bims-medica 2024-06-30 papers

bims-medica

Biomed News

on Metabolism and diet in cancer

Issue of 2024–06–30
25 papers selected by
Brett Chrest, East Carolina University

Mitochondrial puzzle in muscle: Linking the electron transport system to overweight.
Muscle weakness and mitochondrial stress occur before severe metastasis in a novel mouse model of ovarian cancer cachexia.
Implications of mitochondrial membrane potential gradients on signaling and ATP production analyzed by correlative multi-parameter microscopy.
Stable Isotope Tracing Analysis in Cancer Research: Advancements and Challenges in Identifying Dysregulated Cancer Metabolism and Treatment Strategies.
Understanding mechanisms of resistance to FLT3 inhibitors in adult FLT3-mutated Acute Myeloid Leukemia (AML) to guide treatment strategy.
UCP2, a Member of the Mitochondrial Uncoupling Proteins: An Overview from Physiological to Pathological Roles.
ATP Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance And Is Depressed in Human Heart Failure.
PCK2 maintains intestinal homeostasis and prevents colitis by protecting antibody-secreting cells from oxidative stress.
Application of the Hydrophilic Interaction Liquid Chromatography (HILIC-MS) Novel Protocol to Study the Metabolic Heterogeneity of Glioblastoma Cells.
Detection of early-stage NASH using non-invasive hyperpolarized 13C metabolic imaging.
Moderate-Intensity Exercise Enhances Mitochondrial Biogenesis Markers in the Skeletal Muscle of a Mouse Model Affected by Diet-Induced Obesity.
Glutaminase - A potential target for cancer treatment.
Dietary intervention for adult survivors of cancers other than breast cancer: A systematic review.
International society of sports nutrition position stand: ketogenic diets.
Targeted Metabolomics of Tissue and Plasma Identifies Biomarkers in Mice with NOTCH1-Dependent T-Cell Acute Lymphoblastic Leukemia.
Intensive Induction Chemotherapy versus Hypomethylating Agents in Combination with Venetoclax in NPM1-mutant AML.
Investigating the Relationship between Body Mass Index, Cholesterol, and Cancer in United States Adults: A Cross-Sectional Study.
FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer.
Isocitrate Dehydrogenase Inhibitors in Glioma: From Bench to Bedside.
A temporal and multinational assessment of acute myeloid leukemia (AML) cancer incidence, survival, and disease burden.
Targeting lipid peroxidation-associated ferroptosis suppresses lung carcinoma progression by regulating cell cycle arrest.
SGLT2 inhibition leads to a restoration of hepatic and circulating metabolites involved in the folate cycle and pyrimidine biosynthesis.
The Multifaceted Roles of Mitochondria in Osteoblasts: from Energy Production to Mitochondrial-Derived Vesicle Secretion.
Effects of ketogenic diets on cancer-related variables: A systematic review and meta-analysis of randomised controlled trials.
Critical Role of Mitochondrial Fatty Acid Metabolism in Normal Cell Function and Pathological Conditions.

Obes Rev. 2024 Jun 24. e13794

Mitochondrial puzzle in muscle: Linking the electron transport system to overweight.

Rafael A Casuso.

  Human skeletal muscle mitochondria regulate energy expenditure. Research has shown that the functionality of muscle mitochondria is altered in subjects with overweight, as well as in response to nutrient excess and calorie restriction. Two metabolic features of obesity and overweight are (1) incomplete muscular fatty acid oxidation and (2) increased circulating lactate levels. In this study, I propose that these metabolic disturbances may originate from a common source within the muscle mitochondrial electron transport system. Specifically, a reorganization of the supramolecular structure of the electron transport chain could facilitate the maintenance of readily accessible coenzyme Q pools, which are essential for metabolizing lipid substrates. This approach is expected to maintain effective electron transfer, provided that there is sufficient complex III to support the Q-cycle. Such an adaptation could enhance fatty acid oxidation and prevent mitochondrial overload, thereby reducing lactate production. These insights advance our understanding of the molecular mechanisms underpinning metabolic dysregulation in overweight states. This provides a basis for targeted interventions in the quest for metabolic health.

Keywords:  coenzyme Q; electron transport chain; metabolism; obesity; respiratory supercomplexes; skeletal muscle

DOI:  https://doi.org/10.1111/obr.13794
Mol Metab. 2024 Jun 24. pii: S2212-8778(24)00107-8. [Epub ahead of print] 101976

Muscle weakness and mitochondrial stress occur before severe metastasis in a novel mouse model of ovarian cancer cachexia.

Luca J Delfinis, Leslie M Ogilvie, Shahrzad Khajehzadehshoushtar, Shivam Gandhi, Madison C Garibotti, Arshdeep K Thuhan, Kathy Matuszewska, Madison Pereira, Ronald G Jones, Arthur J Cheng, Thomas J Hawke, Nicholas P Greene, Kevin A Murach, Jeremy A Simpson, Jim Petrik, Christopher G R Perry.

   OBJECTIVES: A high proportion of women with advanced epithelial ovarian cancer (EOC) experience weakness and cachexia. This relationship is associated with increased morbidity and mortality. EOC is the most lethal gynecological cancer, yet no preclinical cachexia model has demonstrated the combined hallmark features of metastasis, ascites development, muscle loss and weakness in adult immunocompetent mice.
METHODS: Here, we evaluated a new model of ovarian cancer-induced cachexia with the advantages of inducing cancer in adult immunocompetent C57BL/6J mice through orthotopic injections of EOC cells in the ovarian bursa. We characterized the development of metastasis, ascites, muscle atrophy, muscle weakness, markers of inflammation, and mitochondrial stress in the tibialis anterior (TA) and diaphragm ∼45, ∼75 and ∼90 days after EOC injection.
RESULTS: Primary ovarian tumour sizes were progressively larger at each time point while severe metastasis, ascites development, and reductions in body, fat and muscle weights occurred by 90 Days. There were no changes in certain inflammatory (TNFα), atrogene (MURF1 and Atrogin) or GDF15 markers within both muscles whereas IL-6 was increased at 45 and 90 Day groups in the diaphragm. TA weakness in 45 Day preceded atrophy and metastasis that were observed later (75 and 90 Day, respectively). The diaphragm demonstrated both weakness and atrophy in 45 Day. In both muscles, this pre-severe-metastatic muscle weakness corresponded with considerable reprogramming of gene pathways related to mitochondrial bioenergetics as well as reduced functional measures of mitochondrial pyruvate oxidation and creatine-dependent ADP/ATP cycling as well as increased reactive oxygen species emission (hydrogen peroxide). Remarkably, muscle force per unit mass at 90 days was partially restored in the TA despite the presence of atrophy and severe metastasis. In contrast, the diaphragm demonstrated progressive weakness. At this advanced stage, mitochondrial pyruvate oxidation in both muscles exceeded control mice suggesting an apparent metabolic super-compensation corresponding with restored indices of creatine-dependent adenylate cycling.
CONCLUSION: This mouse model demonstrates the concurrent development of cachexia and metastasis that occurs in women with EOC. The model provides physiologically relevant advantages of inducing tumour development within the ovarian bursa in immunocompetent adult mice. Moreover, the model reveals that muscle weakness in both TA and diaphragm precedes severe metastasis while weakness also precedes atrophy in the TA. An underlying mitochondrial bioenergetic stress corresponded with this early weakness. Collectively, these discoveries can direct new research towards the development of therapies that target pre-atrophy and pre-severe-metastatic weakness during EOC in addition to therapies targeting cachexia.

