Research

Jump to: Review

18 pages, 6137 KiB

Open AccessArticle

Lipidomic and Proteomic Alterations Induced by Even and Odd Medium-Chain Fatty Acids on Fibroblasts of Long-Chain Fatty Acid Oxidation Disorders

by Khaled I. Alatibi, Stefan Tholen, Zeinab Wehbe, Judith Hagenbuchner, Daniela Karall, Michael J. Ausserlechner, Oliver Schilling, Sarah C. Grünert, Jerry Vockley and Sara Tucci

Int. J. Mol. Sci. 2021, 22(19), 10556; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms221910556 - 29 Sep 2021

Cited by 5 | Viewed by 2244

Abstract

Medium-chain fatty acids (mc-FAs) are currently applied in the treatment of long-chain fatty acid oxidation disorders (lc-FAOD) characterized by impaired β-oxidation. Here, we performed lipidomic and proteomic analysis in fibroblasts from patients with very long-chain acyl-CoA dehydrogenase (VLCADD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) [...] Read more.

Medium-chain fatty acids (mc-FAs) are currently applied in the treatment of long-chain fatty acid oxidation disorders (lc-FAOD) characterized by impaired β-oxidation. Here, we performed lipidomic and proteomic analysis in fibroblasts from patients with very long-chain acyl-CoA dehydrogenase (VLCADD) and long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHADD) deficiencies after incubation with heptanoate (C7) and octanoate (C8). Defects of β-oxidation induced striking proteomic alterations, whereas the effect of treatment with mc-FAs was minor. However, mc-FAs induced a remodeling of complex lipids. Especially C7 appeared to act protectively by restoring sphingolipid biosynthesis flux and improving the observed dysregulation of protein homeostasis in LCHADD under control conditions. Full article

(This article belongs to the Special Issue Energy Metabolism in Health and Disease)

► Show Figures

Figure 1

21 pages, 4120 KiB

Open AccessArticle

Mice with Whole-Body Disruption of AMPK-Glycogen Binding Have Increased Adiposity, Reduced Fat Oxidation and Altered Tissue Glycogen Dynamics

by Natalie R. Janzen, Jamie Whitfield, Lisa Murray-Segal, Bruce E. Kemp, John A. Hawley and Nolan J. Hoffman

Int. J. Mol. Sci. 2021, 22(17), 9616; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22179616 - 05 Sep 2021

Cited by 6 | Viewed by 3452

Abstract

The AMP-activated protein kinase (AMPK), a central regulator of cellular energy balance and metabolism, binds glycogen via its β subunit. However, the physiological effects of disrupting AMPK-glycogen interactions remain incompletely understood. To chronically disrupt AMPK-glycogen binding, AMPK β double knock-in (DKI) mice were [...] Read more.

The AMP-activated protein kinase (AMPK), a central regulator of cellular energy balance and metabolism, binds glycogen via its β subunit. However, the physiological effects of disrupting AMPK-glycogen interactions remain incompletely understood. To chronically disrupt AMPK-glycogen binding, AMPK β double knock-in (DKI) mice were generated with mutations in residues critical for glycogen binding in both the β1 (W100A) and β2 (W98A) subunit isoforms. We examined the effects of this DKI mutation on whole-body substrate utilization, glucose homeostasis, and tissue glycogen dynamics. Body composition, metabolic caging, glucose and insulin tolerance, serum hormone and lipid profiles, and tissue glycogen and protein content were analyzed in chow-fed male DKI and age-matched wild-type (WT) mice. DKI mice displayed increased whole-body fat mass and glucose intolerance associated with reduced fat oxidation relative to WT. DKI mice had reduced liver glycogen content in the fed state concomitant with increased utilization and no repletion of skeletal muscle glycogen in response to fasting and refeeding, respectively, despite similar glycogen-associated protein content relative to WT. DKI liver and skeletal muscle displayed reductions in AMPK protein content versus WT. These findings identify phenotypic effects of the AMPK DKI mutation on whole-body metabolism and tissue AMPK content and glycogen dynamics. Full article

(This article belongs to the Special Issue Energy Metabolism in Health and Disease)

► Show Figures

Graphical abstract

12 pages, 1650 KiB

Open AccessArticle

Mitochondrial Mistranslation in Brain Provokes a Metabolic Response Which Mitigates the Age-Associated Decline in Mitochondrial Gene Expression

by Dimitri Shcherbakov, Reda Juskeviciene, Adrián Cortés Sanchón, Margarita Brilkova, Hubert Rehrauer, Endre Laczko and Erik C. Böttger

Int. J. Mol. Sci. 2021, 22(5), 2746; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22052746 - 09 Mar 2021

Cited by 5 | Viewed by 2087

Abstract

Mitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5^V338Y/V338Y mice show decreased oxygen consumption and reduced ATP levels. Using a combination of unbiased RNA-Seq with untargeted [...] Read more.

