bims-fatoxi 2024-03-10 papers

Issue of 2024–03–10
six papers selected by
Shashwat Sharma, Deakin University

Mol Genet Metab. 2024 Feb 23. pii: S1096-7192(24)00235-X. [Epub ahead of print]142(1): 108350

Major clinical events and healthcare resource use among patients with long-chain fatty acid oxidation disorders in the United States: Results from LC-FAOD Odyssey program.

Erru Yang, Eliza Kruger, David Yin, Kieran Mace, Meghan Tierney, Noelle Liao, Emily Cibelli, Dan Drozd, Nathan Ross, Kathleen L Deering, Peter Herout, Qing Harshaw, Alicia Shillington, Nina Thomas, Deborah Marsden, Amy Kritzer, Jerry Vockley.

Major clinical events (MCEs) related to long-chain fatty acid oxidation disorders (LC-FAOD) in triheptanoin clinical trials include inpatient or emergency room (ER) visits for three major clinical manifestations: rhabdomyolysis, hypoglycemia, and cardiomyopathy. However, outcomes data outside of LC-FAOD clinical trials are limited. The non-interventional cohort LC-FAOD Odyssey study examines data derived from US medical records and patient reported outcomes to quantify LC-FAOD burden according to management strategy including MCE frequency and healthcare resource utilization (HRU). Thirty-four patients were analyzed of which 21 and 29 patients had received triheptanoin and/or medium chain triglycerides (MCT), respectively. 36% experienced MCEs while receiving triheptanoin versus 54% on MCT. Total mean annualized MCE rates on triheptanoin and MCT were 0.1 and 0.7, respectively. Annualized disease-related inpatient and ER events were lower on triheptanoin (0.2, 0.3, respectively) than MCT (1.2, 1.0, respectively). Patients were managed more in an outpatient setting on triheptanoin (8.9 annualized outpatient visits) vs MCT (7.9). Overall, this shows that those with LC-FAOD in the Odyssey program experienced fewer MCEs and less HRU in inpatient and ER settings during triheptanoin-treated periods compared with the MCT-treated periods. The MCE rate was lower after initiation of triheptanoin, consistent with clinical trials.

Keywords: Long-chain fatty acid oxidation disorder; Medium chain triglyceride; Metabolism; Rare disease

DOI: https://doi.org/10.1016/j.ymgme.2024.108350

Mol Genet Metab. 2024 Feb 23. pii: S1096-7192(24)00236-1. [Epub ahead of print]142(1): 108351

A review of fatty acid oxidation disorder mouse models.

Shannon J Babcock, Sander M Houten, Melanie B Gillingham.

Fatty acid oxidation disorders (FAODs) are a family of rare, genetic disorders that affect any part of the fatty acid oxidation pathway. Patients present with severe phenotypes, such as hypoketotic hypoglycemia, cardiomyopathy, and rhabdomyolysis, and currently manage these symptoms by the avoidance of fasting and maintaining a low-fat, high-carbohydrate diet. Because knowledge about FAODs is limited due to the small number of patients, rodent models have been crucial in learning more about these disorders, particularly in studying the molecular mechanisms involved in different phenotypes and in evaluating treatments for patients. The purpose of this review is to present the different FAOD mouse models and highlight the benefits and limitations of using these models. Specifically, we discuss the phenotypes of the available FAOD mouse models, the potential molecular causes of prominent FAOD phenotypes that have been studied using FAOD mouse models, and how FAOD mouse models have been used to evaluate treatments for patients.

Keywords: Cardiomyopathy; Exercise; Fatty acid β-oxidation; Gene addition; Hypoglycemia; Inborn errors of metabolism; Mouse models

DOI: https://doi.org/10.1016/j.ymgme.2024.108351

Proc Natl Acad Sci U S A. 2024 Mar 12. 121(11): e2319254121

Fatty acid oxidation fuels natural killer cell responses against infection and cancer.

Sam Sheppard, Katja Srpan, Wendy Lin, Mariah Lee, Rebecca B Delconte, Mark Owyong, Peter Carmeliet, Daniel M Davis, Joao B Xavier, Katharine C Hsu, Joseph C Sun.

Natural killer (NK) cells are a vital part of the innate immune system capable of rapidly clearing mutated or infected cells from the body and promoting an immune response. Here, we find that NK cells activated by viral infection or tumor challenge increase uptake of fatty acids and their expression of carnitine palmitoyltransferase I (CPT1A), a critical enzyme for long-chain fatty acid oxidation. Using a mouse model with an NK cell-specific deletion of CPT1A, combined with stable 13C isotope tracing, we observe reduced mitochondrial function and fatty acid-derived aspartate production in CPT1A-deficient NK cells. Furthermore, CPT1A-deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. Together, our findings highlight that fatty acid oxidation promotes NK cell metabolic resilience, processes that can be optimized in NK cell-based immunotherapies.

