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Biomolecules
Special Issues
Research on Fatty Acid Oxidation and Fatty Acid Oxidation Disorders
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Research on Fatty Acid Oxidation and Fatty Acid Oxidation Disorders

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (15 March 2025) | Viewed by 3068

Special Issue Editor

Dr. Paschalis-Thomas Doulias

E-Mail Website
Guest Editor
Laboratory of Biochmemistry, Department of Chemistry and Institute of Biosciences, University Research Center of Ioannina, University of Ioannina, 45110 Ioannina, Greece
Interests: fatty acid oxidation; fatty acid oxidation disorders; regulation of fatty acid oxidation; nitric oxide signaling; proteomics; protein post translational modifications; therapeutics

Special Issue Information

Dear Colleagues,

Mitochondrial β-oxidation (mFAO) is the main route for the metabolism of long-chain fatty acids under normal, metabolic and physical stress conditions. Contracting cardiomyocytes generate 50-70% of the ATP molecules that are required for normal contractile and ionic functions through the oxidation of long-chain fatty acids. In addition, in the liver and skeletal muscle, the generation of energy through mFAO is adaptive and occurs during metabolic stress or physical exercise.

Defects in nuclear genes encoding for enzymes and transporters of the mFAO pathway cause a family of rare, inherited autosomal recessive diseases that are collectively known as long fatty acid oxidation disorders (FAODs). Clinical manifestations include cardiomyopathy, intermittent muscle breakdown and liver failure.  

The molecular mechanisms underlying the regulation of β-oxidation in health and disease are incompletely understood. Fatty acid oxidation disorders demonstrate a high morbidity and mortality rate, highlighting the need for a better understanding of the physiology, as well as the development, of novel concepts and treatments for these life-threatening disorders.

The focus of this Special Issue of Biomolecules will be on the mechanisms and therapeutics of fatty acid oxidation (FAO) and FAO disorders. Both research and review articles are welcome.

Dr. Paschalis-Thomas Doulias
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • fatty acid oxidation
  • fatty acid oxidation disorders
  • regulation of fatty acid oxidation
  • therapeutics

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Published Papers (3 papers)

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Research

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15 pages, 1672 KiB  
Article
Sirtuin-5 Is Recruited to Hepatic Peroxisomes in Mice Fed Dodecanedioic Acid but Has Little Impact on the Peroxisomal Succinylome
by Yuxun Zhang, Bob B. Zhang, Sivakama S. Bharathi, Joanna Bons, Jacob P. Rose, Samah Shah, Steven F. Dobrowolski, Sunder Sims-Lucas, Birgit Schilling and Eric S. Goetzman
Biomolecules 2024, 14(12), 1508; https://doi.org/10.3390/biom14121508 - 26 Nov 2024
Viewed by 933
Abstract
Lysine succinylation, and its reversal by sirtuin-5 (SIRT5), is known to modulate mitochondrial fatty acid β-oxidation (FAO). We recently showed that feeding mice dodecanedioic acid, a 12-carbon dicarboxylic acid (DC12) that can be chain-shortened four rounds to succinyl-CoA, drives high-level protein [...] Read more.
Lysine succinylation, and its reversal by sirtuin-5 (SIRT5), is known to modulate mitochondrial fatty acid β-oxidation (FAO). We recently showed that feeding mice dodecanedioic acid, a 12-carbon dicarboxylic acid (DC12) that can be chain-shortened four rounds to succinyl-CoA, drives high-level protein hypersuccinylation in the peroxisome, particularly on peroxisomal FAO enzymes. However, the ability of SIRT5 to reverse DC12-induced peroxisomal succinylation, or to regulate peroxisomal FAO in this context, remained unexplored. Here, we showed that feeding DC12 strongly recruits SIRT5 into hepatic peroxisomes. Knocking out SIRT5 impaired peroxisomal FAO as evidenced by reduced 14C-DC12 flux in liver homogenates and elevated levels of partially shortened DC12 catabolites in urine. Further, mass spectrometry revealed a trend toward less peroxisomal protein succinylation in SIRT5 knockout liver. This is consistent with a reduced flux of DC12 through the peroxisomal FAO pathway, thereby reducing the production of the succinyl-CoA that chemically reacts with lysine residues to produce protein succinylation. Mass spectrometry comparisons of site-level succinylation in wildtype and SIRT5 knockout liver did not reveal any clear pattern of SIRT5 target sites in the peroxisome after DC12 feeding. However, SIRT5 co-immunoprecipitated with 15 peroxisomal proteins, including the key peroxisomal FAO enzymes acyl-CoA oxidase-1 and enoyl-CoA/3-hydroxyacyl-CoA dehydrogenase (EHHADH). In vitro, recombinant SIRT5 partially desuccinylated chemically modified recombinants ACOX1a, ACOX1b, and EHHADH. Desuccinylation by SIRT5 had no effect on enzyme activity for ACOX1a and EHHADH. For ACOX1b, SIRT5-mediated desuccinylation decreased activity by ~15%. Possible interpretations of these data are discussed. Full article
(This article belongs to the Special Issue Research on Fatty Acid Oxidation and Fatty Acid Oxidation Disorders)
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Review

