from adipose tissues, it remains largely obscure how circulating lipids are distributed tissue-specifically according to distinct energy requirements. Here, we demonstrate that aerobic exercise is linked to nutrient availability to regulate tissue-specific activities of lipoprotein lipase (LPL), the key enzyme catabolizing circulating triglyceride (TG) for tissue uptake, through the differential actions of angiopoietin-like (ANGPTL) proteins. Exercise reduced the tissue binding of ANGPTL3 protein, increasing LPL activity and TG uptake in the heart and skeletal muscle in the postprandial state specifically. Mechanistically, exercise suppressed insulin secretion, attenuating hepatic Angptl8 transcription through the PI3K/mTOR/CEBPα pathway, which is imperative for the tissue binding of its partner ANGPTL3. Constitutive expression of ANGPTL8 hampered lipid utilization and resulted in cardiac dysfunction in response to exercise. Conversely, exercise promoted the expression of ANGPTL4 in white adipose tissues, overriding the regulatory actions of ANGPTL8/ANGPTL3 in suppressing adipose LPL activity, thereby diverting circulating TG away from storage. Collectively, our findings show an overlooked bifurcated ANGPTL-LPL network that orchestrates fuel switching in response to aerobic exercise.
Xiaomin Liu, Yiliang Zhang, Bingqian Han, Lin Li, Ying Li, Yifan Ma, Shijia Kang, Quan Li, Lingkai Kong, Kun Huang, Bao-liang Song, Yong Liu, Yan Wang
Friedreich’s ataxia (FRDA) is a progressive disorder caused by insufficient expression of frataxin, which plays a critical role in assembly of iron-sulfur centers in mitochondria. Individuals are cognitively normal but display a loss of motor coordination and cardiac abnormalities. Many ultimately develop heart failure. Administration of nicotinamide adenine dinucleotide–positive (NAD+) precursors has shown promise in human mitochondrial myopathy and rodent models of heart failure, including mice lacking frataxin in cardiomyocytes. We studied mice with systemic knockdown of frataxin (shFxn), which display motor deficits and early mortality with cardiac hypertrophy. Hearts in these mice do not “fail” per se but become hyperdynamic with small chamber sizes. Data from an ongoing natural history study indicate that hyperdynamic hearts are observed in young individuals with FRDA, suggesting that the mouse model could reflect early pathology. Administering nicotinamide mononucleotide or riboside to shFxn mice increases survival, modestly improves cardiac hypertrophy, and limits increases in ejection fraction. Mechanistically, most of the transcriptional and metabolic changes induced by frataxin knockdown are insensitive to NAD+ precursor administration, but glutathione levels are increased, suggesting improved antioxidant capacity. Overall, our findings indicate that NAD+ precursors are modestly cardioprotective in this model of FRDA and warrant further investigation.
Caroline E. Perry, Sarah M. Halawani, Sarmistha Mukherjee, Lucie V. Ngaba, Melissa Lieu, Won Dong Lee, James G. Davis, Gabriel K. Adzika, Alyssa N. Bebenek, Daniel D. Bazianos, Beishan Chen, Elizabeth Mercado-Ayon, Liam P. Flatley, Arjun P. Suryawanshi, Isabelle Ho, Joshua D. Rabinowitz, Suraj D. Serai, David M. Biko, Jaclyn Tamaroff, Anna DeDio, Kristin Wade, Kimberly Y. Lin, David J. Livingston, Shana E. McCormack, David R. Lynch, Joseph A. Baur
Dihydrolipoamide dehydrogenase (DLD) deficiency is a recessive mitochondrial disease caused by variants in DLD, the E3 subunit of mitochondrial α-keto acid dehydrogenase complexes. DLD disease symptoms are multi-systemic, variably manifesting as Leigh syndrome, neurodevelopmental disability, seizures, cardiomyopathy, liver disease, fatigue and lactic acidemia. While most DLD disease symptoms are attributed to dysfunction of the pyruvate dehydrogenase complex, understanding the effects of other α-keto acid dehydrogenase deficiencies remain unclear. Current therapies for DLD deficiency are ineffective, with no vertebrate animal model available for preclinical study. We created a viable Danio rerio (zebrafish) KO model of DLD deficiency, dldhcri3. Detailed phenotypic characterization revealed shortened larval survival, uninflated swim bladder, hepatomegaly and fatty liver, and reduced swim activity. These animals displayed increased pyruvate and lactate levels, with severe disruption of branched-chain amino acid catabolism manifest as increased valine, leucine, isoleucine, α-ketoisovalerate, and α-ketoglutarate levels. Evaluation of mitochondrial ultrastructure revealed gross enlargement, severe cristae disruption and reduction in matrix electron density in liver, intestines, and muscle. Therapeutic modeling of candidate therapies demonstrated probucol or thiamine improved larval swim activity. Overall, this vertebrate model demonstrated characteristic phenotypic and metabolic alterations of DLD disease, offering a robust platform to screen and characterize candidate therapies.