Keywords:  Ovarian cancer cachexia; metastasis; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1016/j.molmet.2024.101976
Sci Rep. 2024 06 26. 14(1): 14784

Implications of mitochondrial membrane potential gradients on signaling and ATP production analyzed by correlative multi-parameter microscopy.

Benjamin Gottschalk, Zhanat Koshenov, Roland Malli, Wolfgang F Graier.

  The complex architecture and biochemistry of the inner mitochondrial membrane generate ultra-structures with different phospholipid and protein compositions, shapes, characteristics, and functions. The crista junction (CJ) serves as an important barrier separating the cristae (CM) and inner boundary membranes (IBM). Thereby CJ regulates the movement of ions and ensures distinct electrical potentials across the cristae (ΔΨC) and inner boundary (ΔΨIBM) membranes. We have developed a robust and flexible approach to visualize the CJ permeability with super-resolution microscopy as a readout of local mitochondrial membrane potential (ΔΨmito) fluctuations. This method involves analyzing the distribution of TMRM fluorescence intensity in a model that is restricted to the mitochondrial geometry. We show that mitochondrial Ca2+ elevation hyperpolarizes the CM most likely caused by Ca2+ sensitive increase of mitochondrial tricarboxylic acid cycle (TCA) and subsequent oxidative phosphorylation (OXPHOS) activity in the cristae. Dynamic multi-parameter correlation measurements of spatial mitochondrial membrane potential gradients, ATP levels, and mitochondrial morphometrics revealed a CJ-based membrane potential overflow valve mechanism protecting the mitochondrial integrity during excessive cristae hyperpolarization.

Keywords:  Correlative microscopy; Cristae junctions; Membrane potential gradient; Mitochondria; Mitochondrial membranes

DOI:  https://doi.org/10.1038/s41598-024-65595-z
Metabolites. 2024 May 31. pii: 318. [Epub ahead of print]14(6):

Stable Isotope Tracing Analysis in Cancer Research: Advancements and Challenges in Identifying Dysregulated Cancer Metabolism and Treatment Strategies.

Dalton Hilovsky, Joshua Hartsell, Jamey D Young, Xiaojing Liu.

  Metabolic reprogramming is a hallmark of cancer, driving the development of therapies targeting cancer metabolism. Stable isotope tracing has emerged as a widely adopted tool for monitoring cancer metabolism both in vitro and in vivo. Advances in instrumentation and the development of new tracers, metabolite databases, and data analysis tools have expanded the scope of cancer metabolism studies across these scales. In this review, we explore the latest advancements in metabolic analysis, spanning from experimental design in stable isotope-labeling metabolomics to sophisticated data analysis techniques. We highlight successful applications in cancer research, particularly focusing on ongoing clinical trials utilizing stable isotope tracing to characterize disease progression, treatment responses, and potential mechanisms of resistance to anticancer therapies. Furthermore, we outline key challenges and discuss potential strategies to address them, aiming to enhance our understanding of the biochemical basis of cancer metabolism.

Keywords:  cancer metabolism; high resolution mass spectrometry; stable isotope tracing

DOI:  https://doi.org/10.3390/metabo14060318
Crit Rev Oncol Hematol. 2024 Jun 23. pii: S1040-8428(24)00167-7. [Epub ahead of print] 104424

Understanding mechanisms of resistance to FLT3 inhibitors in adult FLT3-mutated Acute Myeloid Leukemia (AML) to guide treatment strategy.

Martina Ruglioni, Stefania Crucitta, Giovanna Irene Luculli, Gaspare Tancredi, Maria Livia Del Giudice, Sandra Mechell, Sara Galimberti, Romano Danesi, Marzia Del Re.

  The presence of FLT3 mutations, including the most common FLT3-ITD (internal tandem duplications) and FLT3-TKD (tyrosine kinase domain), is associated with an unfavorable prognosis in patients affected by Acute Myeloid Leukemia (AML). In this setting, in recent years, new FLT3-inhibitors have demonstrated efficacy in improving survival and treatment response. Nevertheless, the development of primary and secondary mechanisms of resistance poses a significant obstacle to their efficacy. Understanding these mechanisms is crucial for developing novel therapeutic approaches to overcome resistance and improve the outcomes of patients. In this context, the use of novel FLT3 inhibitors and the combination of different targeted therapies have been studied. This review provides an update on the molecular alterations involved in FLT3 AML mechanisms of resistance, exploring how the molecular monitoring may be used to guide treatment strategy in FLT3-mutated AML.

Keywords:  Acute myeloid leukemia; FLT3 inhibitors; FLT3 mutation; mechanisms of resistance

DOI:  https://doi.org/10.1016/j.critrevonc.2024.104424
Biomedicines. 2024 Jun 13. pii: 1307. [Epub ahead of print]12(6):

UCP2, a Member of the Mitochondrial Uncoupling Proteins: An Overview from Physiological to Pathological Roles.

Salvatore Nesci, Speranza Rubattu.