Mitochondrial misreading, conferred by mutation V338Y in mitoribosomal protein Mrps5, in-vivo is associated with a subtle neurological phenotype. Brain mitochondria of homozygous knock-in mutant Mrps5^V338Y/V338Y mice show decreased oxygen consumption and reduced ATP levels. Using a combination of unbiased RNA-Seq with untargeted metabolomics, we here demonstrate a concerted response, which alleviates the impaired functionality of OXPHOS complexes in Mrps5 mutant mice. This concerted response mitigates the age-associated decline in mitochondrial gene expression and compensates for impaired respiration by transcriptional upregulation of OXPHOS components together with anaplerotic replenishment of the TCA cycle (pyruvate, 2-ketoglutarate). Full article

(This article belongs to the Special Issue Energy Metabolism in Health and Disease)

► Show Figures

Figure 1

22 pages, 9031 KiB

Open AccessArticle

A Mitochondrial Polymorphism Alters Immune Cell Metabolism and Protects Mice from Skin Inflammation

by Paul Schilf, Axel Künstner, Michael Olbrich, Silvio Waschina, Beate Fuchs, Christina E. Galuska, Anne Braun, Kerstin Neuschütz, Malte Seutter, Katja Bieber, Lars Hellberg, Christian Sina, Tamás Laskay, Jan Rupp, Ralf J. Ludwig, Detlef Zillikens, Hauke Busch, Christian D. Sadik, Misa Hirose and Saleh M. Ibrahim

Int. J. Mol. Sci. 2021, 22(3), 1006; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031006 - 20 Jan 2021

Cited by 17 | Viewed by 3251

Abstract

Several genetic variants in the mitochondrial genome (mtDNA), including ancient polymorphisms, are associated with chronic inflammatory conditions, but investigating the functional consequences of such mtDNA polymorphisms in humans is challenging due to the influence of many other polymorphisms in both mtDNA and the [...] Read more.

Several genetic variants in the mitochondrial genome (mtDNA), including ancient polymorphisms, are associated with chronic inflammatory conditions, but investigating the functional consequences of such mtDNA polymorphisms in humans is challenging due to the influence of many other polymorphisms in both mtDNA and the nuclear genome (nDNA). Here, using the conplastic mouse strain B6-mt^FVB, we show that in mice, a maternally inherited natural mutation (m.7778G > T) in the mitochondrially encoded gene ATP synthase 8 (mt-Atp8) of complex V impacts on the cellular metabolic profile and effector functions of CD4⁺ T cells and induces mild changes in oxidative phosphorylation (OXPHOS) complex activities. These changes culminated in significantly lower disease susceptibility in two models of inflammatory skin disease. Our findings provide experimental evidence that a natural variation in mtDNA influences chronic inflammatory conditions through alterations in cellular metabolism and the systemic metabolic profile without causing major dysfunction in the OXPHOS system. Full article

(This article belongs to the Special Issue Energy Metabolism in Health and Disease)

► Show Figures

Figure 1

Review

Jump to: Research

12 pages, 925 KiB

Open AccessReview

Altered Metabolic Flexibility in Inherited Metabolic Diseases of Mitochondrial Fatty Acid Metabolism

by Sara Tucci, Khaled Ibrahim Alatibi and Zeinab Wehbe

Int. J. Mol. Sci. 2021, 22(7), 3799; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073799 - 06 Apr 2021

Cited by 9 | Viewed by 4162

Abstract

In general, metabolic flexibility refers to an organism’s capacity to adapt to metabolic changes due to differing energy demands. The aim of this work is to summarize and discuss recent findings regarding variables that modulate energy regulation in two different pathways of mitochondrial [...] Read more.

In general, metabolic flexibility refers to an organism’s capacity to adapt to metabolic changes due to differing energy demands. The aim of this work is to summarize and discuss recent findings regarding variables that modulate energy regulation in two different pathways of mitochondrial fatty metabolism: β-oxidation and fatty acid biosynthesis. We focus specifically on two diseases: very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) and malonyl-CoA synthetase deficiency (acyl-CoA synthetase family member 3 (ACSF3)) deficiency, which are both characterized by alterations in metabolic flexibility. On the one hand, in a mouse model of VLCAD-deficient (VLCAD^−/−) mice, the white skeletal muscle undergoes metabolic and morphologic transdifferentiation towards glycolytic muscle fiber types via the up-regulation of mitochondrial fatty acid biosynthesis (mtFAS). On the other hand, in ACSF3-deficient patients, fibroblasts show impaired mitochondrial respiration, reduced lipoylation, and reduced glycolytic flux, which are compensated for by an increased β-oxidation rate and the use of anaplerotic amino acids to address the energy needs. Here, we discuss a possible co-regulation by mtFAS and β-oxidation in the maintenance of energy homeostasis. Full article

(This article belongs to the Special Issue Energy Metabolism in Health and Disease)

► Show Figures

Figure 1

19 pages, 907 KiB

Open AccessReview

Energy Metabolism in the Inner Retina in Health and Glaucoma

by Hanhan Liu and Verena Prokosch

Int. J. Mol. Sci. 2021, 22(7), 3689; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073689 - 01 Apr 2021

Cited by 42 | Viewed by 4349

Abstract

Glaucoma, the leading cause of irreversible blindness, is a heterogeneous group of diseases characterized by progressive loss of retinal ganglion cells (RGCs) and their axons and leads to visual loss and blindness. Risk factors for the onset and progression of glaucoma include systemic [...] Read more.

