Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle

Knottnerus, Suzan J. G.; Bleeker, Jeannette C.; Wüst, Rob C I; Ferdinandusse, Sacha; IJlst, Lodewijk; Wijburg, Frits A.; Wanders, Ronald J. A.; Visser, Gepke; Houtkooper, Riekelt H.

doi:10.1007/s11154-018-9448-1

Cited by 245 publications

(238 citation statements)

References 172 publications

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“…We tested this hypothesis by quantifying acylcarnitines in plasma and liver, which are elevated when oxidation of fatty acids or amino acids is impaired. For instance, elevation of C2-C5 carnitines suggests defects in oxidation of short chain fatty acids or amino acids, whereas increases in C6-C18 carnitines is clinically diagnostic of defects in oxidation of medium-and long-chain fatty acids (Knottnerus et al, 2018). Congruent with the RNA-seq data, liquid chromatographymass spectrometry (LC-MS) analysis of acylcarnitines in plasma and liver revealed a general impairment in oxidation of mediumand long-chain fatty acids.…”

Section: Activation Of Immunity Reprograms Nutrient Metabolism In Thementioning

confidence: 99%

Energetic Trade-Offs and Hypometabolic States Promote Disease Tolerance

Ganeshan

Nikkanen

Man

et al. 2019

Cell

206

212

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Graphical AbstractHighlights d Activated immunity engages in an energetic trade-off with homeothermy d Immunity reprograms hepatic metabolism to meet host energetic priorities d Energetic trade-off between immunity and homeothermy promotes disease tolerance d Hypometabolic states promote disease tolerance during bacterial infections In BriefImmune activation after infection is metabolically costly, competing for energy with the maintenance of normal body temperature, and this dynamic trade-off leads to preferential use of tolerance as a mechanism of bacterial defense. SUMMARYHost defenses against pathogens are energetically expensive, leading ecological immunologists to postulate that they might participate in energetic trade-offs with other maintenance programs. However, the metabolic costs of immunity and the nature of physiologic trade-offs it engages are largely unknown. We report here that activation of immunity causes an energetic trade-off with the homeothermy (the stable maintenance of core temperature), resulting in hypometabolism and hypothermia. This immunity-induced physiologic trade-off was independent of sickness behaviors but required hematopoietic sensing of lipopolysaccharide (LPS) via the toll-like receptor 4 (TLR4). Metabolomics and genome-wide expression profiling revealed that distinct metabolic programs supported entry and recovery from the energy-conserving hypometabolic state. During bacterial infections, hypometabolic states, which could be elicited by competition for energy between maintenance programs or energy restriction, promoted disease tolerance. Together, our findings suggest that energy-conserving hypometabolic states, such as dormancy, might have evolved as a mechanism of tissue tolerance.

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Section: Activation Of Immunity Reprograms Nutrient Metabolism In Thementioning

confidence: 99%

Energetic Trade-Offs and Hypometabolic States Promote Disease Tolerance

Ganeshan

Nikkanen

Man

et al. 2019

Cell

206

212

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“…Transfer of fatty acids across the inner membrane into the matrix is then mediated by Cpt2 through a process that is coupled to the removal of carnitine. 91 Within the matrix, fatty acids can be used to fuel FAO. This work therefore linked increased mitochondrial activity and FAO specifically in the IL-4 driven activation process.…”

Section: The Etomoxir Controversy-a Role For Fao?mentioning

confidence: 99%

Cell‐intrinsic metabolic regulation of mononuclear phagocyte activation: Findings from the tip of the iceberg

Bakker

Pearce

2020

Immunological Reviews

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We have only recently started to appreciate the extent to which immune cell activation involves significant changes in cellular metabolism. We are now beginning to understand how commitment to specific metabolic pathways influences aspects of cellular biology that are the more usual focus of immunological studies, such as activation-induced changes in gene transcription, post-transcriptional regulation of transcription, post-translational modifications of proteins, cytokine secretion, etc. Here, we focus on metabolic reprogramming in mononuclear phagocytes downstream of stimulation with inflammatory signals (such as LPS and IFNγ) vs alternative activation signals (IL-4), with an emphasis on work on dendritic cells and macrophages from our laboratory, and related studies from others. We cover aspects of glycolysis and its branching pathways (glycogen synthesis, pentose phosphate, serine synthesis, hexose synthesis, and glycerol 3 phosphate shuttle), the tricarboxylic acid pathway, fatty acid synthesis and oxidation, and mitochondrial biology. Although our understanding of the metabolism of mononuclear phagocytes has progressed significantly over the last 10 years, major challenges remain, including understanding the effects of tissue residence on metabolic programming related to cellular activation, and the translatability of findings from mouse to human biology. K E Y W O R D SThis is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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“…Oxidative stress is a hallmark of HF, and mitochondria are the main source of reactive oxygen species (ROS) in cardiac myocytes [21,22]. In the failing heart, the emission of ROS from mitochondria is the result of their increased production, which is mainly secondary to the leakage of electrons from complex I of the respiratory chain to oxygen [23,24], and their impaired elimination by mitochondrial antioxidant system [20,25].…”

Section: Altered Mechano-chemo-transduction and Oxidative Stress In Hmentioning

confidence: 99%

Metabolic Alterations in Inherited Cardiomyopathies

Sacchetto

Sequeira

Bertero

et al. 2019

JCM

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The normal function of the heart relies on a series of complex metabolic processes orchestrating the proper generation and use of energy. In this context, mitochondria serve a crucial role as a platform for energy transduction by supplying ATP to the varying demand of cardiomyocytes, involving an intricate network of pathways regulating the metabolic flux of substrates. The failure of these processes results in structural and functional deficiencies of the cardiac muscle, including inherited cardiomyopathies. These genetic diseases are characterized by cardiac structural and functional anomalies in the absence of abnormal conditions that can explain the observed myocardial abnormality, and are frequently associated with heart failure. Since their original description, major advances have been achieved in the genetic and phenotype knowledge, highlighting the involvement of metabolic abnormalities in their pathogenesis. This review provides a brief overview of the role of mitochondria in the energy metabolism in the heart and focuses on metabolic abnormalities, mitochondrial dysfunction, and storage diseases associated with inherited cardiomyopathies.

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Disorders of mitochondrial long-chain fatty acid oxidation and the carnitine shuttle

Cited by 245 publications

References 172 publications

Energetic Trade-Offs and Hypometabolic States Promote Disease Tolerance

Energetic Trade-Offs and Hypometabolic States Promote Disease Tolerance

Cell‐intrinsic metabolic regulation of mononuclear phagocyte activation: Findings from the tip of the iceberg

Metabolic Alterations in Inherited Cardiomyopathies

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