  UCP2 is an uncoupling protein homolog to UCP1. Unlike UCP1, which participates in non-shivering thermogenesis by uncoupling oxidative phosphorylation (OXPHOS), UCP2 does not perform a canonical H+ leak, consuming the protonmotive force (Δp) through the inner mitochondrial membrane. The UCP2 biological role is elusive. It can counteract oxidative stress, acting with a "mild uncoupling" process to reduce ROS production, and, in fact, UCP2 activities are related to inflammatory processes, triggering pathological conditions. However, the Δp dissipation by UCP2 activity reduces the mitochondrial ATP production and rewires the bioenergetic metabolism of the cells. In all likelihood, UCP2 works as a carrier of metabolites with four carbon atoms (C4), reversing the anaerobic glycolysis-dependent catabolism to OXPHOS. Indeed, UCP2 can perform catalysis in dual mode: mild uncoupling of OXPHOS and metabolite C4 exchange of mitochondria. In vivo, the UCP2 features in the biology of mitochondria promote healthy ageing, increased lifespan, and can assure cerebro- and cardiovascular protection. However, the pathological conditions responsible for insulin secretion suppression are dependent on UCP2 activity. On balance, the uncertain biochemical mechanisms dependent on UCP2 do not allow us to depict the protective role in mitochondrial bioenergetics.

Keywords:  H+ leak; UCP2; bioenergetics; cardiovascular diseases; mitochondria; oxidative phosphorylation

DOI:  https://doi.org/10.3390/biomedicines12061307
bioRxiv. 2024 Jun 10. pii: 2024.06.09.598152. [Epub ahead of print]

ATP Citrate Lyase Supports Cardiac Function and NAD+/NADH Balance And Is Depressed in Human Heart Failure.

Mariam Meddeb, Navid Koleini, Seungho Jun, Mohammad Keykhaei, Farnaz Farshidfar, Liang Zhao, Seoyoung Kwon, Brian Lin, Gizem Keceli, Nazareno Paolocci, Virginia Hahn, Kavita Sharma, Erika L Pearce, David A Kass.

BACKGROUND: ATP-citrate lyase (ACLY) converts citrate into acetyl-CoA and oxaloacetate in the cytosol. It plays a prominent role in lipogenesis and fat accumulation coupled to excess glucose, and its inhibition is approved for treating hyperlipidemia. In RNAseq analysis of human failing myocardium, we found ACLY gene expression is reduced; however the impact this might have on cardiac function and/or metabolism has not been previously studied. As new ACLY inhibitors are in development for cancer and other disorders, such understanding has added importance.
METHODS: Cardiomyocytes, ex-vivo beating hearts, and in vivo hearts with ACLY inhibited by selective pharmacologic (BMS303141, ACLYi) or genetic suppression, were studied. Regulation of ACLY gene/protein expression, and effects of ACLYi on function, cytotoxicity, tricarboxylic acid (TCA)-cycle metabolism, and redox and NAD+/NADH balance were assessed. Mice with cardiac ACLY knockdown induced by AAV9-acly-shRNA or cardiomyocyte tamoxifen-inducible Acly knockdown were studied.
RESULTS: Acly gene expression was reduced more in obese patients with heart failure and preserved EF (HFpEF) than HF with reduced EF. In vivo pressure-overload and in vitro hormonal stress increased ACLY protein expression, whereas it declined upon fatty-acid exposure. Acute ACLYi (1-hr) dose-dependently induced cytotoxicity in adult and neonatal cardiomyocytes, and caused substantial reduction of systolic and diastolic function in myocytes and ex-vivo beating hearts. In the latter, ATP/ADP ratio also fell and lactate increased. U13C-glucose tracing revealed an ACLYdependent TCA-bypass circuit in myocytes, where citrate generated in mitochondria is transported to the cytosol, metabolized by ACLY and then converted to malate to re-enter mitochondria,bypassing several NADH-generating steps. ACLYi lowered NAD+/NADH ratio and restoring this balance ameliorated cardiomyocyte toxicity. Oxidative stress was undetected with ACLYi. Adult hearts following 8-weeks of reduced cardiac and/or cardiomyocyte ACLY downregulation exhibited ventricular dilation and reduced function that was prevented by NAD augmentation. Cardiac dysfunction from ACLY knockdown was worse in hearts subjected to sustained pressureoverload, supporting a role in stress responses.
CONCLUSIONS: ACLY supports normal cardiac function through maintenance of the NAD+/NADH balance and is upregulated by hemodynamic and hormonal stress, but depressed by lipid excess. ACLY levels are most reduced in human HFpEF with obesity potentially worsening cardio-metabolic reserve.

DOI: https://doi.org/10.1101/2024.06.09.598152
Immunology. 2024 Jun 27.

PCK2 maintains intestinal homeostasis and prevents colitis by protecting antibody-secreting cells from oxidative stress.

Kun-Long Duan, Tian-Xiang Wang, Jian-Wei You, Hai-Ning Wang, Zhi-Qiang Wang, Zi-Xuan Huang, Jin-Ye Zhang, Yi-Ping Sun, Yue Xiong, Kun-Liang Guan, Dan Ye, Li Chen, Ronghua Liu, Hai-Xin Yuan.

  Maintaining intracellular redox balance is essential for the survival, antibody secretion, and mucosal immune homeostasis of immunoglobulin A (IgA) antibody-secreting cells (ASCs). However, the relationship between mitochondrial metabolic enzymes and the redox balance in ASCs has yet to be comprehensively studied. Our study unveils the pivotal role of mitochondrial enzyme PCK2 in regulating ASCs' redox balance and intestinal homeostasis. We discover that PCK2 loss, whether globally or in B cells, exacerbates dextran sodium sulphate (DSS)-induced colitis due to increased IgA ASC cell death and diminished antibody production. Mechanistically, the absence of PCK2 diverts glutamine into the TCA cycle, leading to heightened TCA flux and excessive mitochondrial reactive oxygen species (mtROS) production. In addition, PCK2 loss reduces glutamine availability for glutathione (GSH) synthesis, resulting in a decrease of total glutathione level. The elevated mtROS and reduced GSH expose ASCs to overwhelming oxidative stress, culminating in cell apoptosis. Crucially, we found that the mitochondria-targeted antioxidant Mitoquinone (Mito-Q) can mitigate the detrimental effects of PCK2 deficiency in IgA ASCs, thereby alleviating colitis in mice. Our findings highlight PCK2 as a key player in IgA ASC survival and provide a potential new target for colitis treatment.

Keywords:  B cell; mucosal immunology; reactive oxygen species

DOI:  https://doi.org/10.1111/imm.13827
Metabolites. 2024 May 23. pii: 297. [Epub ahead of print]14(6):

Application of the Hydrophilic Interaction Liquid Chromatography (HILIC-MS) Novel Protocol to Study the Metabolic Heterogeneity of Glioblastoma Cells.