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34 pages, 3038 KiB  
Review
Not Just an Alternative Energy Source: Diverse Biological Functions of Ketone Bodies and Relevance of HMGCS2 to Health and Disease
by Varshini V. Suresh, Sathish Sivaprakasam, Yangzom D. Bhutia, Puttur D. Prasad, Muthusamy Thangaraju and Vadivel Ganapathy
Biomolecules 2025, 15(4), 580; https://doi.org/10.3390/biom15040580 - 14 Apr 2025
Viewed by 440
Abstract
Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by “keto” diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal [...] Read more.
Ketogenesis, a mitochondrial metabolic pathway, occurs primarily in liver, but kidney, colon and retina are also capable of this pathway. It is activated during fasting and exercise, by “keto” diets, and in diabetes as well as during therapy with SGLT2 inhibitors. The principal ketone body is β-hydroxybutyrate, a widely recognized alternative energy source for extrahepatic tissues (brain, heart, muscle, and kidney) when blood glucose is sparse or when glucose transport/metabolism is impaired. Recent studies have identified new functions for β-hydroxybutyrate: it serves as an agonist for the G-protein-coupled receptor GPR109A and also works as an epigenetic modifier. Ketone bodies protect against inflammation, cancer, and neurodegeneration. HMGCS2, as the rate-limiting enzyme, controls ketogenesis. Its expression and activity are regulated by transcriptional and post-translational mechanisms with glucagon, insulin, and glucocorticoids as the principal participants. Loss-of-function mutations occur in HMGCS2 in humans, resulting in a severe metabolic disease. These patients typically present within a year after birth with metabolic acidosis, hypoketotic hypoglycemia, hepatomegaly, steatotic liver damage, hyperammonemia, and neurological complications. Nothing is known about the long-term consequences of this disease. This review provides an up-to-date summary of the biological functions of ketone bodies with a special focus on HMGCS2 in health and disease. Full article
(This article belongs to the Special Issue Research on Fatty Acid Oxidation and Fatty Acid Oxidation Disorders)
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22 pages, 5340 KiB  
Review
Carnitine O-Acetyltransferase as a Central Player in Lipid and Branched-Chain Amino Acid Metabolism, Epigenetics, Cell Plasticity, and Organelle Function
by Mariateresa Volpicella, Maria Noemi Sgobba, Luna Laera, Anna Lucia Francavilla, Danila Imperia De Luca, Lorenzo Guerra, Ciro Leonardo Pierri and Anna De Grassi
Biomolecules 2025, 15(2), 216; https://doi.org/10.3390/biom15020216 - 2 Feb 2025
Viewed by 1173
Abstract
Carnitine O-acetyltransferase (CRAT) is a key mitochondrial enzyme involved in maintaining metabolic homeostasis by mediating the reversible transfer of acetyl groups between acetyl-CoA and carnitine. This enzymatic activity ensures the optimal functioning of mitochondrial carbon flux by preventing acetyl-CoA accumulation, buffering metabolic flexibility, [...] Read more.
Carnitine O-acetyltransferase (CRAT) is a key mitochondrial enzyme involved in maintaining metabolic homeostasis by mediating the reversible transfer of acetyl groups between acetyl-CoA and carnitine. This enzymatic activity ensures the optimal functioning of mitochondrial carbon flux by preventing acetyl-CoA accumulation, buffering metabolic flexibility, and regulating the balance between fatty acid and glucose oxidation. CRAT’s interplay with the mitochondrial carnitine shuttle, involving carnitine palmitoyltransferases (CPT1 and CPT2) and the carnitine carrier (SLC25A20), underscores its critical role in energy metabolism. Emerging evidence highlights the structural and functional diversity of CRAT and structurally related acetyltransferases across cellular compartments, illustrating their coordinated role in lipid metabolism, amino acid catabolism, and mitochondrial bioenergetics. Moreover, the structural insights into CRAT have paved the way for understanding its regulation and identifying potential modulators with therapeutic applications for diseases such as diabetes, mitochondrial disorders, and cancer. This review examines CRAT’s structural and functional aspects, its relationships with carnitine shuttle members and other carnitine acyltransferases, and its broader role in metabolic health and disease. The potential for targeting CRAT and its associated pathways offers promising avenues for therapeutic interventions aimed at restoring metabolic equilibrium and addressing metabolic dysfunction in disease states. Full article
(This article belongs to the Special Issue Research on Fatty Acid Oxidation and Fatty Acid Oxidation Disorders)
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