Manuela Lavorato, Donna Iadarola, Cristina Remes, Prabhjot Kaur, Chynna Broxton, Neal D. Mathew, Rui Xiao, Christoph Seiler, Eiko Nakamaru-Ogiso, Vernon E. Anderson, Marni J. Falk
Current antiretroviral therapy (ART) regimens efficiently limit HIV replication, thereby improving life expectancy of people living with HIV, but also cause metabolic side effects. The ongoing obesity epidemic has resulted in more people with metabolic comorbidities at the time of HIV infection, yet the impact of pre-existing metabolic dysregulation on infection sequelae and response to ART is unclear. Here, to investigate the impact of preexisting obesity and insulin resistance on acute infection and subsequent long-term ART, we infected a cohort of lean and obese adult male macaques with SIV and administered ART. The responses of lean and obese macaques to SIV and ART were similar with respect to plasma and cell-associated viral loads, ART drug levels in plasma and tissues, SIV-specific immune responses, adipose tissue and islet morphology, and colon inflammation, with baseline differences between lean and obese groups largely maintained. Both groups exhibited a striking depletion of CD4+ T cells from adipose tissue that did not recover with ART. However, differential responses to SIV and ART were observed for body weight, omental adipocyte size, and the adiponectin/leptin ratio, a marker of cardiometabolic risk. Thus, obesity and insulin resistance had limited effects on multiple responses to acute SIV infection and ART, while several factors that underlie long-term metabolic comorbidities were influenced by prior obesity and insulin resistance. These studies provide the foundation for future investigations into the efficacy of adjunct therapies such as metformin and glucagon-like peptide-1 receptor agonists in the prevention of metabolic comorbidities in people living with HIV.
Gabriela M. Webb, Kristin A. Sauter, Diana Takahashi, Melissa Kirigiti, Lindsay Bader, Sarah R. Lindsley, Hannah M. Blomenkamp, Cicely Zaro, Molly Shallman, Casey M. McGuire, Heather Hofmeister, Uriel Avila, Cleiton Pessoa, Joseph M. Hwang, Allyson J. McCullen, Matthew Humkey, Jason Reed, Lina Gao, Lee Winchester, Courtney V. Fletcher, Oleg Varlamov, Todd T. Brown, Jonah B. Sacha, Paul Kievit, Charles T. Roberts
Mitochondrial trifunctional protein (TFP) deficiency is an inherited metabolic disorder leading to a block in long-chain fatty acid β-oxidation. Mutations in either HADHA and HADHB, which encode the TFPα and β subunits, respectively, usually result in combined TFP deficiency. A single common mutation, HADHA c.1528G>C (p.E510Q), leads to isolated 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. TFP also catalyzes a step in the remodeling of cardiolipin (CL), a phospholipid critical to mitochondrial membrane stability and function. We explored the effect of mutations in TFP subunits on CL and other phospholipid content and composition and the consequences of these changes on mitochondrial bioenergetics in patient-derived fibroblasts. Abnormalities in these parameters varied extensively among different fibroblasts, and some cells were able to maintain basal oxygen consumption rates similar to controls. Although CL reduction was universally identified, a simultaneous increase in monolysocardiolipins was discrepant among cells. A similar profile was seen in liver mitochondria isolates from a TFP-deficient mouse model. Response to new potential drugs targeting cardiolipin metabolism might be dependent on patient genotype.
Eduardo Vieira Neto, Meicheng Wang, Austin J. Szuminsky, Lethicia Ferraro, Erik Koppes, Yudong Wang, Clinton Van’t Land, Al-Walid Mohsen, Geancarlo Zanatta, Areeg H. El-Gharbawy, Tamil S. Anthonymuthu, Yulia Y. Tyurina, Vladimir A. Tyurin, Valerian Kagan, Hülya Bayir, Jerry Vockley
The clinical therapy for treating acute myocardial infarction is primary percutaneous coronary intervention (PPCI). PPCI is effective at reperfusing the heart, however the rapid re-introduction of blood can cause ischemia-reperfusion (I/R). Reperfusion injury is responsible for up to half of the final myocardial damage, but there are no pharmacological interventions to reduce I/R. We previously demonstrated that inhibiting monocarboxylate transporter 4 (MCT4) and re-directing pyruvate towards oxidation can blunt hypertrophy. We hypothesized this pathway might be important during I/R. Here, we establish that the pyruvate-lactate axis plays a role in determining myocardial salvage following injury. Post-I/R, the mitochondrial pyruvate carrier (MPC), required for pyruvate oxidation, is upregulated in the surviving myocardium. In cardiomyocytes lacking the MPC, there was increased cell death and less salvage after I/R, which was associated with an upregulation of MCT4. To determine the importance of pyruvate oxidation, we inhibited MCT4 with a small-molecule drug (VB124) at reperfusion. This strategy normalized reactive oxygen species (ROS), mitochondrial membrane potential (∆Ψ), and Ca2+, increased pyruvate entry to TCA cycle, increased oxygen consumption, improved myocardial salvage and functional outcomes following I/R. Our data suggests normalizing pyruvate-lactate metabolism by inhibiting MCT4 is a promising therapy to mitigate I/R injury.
Joseph R. Visker, Ahmad A. Cluntun, Jesse N. Velasco-Silva, David R. Eberhardt, Luis Cedeno-Rosario, Thirupura S. Shankar, Rana Hamouche, Jing Ling, Hyoin Kwak, J. Yanni Hillas, Ian Aist, Eleni Tseliou, Sutip Navankasattusas, Dipayan Chaudhuri, Gregory S. Ducker, Stavros G. Drakos, Jared Rutter
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