Jakub Šofranko, Eduard Gondáš, Radovan Murín.

  Glioblastoma is a highly malignant brain tumor consisting of a heterogeneous cellular population. The transformed metabolism of glioblastoma cells supports their growth and division on the background of their milieu. One might hypothesize that the transformed metabolism of a primary glioblastoma could be well adapted to limitations in the variety and number of substrates imported into the brain parenchyma and present it their microenvironment. Additionally, the phenotypic heterogeneity of cancer cells could promote the variations among their metabolic capabilities regarding the utilization of available substrates and release of metabolic intermediates. With the aim to identify the putative metabolic footprint of different types of glioblastoma cells, we exploited the possibility for separation of polar and ionic molecules present in culture media or cell lysates by hydrophilic interaction liquid chromatography (HILIC). The mass spectrometry (MS) was then used to identify and quantify the eluted compounds. The introduced method allows the detection and quantification of more than 150 polar and ionic metabolites in a single run, which may be present either in culture media or cell lysates and provide data for polaromic studies within metabolomics. The method was applied to analyze the culture media and cell lysates derived from two types of glioblastoma cells, T98G and U118. The analysis revealed that even both types of glioblastoma cells share several common metabolic aspects, and they also exhibit differences in their metabolic capability. This finding agrees with the hypothesis about metabolic heterogeneity of glioblastoma cells. Furthermore, the combination of both analytical methods, HILIC-MS, provides a valuable tool for metabolomic studies based on the simultaneous identification and quantification of a wide range of polar and ionic metabolites-polaromics.

Keywords:  HILIC; LC-MS; amino acid; glioblastoma; metabolic heterogeneity; metabolomics

DOI:  https://doi.org/10.3390/metabo14060297
Sci Rep. 2024 06 27. 14(1): 14854

Detection of early-stage NASH using non-invasive hyperpolarized 13C metabolic imaging.

Cornelius von Morze, Tyler Blazey, Ashley Shaw, William M Spees, Kooresh I Shoghi, Michael A Ohliger.

Non-alcoholic steatohepatitis (NASH) is characterized from its early stages by a profound remodeling of the liver microenvironment, encompassing changes in the composition and activities of multiple cell types and associated gene expression patterns. Hyperpolarized (HP) 13C MRI provides a unique view of the metabolic microenvironment, with potential relevance for early diagnosis of liver disease. Previous studies have detected changes in HP 13C pyruvate to lactate conversion, catalyzed by lactate dehydrogenase (LDH), with experimental liver injury. HP ∝ -ketobutyrate ( ∝ KB) is a close molecular analog of pyruvate with modified specificity for LDH isoforms, specifically attenuated activity with their LDHA-expressed subunits that dominate liver parenchyma. Building on recent results with pyruvate, we investigated HP ∝ KB in methionine-choline deficient (MCD) diet as a model of early-stage NASH. Similarity of results between this new agent and pyruvate (~ 50% drop in cytoplasmic reducing capacity), interpreted together with gene expression data from the model, suggests that changes are mediated through broad effects on intermediary metabolism. Plausible mechanisms are depletion of the lactate pool by upregulation of gluconeogenesis (GNG) and pentose phosphate pathway (PPP) flux, and a possible shift toward increased lactate oxidation. These changes may reflect high levels of oxidative stress and/or shifting macrophage populations in NASH.

DOI: https://doi.org/10.1038/s41598-024-65951-z
Nutrients. 2024 Jun 12. pii: 1836. [Epub ahead of print]16(12):

Moderate-Intensity Exercise Enhances Mitochondrial Biogenesis Markers in the Skeletal Muscle of a Mouse Model Affected by Diet-Induced Obesity.

Lauren Jun, Emily Knight, Tom L Broderick, Layla Al-Nakkash, Brielle Tobin, Thangiah Geetha, Jeganathan Ramesh Babu.

  Skeletal muscle is composed of bundles of muscle fibers with distinctive characteristics. Oxidative muscle fiber types contain higher mitochondrial content, relying primarily on oxidative phosphorylation for ATP generation. Notably, as a result of obesity, or following prolonged exposure to a high-fat diet, skeletal muscle undergoes a shift in fiber type toward a glycolytic type. Mitochondria are highly dynamic organelles, constantly undergoing mitochondrial biogenesis and dynamic processes. Our study aims to explore the impact of obesity on skeletal muscle mitochondrial biogenesis and dynamics and also ascertain whether the skeletal muscle fiber type shift occurs from the aberrant mitochondrial machinery. Furthermore, we investigated the impact of exercise in preserving the oxidative muscle fiber types despite obesity. Mice were subjected to a normal standard chow and water or high-fat diet with sugar water (HFS) with or without exercise training. After 12 weeks of treatment, the HFS diet resulted in a noteworthy reduction in the markers of mitochondrial content, which was recovered by exercise training. Furthermore, higher mitochondrial biogenesis markers were observed in the exercised group with a subsequent increase in the mitochondrial fission marker. In conclusion, these findings imply a beneficial impact of moderate-intensity exercise on the preservation of oxidative capacity in the muscle of obese mouse models.

Keywords:  exercise; high-fat diet; mitochondria; obesity; skeletal muscle

DOI:  https://doi.org/10.3390/nu16121836
Biomedicine (Taipei). 2024 ;14(2): 29-37

Glutaminase - A potential target for cancer treatment.

Josephine Anthony, Sureka Varalakshmi, Ashok Kumar Sekar, Nalini Devarajan, Balamurugan Janakiraman, Rajendran Peramaiyan.

  The overexpression of glutaminase is reported to influence cancer growth and metastasis through glutaminolysis. Upregulation of glutamine catabolism is recently recognized as a critical feature of cancer, and cancer cells are observed to reprogram glutamine metabolism to maintain its survival and proliferation. Special focus is given on the glutaminase isoform, GLS1 (kidney type glutaminase), as the other isoform GLS2 (Liver type glutaminase) acts as a tumour suppressor in some conditions. Glutaminolysis linked with autophagy, which is mediated via mTORC1, also serves as a promising target for cancer therapy. Glutamine also plays a vital role in maintaining redox homeostasis. Inhibition of glutaminase aggravates oxidative stress by reducing glutathione level, thus leading to apoptotic-mediated cell death in cancer cells Therefore, inhibiting the glutaminase activity using glutaminase inhibitors such as BPTES, DON, JHU-083, CB-839, compound 968, etc. may answer many intriguing questions behind the uncontrolled proliferation of cancer cells and serve as a prophylactic treatment for cancer. Earlier reports neither discuss nor provide perspectives on exact signaling gene or pathway. Hence, the present review highlights the plausible role of glutaminase in cancer and the current therapeutic approaches and clinical trials to target and inhibit glutaminase enzymes for better cancer treatment.