Keywords: NK cells; T cells; cancer; metabolism; virus infection

DOI: https://doi.org/10.1073/pnas.2319254121

Hepatol Commun. 2024 Mar 01. pii: e0395. [Epub ahead of print]8(3):

Hepatocellular carcinoma cells downregulate NADH:Ubiquinone Oxidoreductase Subunit B3 to maintain reactive oxygen species homeostasis.

Zhendong Zhang, Qianwei Zhao, Zexuan Wang, Fang Xu, Yixian Liu, Yaoyu Guo, Chenglong Li, Ting Liu, Ying Zhao, Xiaolei Tang, Jintao Zhang.

BACKGROUND: HCC is a leading cause of cancer-related death. The role of reactive oxygen species (ROS) in HCC remains elusive. Since a primary ROS source is the mitochondrial electron transport chain complex Ι and the NADH:ubiquinone Oxidoreductase Subunit B3 (NDUFB3), a complex I subunit, is critical for complex I assembly and regulates the associated ROS production, we hypothesize that some HCCs progress by hijacking NDUFB3 to maintain ROS homeostasis.
METHODS: NDUFB3 in human HCC lines was either knocked down or overexpressed. The cells were then analyzed in vitro for proliferation, migration, invasiveness, colony formation, complex I activity, ROS production, oxygen consumption, apoptosis, and cell cycle. In addition, the in vivo growth of the cells was evaluated in nude mice. Moreover, the role of ROS in the NDUFB3-mediated changes in the HCC lines was determined using cellular and mitochondrion-targeted ROS scavengers.
RESULTS: HCC tissues showed reduced NDUFB3 protein expression compared to adjacent healthy tissues. In addition, NDUFB3 knockdown promoted, while its overexpression suppressed, HCC cells' growth, migration, and invasiveness. Moreover, NDUFB3 knockdown significantly decreased, whereas its overexpression increased complex I activity. Further studies revealed that NDUFB3 overexpression elevated mitochondrial ROS production, causing cell apoptosis, as manifested by the enhanced expressions of proapoptotic molecules and the suppressed expression of the antiapoptotic molecule B cell lymphoma 2. Finally, our data demonstrated that the apoptosis was due to the activation of the c-Jun N-terminal kinase (JNK) signaling pathway and cell cycle arrest at G0/G1 phase.
CONCLUSIONS: Because ROS plays essential roles in many biological processes, such as aging and cancers, our findings suggest that NDFUB3 can be targeted for treating HCC and other human diseases.

DOI: https://doi.org/10.1097/HC9.0000000000000395

Trends Pharmacol Sci. 2024 Mar 07. pii: S0165-6147(24)00028-2. [Epub ahead of print]

Targeting mitochondrial dynamics and redox regulation in cardiovascular diseases.

Mirza Ahmar Beg, Minqi Huang, Lance Vick, K N Shashanka Rao, Jue Zhang, Yiliang Chen.

Accumulating evidence highlights the pivotal role of mitochondria in cardiovascular diseases (CVDs). Understanding the molecular mechanisms underlying mitochondrial dysfunction is crucial for developing targeted therapeutics. Recent years have seen substantial advancements in unraveling mitochondrial regulatory pathways in both normal and pathological states and the development of potent drugs. However, specific delivery of drugs into the mitochondria is still a challenge. We present recent findings on regulators of mitochondrial dynamics and reactive oxygen species (ROS), critical factors influencing mitochondrial function in CVDs. We also discuss advancements in drug delivery strategies aimed at overcoming the technical barrier in targeting mitochondria for CVD treatment.

Keywords: atherosclerosis; cardiovascular disease; drug delivery; fission/fusion; mitochondria; reactive oxygen species

DOI: https://doi.org/10.1016/j.tips.2024.02.001

Chem Asian J. 2024 Mar 06. e202400105

Recent Advances in Detection of Hydroxyl Radical by Responsive Fluorescence Nanoprobes.

Mazen Alanazi, Jiaxi Yong, Miaomiao Wu, Zexi Zhang, Dihua Tian, Run Zhang.

Hydroxyl radical (•OH), a highly reactive oxygen species (ROS), is assumed as one of the most aggressive free radicals. This radical has a detrimental impact on cells as it can react with different biological substrates leading to pathophysiological disorders, including inflammation, mitochondrion dysfunction, and cancer. Quantification of this free radical in-situ plays critical roles in early diagnosis and treatment monitoring of various disorders, like macrophage polarization and tumor cell development. Luminescence analysis using responsive probes has been an emerging and reliable technique for in-situ detection of various cellular ROS, and some recently developed •OH responsive nanoprobes have confirmed the association with cancer development. This paper aims to summarize the recent advances in the characterization of •OH in living organisms using responsive nanoprobes, covering the production, the sources of •OH, and biological function, especially in the development of related diseases followed by the discussion of luminescence nanoprobes for •OH detection.

Keywords: Fluorescence detection; Hydroxyl radical; Reactive oxygen species; Responsive nanoprobe

DOI: https://doi.org/10.1002/asia.202400105