Keywords:  Autophagy; Cancer; Glutaminase; Glutaminase inhibitor; Glutamine; Redox homeostasis

DOI:  https://doi.org/10.37796/2211-8039.1445
Medicine (Baltimore). 2024 Jun 28. 103(26): e38675

Dietary intervention for adult survivors of cancers other than breast cancer: A systematic review.

Hideo Matsumoto, Seiji Onogawa, Norihiro Sonoi, Masano Sagawa, Shigeki Wakiyama, Ryo Ogawa, Yasuhiro Miyazaki, Shigeyuki Nagata, Takehiro Okabayashi, Susumu Tazuma, Akihiko Futamura, Yu Uneno, Naoki Higashibeppu, Joji Kotani.

INTRODUCTION: Healthy eating and weight control are recommended for cancer survivors; however, dietary interventions are not routinely offered to them. This study aimed to assess the effects of dietary interventions on survival, nutritional status, morbidity, dietary changes, health-related quality of life (QOL), and clinical measures in cancer survivors.
METHODS: Searches were conducted from October 1, 2018 to November 21, 2011 in the Medline, EMBASE, CENTRAL, Emcare, and DARE electronic databases. We included randomized controlled trials (RCTs) that involved individuals diagnosed with cancer, excluding conference abstracts, case studies, other reviews, and meta-analyses, and screened the articles.
RESULTS: Eight studies were included in this meta-analysis. We observed significant improvements in QOL and clinical data in 3 of 6 studies and in one study, respectively, significant weight loss on anthropometry in 2 of 5 studies, and dietary improvement in 4 of 5 studies of adult cancer survivors. However, we did not observe any benefits of dietary intervention for cancer survivors with undernutrition.
DISCUSSION: Dietary interventions for adult cancer survivors might contribute to improving their nutritional status; however, further clarification requires a study that standardizes the intervention method. Furthermore, RCTs are required to determine the effects on cancer survivors with undernutrition.

DOI: https://doi.org/10.1097/MD.0000000000038675
J Int Soc Sports Nutr. 2024 Dec;21(1): 2368167

International society of sports nutrition position stand: ketogenic diets.

Alex Leaf, Jeffrey A Rothschild, Tim M Sharpe, Stacy T Sims, Chad J Macias, Geoff G Futch, Michael D Roberts, Jeffrey R Stout, Michael J Ormsbee, Alan A Aragon, Bill I Campbell, Shawn M Arent, Dominic P D'Agostino, Michelle T Barrack, Chad M Kerksick, Richard B Kreider, Douglas S Kalman, Jose Antonio.

   POSITION STATEMENT: The International Society of Sports Nutrition (ISSN) provides an objective and critical review of the use of a ketogenic diet in healthy exercising adults, with a focus on exercise performance and body composition. However, this review does not address the use of exogenous ketone supplements. The following points summarize the position of the ISSN.
1. A ketogenic diet induces a state of nutritional ketosis, which is generally defined as serum ketone levels above 0.5 mM. While many factors can impact what amount of daily carbohydrate intake will result in these levels, a broad guideline is a daily dietary carbohydrate intake of less than 50 grams per day.
2. Nutritional ketosis achieved through carbohydrate restriction and a high dietary fat intake is not intrinsically harmful and should not be confused with ketoacidosis, a life-threatening condition most commonly seen in clinical populations and metabolic dysregulation.
3. A ketogenic diet has largely neutral or detrimental effects on athletic performance compared to a diet higher in carbohydrates and lower in fat, despite achieving significantly elevated levels of fat oxidation during exercise (~1.5 g/min).
4. The endurance effects of a ketogenic diet may be influenced by both training status and duration of the dietary intervention, but further research is necessary to elucidate these possibilities. All studies involving elite athletes showed a performance decrement from a ketogenic diet, all lasting six weeks or less. Of the two studies lasting more than six weeks, only one reported a statistically significant benefit of a ketogenic diet.
5. A ketogenic diet tends to have similar effects on maximal strength or strength gains from a resistance training program compared to a diet higher in carbohydrates. However, a minority of studies show superior effects of non-ketogenic comparators.
6. When compared to a diet higher in carbohydrates and lower in fat, a ketogenic diet may cause greater losses in body weight, fat mass, and fat-free mass, but may also heighten losses of lean tissue. However, this is likely due to differences in calorie and protein intake, as well as shifts in fluid balance.
7. There is insufficient evidence to determine if a ketogenic diet affects males and females differently. However, there is a strong mechanistic basis for sex differences to exist in response to a ketogenic diet.

Keywords:  Endurance; body composition; exercise; ketogenesis; ketosis; strength

DOI:  https://doi.org/10.1080/15502783.2024.2368167
Int J Mol Sci. 2024 Jun 13. pii: 6543. [Epub ahead of print]25(12):

Targeted Metabolomics of Tissue and Plasma Identifies Biomarkers in Mice with NOTCH1-Dependent T-Cell Acute Lymphoblastic Leukemia.

Valeria Tosello, Ludovica Di Martino, Erich Piovan.

  While the genomics era has allowed remarkable advances in understanding the mechanisms driving the biology and pathogenesis of numerous blood cancers, including acute lymphoblastic leukemia (ALL), metabolic studies are still lagging, especially regarding how the metabolism differs between healthy and diseased individuals. T-cell ALL (T-ALL) is an aggressive hematological neoplasm deriving from the malignant transformation of T-cell progenitors characterized by frequent NOTCH1 pathway activation. The aim of our study was to characterize tumor and plasma metabolomes during T-ALL development using a NOTCH1-induced murine T-ALL model (ΔE-NOTCH1). In tissue, we found a significant metabolic shift with leukemia development, as metabolites linked to glycolysis (lactic acid) and Tricarboxylic acid cycle replenishment (succinic and malic acids) were elevated in NOTCH1 tumors, while metabolites associated with lipid oxidation (e.g., carnitine) as well as purine and pyrimidine metabolism were elevated in normal thymic tissue. Glycine, serine, and threonine metabolism, glutathione metabolism, as well as valine, leucine, and isoleucine biosynthesis were enriched pathways in tumor tissue. Phenylalanine and tyrosine metabolism was highly enriched in plasma from leukemia-bearing mice compared to healthy mice. Further, we identified a metabolic signature consisting of glycine, alanine, proline, 3-hydroxybutyrate, and glutamic acid as potential biomarkers for leukemia progression in plasma. Hopefully, the metabolic differences detected in our leukemia model will apply to humans and contribute to the development of metabolism-oriented therapeutic approaches.

Keywords:  NOTCH1 signaling; T-cell lymphoblastic leukemia; leukemia growth; metabolism

DOI:  https://doi.org/10.3390/ijms25126543
Blood Adv. 2024 Jun 28. pii: bloodadvances.2024012858. [Epub ahead of print]

Intensive Induction Chemotherapy versus Hypomethylating Agents in Combination with Venetoclax in NPM1-mutant AML.

Jan Philipp Bewersdorf, Shai Shimony, Rory M Shallis, Yiwen Liu, Guillaume Berton, Eva Johanna Schaefer, Amer M Zeidan, Aaron D Goldberg, Eytan M Stein, Guido Marcucci, Rebecca Bystrom, R Coleman Lindsley, Evan C Chen, Jorge Miguel Ramos Perez, Anthony S Stein, Vinod A Pullarkat, Ibrahim Aldoss, Daniel J DeAngelo, Donna S Neuberg, Richard M Stone, Sylvain Garciaz, Brian J Ball, Maximilian Stahl.

While intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), data from older patients shows that hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remissions among patients with NPM1 mutations. Whether IC or HMA/VEN is superior in patients ≥60 years-old with NPM1-mutant AML is unknown. To compare IC and HMA/VEN, we performed an international, multicenter retrospective cohort study of patients with newly diagnosed, NPM1-mutant AML.We included 221 patients (147 IC, 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR; defined as CR + CR with incomplete count recovery [CRi]) rate was similar for IC and HMA/VEN (cCR: 85% vs. 74%; p=0.067). While OS was favorable with IC in unselected patients compared to HMA/VEN (24-month OS 59% [95% CI: 52-69%] vs. 38% [95% CI 27-55%]; p=0.013), it was not statistically different among patients 60-75 years-old (60% [95% CI 52-70%] vs. 44% [95% CI 29-66%]; p=0.069) and patients who received an allogeneic stem cell transplant (70% [95% CI: 58-85%] vs. 66% [95% CI: 44-100%]; p=0.56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS with IC 65% [95% 56-74%] vs. 40% [95% CI: 26-60%] with HMA/VEN; p=0.009) and without FLT3-ITD mutations might benefit from IC compared with HMA/VEN (24-month OS: 68% [95% CI: 59-79%] vs. 43% [95% CI: 29-63%]; p=0.008). In multivariable analysis, OS was not statistically different for patients treated with IC and HMA/VEN (hazard ratio for death HMA/VEN vs. IC: 0.71; 95% CI: 0.40-1.27; p=0.25).

DOI: https://doi.org/10.1182/bloodadvances.2024012858
Diseases. 2024 Jun 04. pii: 120. [Epub ahead of print]12(6):

Investigating the Relationship between Body Mass Index, Cholesterol, and Cancer in United States Adults: A Cross-Sectional Study.

Anastasija Martinović, David R Axon.

  The purpose of this cross-sectional study was to investigate the relationship between Body Mass Index (BMI), cholesterol, and cancer in United States (US) adults. Data were collected from the 2020 Medical Expenditure Panel Survey (MEPS). Eligible participants were US adults (≥18 years) with data on BMI, cholesterol, and cancer status, who were alive at the end of the data collection period. An adjusted logistic regression model assessed associations between eight possible combinations of BMI and cholesterol status (independent variable) with cancer diagnosis (dependent variable). Among 27,805 individuals in the 2020 MEPS data, 20,818 met the eligibility criteria (weighted N = 252,340,615). Of these 2668 (weighted N = 29,770,359) had cancer and 18,150 (weighted N = 222,570,256) did not have cancer. In the adjusted logistic regression model, underweight and normal weight individuals with high cholesterol were associated with higher odds of cancer (odds ratio, OR = 2.002, and 95% confidence interval, CI = 1.032-3.885, and OR = 1.326 and 95% CI = 1.047-1.681, respectively), while obese individuals with normal cholesterol were associated with lower odds of cancer (OR = 0.681; 95% CI = 0.543-0.853) compared to normal weight individuals with normal cholesterol. This study offers insights into specific groups of individuals who may be prioritized for cancer prevention. Further research is required to investigate these findings in additional subpopulations.

Keywords:  BMI; United States adults; cancer; cholesterol; cross-sectional-study; logistic regression

DOI:  https://doi.org/10.3390/diseases12060120
EMBO Mol Med. 2024 Jun 26.

FADS1/2 control lipid metabolism and ferroptosis susceptibility in triple-negative breast cancer.

Nicla Lorito, Angela Subbiani, Alfredo Smiriglia, Marina Bacci, Francesca Bonechi, Laura Tronci, Elisabetta Romano, Alessia Corrado, Dario Livio Longo, Marta Iozzo, Luigi Ippolito, Giuseppina Comito, Elisa Giannoni, Icro Meattini, Alexandra Avgustinova, Paola Chiarugi, Angela Bachi, Andrea Morandi.

  Triple-negative breast cancer (TNBC) has limited therapeutic options, is highly metastatic and characterized by early recurrence. Lipid metabolism is generally deregulated in TNBC and might reveal vulnerabilities to be targeted or used as biomarkers with clinical value. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation which is facilitated by the presence of polyunsaturated fatty acids (PUFA). Here we identify fatty acid desaturases 1 and 2 (FADS1/2), which are responsible for PUFA biosynthesis, to be highly expressed in a subset of TNBC with a poorer prognosis. Lipidomic analysis, coupled with functional metabolic assays, showed that FADS1/2 high-expressing TNBC are susceptible to ferroptosis-inducing agents and that targeting FADS1/2 by both genetic interference and pharmacological approach renders those tumors ferroptosis-resistant while unbalancing PUFA/MUFA ratio by the supplementation of exogenous PUFA sensitizes resistant tumors to ferroptosis induction. Last, inhibiting lipid droplet (LD) formation and turnover suppresses the buffering capacity of LD and potentiates iron-dependent cell death. These findings have been validated in vitro and in vivo in mouse- and human-derived clinically relevant models and in a retrospective cohort of TNBC patients.

Keywords:  Desaturases; Ferroptosis; Lipid Droplets; Lipid Metabolism; Polyunsaturated Fatty Acids

DOI:  https://doi.org/10.1038/s44321-024-00090-6
Pharmaceuticals (Basel). 2024 May 26. pii: 682. [Epub ahead of print]17(6):

Isocitrate Dehydrogenase Inhibitors in Glioma: From Bench to Bedside.

Merve Hazal Ser, Mason Webb, Anna Thomsen, Ugur Sener.

  Isocitrate dehydrogenase (IDH) mutant gliomas are a primary malignancy of the central nervous system (CNS) malignancies, most commonly affecting adults under the age of 55. Standard of care therapy for IDH-mutant gliomas involves maximal safe resection, radiotherapy, and chemotherapy. However, despite good initial responses to multimodality treatment, recurrence is virtually universal. IDH-mutant gliomas represent a life-limiting prognosis. For this reason, there is a great need for novel treatments that can prolong survival. Uniquely for IDH-mutant gliomas, the IDH mutation is the direct driver of oncogenesis through its oncometabolite 2-hydroxygluterate. Inhibition of this mutated IDH with a corresponding reduction in 2-hydroxygluterate offers an attractive treatment target. Researchers have tested several IDH inhibitors in glioma through preclinical and early clinical trials. A phase III clinical trial of an IDH1 and IDH2 inhibitor vorasidenib yielded promising results among patients with low-grade IDH-mutant gliomas who had undergone initial surgery and no radiation or chemotherapy. However, many questions remain regarding optimal use of IDH inhibitors in clinical practice. In this review, we discuss the importance of IDH mutations in oncogenesis of adult-type diffuse gliomas and current evidence supporting the use of IDH inhibitors as therapeutic agents for glioma treatment. We also examine unresolved questions and propose potential directions for future research.

Keywords:  IDH inhibitor; dual inhibitor of mIDH1/2; glial tumor; vorasidenib

DOI:  https://doi.org/10.3390/ph17060682
Leuk Lymphoma. 2024 Jun 27. 1-10

A temporal and multinational assessment of acute myeloid leukemia (AML) cancer incidence, survival, and disease burden.

Laura J Anderson, Mariam Girguis, Elise Kim, Jitesh Shewale, Megan Braunlin, Winifred Werther, Juliana E Hidalgo-Lopez, Faraz Zaman, Christopher Kim.

  Understanding the global epidemiology of AML is critical for assessing therapeutic demand and informing healthcare resource allocation. This study estimated current and future AML incidence in 27 countries, described AML survival trends in the United States, and calculated average years of life lost (AYLL). Incidence rates were age-standardized using rates from IARC's Cancer Incidence in Five Continents and SEER databases and ranged from 0.70 to 3.23 cases per 100,000 persons. Crude incidence rates were projected from 2024 to 2040; growth varied from +1% to +46%. Median overall survival was derived from SEER databases and increased from 4 to 11 months over the last 40 years. Median AYLL of 18.6 years was estimated for 27 countries. This study projected significant growth in new AML diagnoses over the next two decades. Despite improvements in survival over the last four decades, median survival among AML patients remains poor highlighting the need for novel treatments.

Keywords:  AML; AYLL; Acute myeloid leukemia; epidemiology; incidence; survival

DOI:  https://doi.org/10.1080/10428194.2024.2360536
Int Immunopharmacol. 2024 Jun 24. pii: S1567-5769(24)01039-7. [Epub ahead of print]138 112518

Targeting lipid peroxidation-associated ferroptosis suppresses lung carcinoma progression by regulating cell cycle arrest.

Xiuju Liu, Yuhui Sun, Xue Lv, Mengmeng Song, Jian Sun, Yulan Sun.

  Lung carcinoma is a frequently encountered cancerous growth that affects the respiratory tract and has a high occurrence rate globally. In light of the ongoing worldwide health emergency, the significance of efficient therapeutic agents and strategies is of utmost importance. A meticulous control of the cell cycle is crucial for comprehending the pathophysiology and molecular causes of lung cancer, as well as for the formulation of efficacious therapeutic medicines. The mechanism by which cells synchronize cell cycle with cell survival and death is still not fully understood. In this study, we demonstrate that the halting of the cell cycle has a strong inhibitory impact on ferroptosis, a specific type of controlled cell death triggered by excessive lipid peroxidation at the membranes of cells. Ferroptosis is halted through the mechanism of cell cycle arrest, which involves the deposition of intracellular lipids mediated by diacylglycerol acyltransferase (DGAT). Excessive amounts of polyunsaturated fatty acids (PUFAs) are stored as triacylglycerols (TAGs) within inactive cells. As a result, inhibiting DGAT causes a rearrangement of PUFAs from TAGs to phospholipids and makes arrested cells more susceptible to ferroptosis. We demonstrate that certain lung cancer cells that are resistant to antimitotic drugs and have a slow-cycling behavior exhibit an increase in lipid droplets. Furthermore, we find that the growth of tumors resistant to 5-fluorouracil, lorlatinib, and docetaxel can be effectively suppressed by a combination treatment involving the use of ferroptosis inducers and DGAT inhibitors, which induces ferroptosis. Collectively, these findings demonstrate the involvement of cell cycle arrest in conferring resistance to ferroptosis and propose a potential therapeutic approach for addressing the challenge of slow-cycling malignancies that exhibit resistance to ferroptosis.

Keywords:  Cell cycle; Chemotherapy; Drug resistance of lung cancer; Ferroptosis; Lung cancer

DOI:  https://doi.org/10.1016/j.intimp.2024.112518
Am J Physiol Gastrointest Liver Physiol. 2024 Jun 25.

SGLT2 inhibition leads to a restoration of hepatic and circulating metabolites involved in the folate cycle and pyrimidine biosynthesis.

Ileana Mendez Espinoza, Elijah N D Choos, Carolyn M Ecelbarger, Blythe D Shepard.

  Inhibition of sodium-glucose co-transporter 2 (SGLT2) by Empagliflozin (EMPA) and other 'flozins can improve glycemic control under conditions of diabetes and kidney disease. Though they act on the kidney, they also offer cardiovascular and liver protection. Previously, we found that EMPA decreased circulating triglycerides and hepatic lipid and cholesterol esters in male TallyHo mice fed a high milk fat diet (HMFD). The goal of this study was to determine if the liver protection is associated with a change in metabolic function by characterizing the hepatic and circulating metabolic and lipidomic profiles using targeted LC-MS. In both male and female mice, HMFD feeding significantly altered the circulating and hepatic metabolome compared to low-fat diet (LFD). Addition of EMPA resulted in the restoration of circulating orotate (intermediate in pyrimidine biosynthesis) and hepatic dihydrofolate (intermediate in the folate and methionine cycles) levels in males and acylcarnitines in females. These changes were partially explained by altered expression of rate-limiting enzymes in these pathways. This metabolic signature was not detected when EMPA was incorporated into an LFD suggesting that the restoration requires the metabolic shift that accompanies the HMFD. Notably, the HMFD increased expression of 18/20 circulating amino acids in males and 11/20 in females, and this pattern was reversed by EMPA. Finally, we confirmed that SGLT2 inhibition upregulates ketone bodies including b-hydroxybutyrate. Collectively, this study highlights the metabolic changes that occur with EMPA treatment, and sheds light on the possible mechanisms by which this drug offers liver and systemic protection.

Keywords:  SGLT2i; TallyHo; hepatic steatosis; lipidomics; metabolomics

DOI:  https://doi.org/10.1152/ajpgi.00029.2024
J Bone Miner Res. 2024 Jun 22. pii: zjae088. [Epub ahead of print]

The Multifaceted Roles of Mitochondria in Osteoblasts: from Energy Production to Mitochondrial-Derived Vesicle Secretion.

Joonho Suh, Yun-Sil Lee.

Mitochondria in osteoblasts have been demonstrated to play multiple crucial functions in bone formation from intracellular ATP production to extracellular secretion of mitochondrial components. The present review explores the current knowledge about mitochondrial biology in osteoblasts, including mitochondrial biogenesis, bioenergetics, oxidative stress generation, and dynamic changes in morphology. Special attention is given to recent findings, including mitochondrial donut formation in osteoblasts, which actively generates mitochondrial-derived vesicles (MDVs), followed by extracellular secretion of small mitochondria and MDVs. We also discuss the therapeutic effects of targeting osteoblast mitochondria, highlighting their potential applications in improving bone health.

DOI: https://doi.org/10.1093/jbmr/zjae088
Nutr Bull. 2024 Jun 24.

Effects of ketogenic diets on cancer-related variables: A systematic review and meta-analysis of randomised controlled trials.

Belinda Salido-Bueno, Esther Gil-Hernandez, Lola Rueda-Ruzafa, Pablo Gomez-Chica, Pablo Roman, Diana Cardona.

  Cancer is a global health concern influenced by genetics, environment and lifestyle choices. Recent research shows that a ketogenic diet (KD) might ease cancer symptoms and reduce tumour size. We hypothesised that the KD could result in improvements in cancer-related variables. Therefore, this study aims to perform a systematic review and meta-analysis to assess the KD's efficacy for patients with cancer. The databases PubMed (MEDLINE), Web of Science, CINAHL and Open Grey were utilised for conducting a systematic review and meta-analysis. The analysis was limited to randomised controlled trials with adult participants aged 18 years and above. Levels of glucose, cholesterol, insulin-like growth factor 1, weight and quality of life were evaluated following the KD. After identifying 596 articles in the initial search, eight studies, lasting between 4 and 16 weeks, were included in the systematic review and seven in the meta-analysis. The KD led to decreased glucose levels in patients with cancer but did not show significant improvements in cholesterol, insulin-like growth factor 1, weight or quality of life. Based on the results of this systematic review and meta-analysis, there is insufficient evidence to establish a definitive link between the KD and cancer-related parameters. While some studies suggest potential benefits in terms of some outcomes and tumour size reduction, further research is required to fully comprehend the effects of this diet.

Keywords:  chemotherapy, adjuvant; diet, ketogenic; glucose; neoplasms; systematic review; tumour cells

DOI:  https://doi.org/10.1111/nbu.12693
Int J Mol Sci. 2024 Jun 12. pii: 6498. [Epub ahead of print]25(12):

Critical Role of Mitochondrial Fatty Acid Metabolism in Normal Cell Function and Pathological Conditions.

Sergey Dikalov, Alexander Panov, Anna Dikalova.

  There is a "popular" belief that a fat-free diet is beneficial, supported by the scientific dogma indicating that high levels of fatty acids promote many pathological metabolic, cardiovascular, and neurodegenerative conditions. This dogma pressured scientists not to recognize the essential role of fatty acids in cellular metabolism and focus on the detrimental effects of fatty acids. In this work, we critically review several decades of studies and recent publications supporting the critical role of mitochondrial fatty acid metabolism in cellular homeostasis and many pathological conditions. Fatty acids are the primary fuel source and essential cell membrane building blocks from the origin of life. The essential cell membranes phospholipids were evolutionarily preserved from the earlier bacteria in human subjects. In the past century, the discovery of fatty acid metabolism was superseded by the epidemic growth of metabolic conditions and cardiovascular diseases. The association of fatty acids and pathological conditions is not due to their "harmful" effects but rather the result of impaired fatty acid metabolism and abnormal lifestyle. Mitochondrial dysfunction is linked to impaired metabolism and drives multiple pathological conditions. Despite metabolic flexibility, the loss of mitochondrial fatty acid oxidation cannot be fully compensated for by other sources of mitochondrial substrates, such as carbohydrates and amino acids, resulting in a pathogenic accumulation of long-chain fatty acids and a deficiency of medium-chain fatty acids. Despite popular belief, mitochondrial fatty acid oxidation is essential not only for energy-demanding organs such as the heart, skeletal muscle, and kidneys but also for metabolically "inactive" organs such as endothelial and epithelial cells. Recent studies indicate that the accumulation of long-chain fatty acids in specific organs and tissues support the impaired fatty acid oxidation in cell- and tissue-specific fashion. This work, therefore, provides a basis to challenge these established dogmas and articulate the need for a paradigm shift from the "pathogenic" role of fatty acids to the critical role of fatty acid oxidation. This is important to define the causative role of impaired mitochondrial fatty acid oxidation in specific pathological conditions and develop novel therapeutic approaches targeting mitochondrial fatty acid metabolism.

Keywords:  fatty acid metabolism; mitochondria; pathological conditions; respiration

DOI:  https://doi.org/10.3390/ijms25126498