Glaucoma, the leading cause of irreversible blindness, is a heterogeneous group of diseases characterized by progressive loss of retinal ganglion cells (RGCs) and their axons and leads to visual loss and blindness. Risk factors for the onset and progression of glaucoma include systemic and ocular factors such as older age, lower ocular perfusion pressure, and intraocular pressure (IOP). Early signs of RGC damage comprise impairment of axonal transport, downregulation of specific genes and metabolic changes. The brain is often cited to be the highest energy-demanding tissue of the human body. The retina is estimated to have equally high demands. RGCs are particularly active in metabolism and vulnerable to energy insufficiency. Understanding the energy metabolism of the inner retina, especially of the RGCs, is pivotal for understanding glaucoma’s pathophysiology. Here we review the key contributors to the high energy demands in the retina and the distinguishing features of energy metabolism of the inner retina. The major features of glaucoma include progressive cell death of retinal ganglions and optic nerve damage. Therefore, this review focuses on the energetic budget of the retinal ganglion cells, optic nerve and the relevant cells that surround them. Full article

(This article belongs to the Special Issue Energy Metabolism in Health and Disease)

► Show Figures

Figure 1

33 pages, 2444 KiB

Open AccessReview

Energy Metabolism and Ketogenic Diets: What about the Skeletal Health? A Narrative Review and a Prospective Vision for Planning Clinical Trials on this Issue

by Daniela Merlotti, Roberta Cosso, Cristina Eller-Vainicher, Fabio Vescini, Iacopo Chiodini, Luigi Gennari and Alberto Falchetti

Int. J. Mol. Sci. 2021, 22(1), 435; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010435 - 04 Jan 2021

Cited by 17 | Viewed by 4980

Abstract

The existence of a common mesenchymal cell progenitor shared by bone, skeletal muscle, and adipocytes cell progenitors, makes the role of the skeleton in energy metabolism no longer surprising. Thus, bone fragility could also be seen as a consequence of a “poor” quality [...] Read more.

The existence of a common mesenchymal cell progenitor shared by bone, skeletal muscle, and adipocytes cell progenitors, makes the role of the skeleton in energy metabolism no longer surprising. Thus, bone fragility could also be seen as a consequence of a “poor” quality in nutrition. Ketogenic diet was originally proven to be effective in epilepsy, and long-term follow-up studies on epileptic children undergoing a ketogenic diet reported an increased incidence of bone fractures and decreased bone mineral density. However, the causes of such negative impacts on bone health have to be better defined. In these subjects, the concomitant use of antiepileptic drugs and the reduced mobilization may partly explain the negative effects on bone health, but little is known about the effects of diet itself, and/or generic alterations in vitamin D and/or impaired growth factor production. Despite these remarks, clinical studies were adequately designed to investigate bone health are scarce and bone health related aspects are not included among the various metabolic pathologies positively influenced by ketogenic diets. Here, we provide not only a narrative review on this issue, but also practical advice to design and implement clinical studies on ketogenic nutritional regimens and bone health outcomes. Perspectives on ketogenic regimens, microbiota, microRNAs, and bone health are also included. Full article

(This article belongs to the Special Issue Energy Metabolism in Health and Disease)

► Show Figures

Figure 1

16 pages, 1789 KiB

Open AccessReview

Metabolic Roles of Androgen Receptor and Tip60 in Androgen-Dependent Prostate Cancer

by Kah Ni Tan, Vicky M. Avery and Catalina Carrasco-Pozo

Int. J. Mol. Sci. 2020, 21(18), 6622; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21186622 - 10 Sep 2020

Cited by 11 | Viewed by 3476

Abstract

Androgen receptor (AR)-mediated signaling is essential for the growth and differentiation of the normal prostate and is the primary target for androgen deprivation therapy in prostate cancer. Tat interactive protein 60 kDa (Tip60) is a histone acetyltransferase that is critical for AR activation. [...] Read more.

Androgen receptor (AR)-mediated signaling is essential for the growth and differentiation of the normal prostate and is the primary target for androgen deprivation therapy in prostate cancer. Tat interactive protein 60 kDa (Tip60) is a histone acetyltransferase that is critical for AR activation. It is well known that cancer cells rewire their metabolic pathways in order to sustain aberrant proliferation. Growing evidence demonstrates that the AR and Tip60 modulate key metabolic processes to promote the survival of prostate cancer cells, in addition to their classical roles. AR activation enhances glucose metabolism, including glycolysis, tricarboxylic acid cycle and oxidative phosphorylation, as well as lipid metabolism in prostate cancer. The AR also interacts with other metabolic regulators, including calcium/calmodulin-dependent kinase kinase 2 and mammalian target of rapamycin. Several studies have revealed the roles of Tip60 in determining cell fate indirectly by modulating metabolic regulators, such as c-Myc, hypoxia inducible factor 1α (HIF-1α) and p53 in various cancer types. Furthermore, Tip60 has been shown to regulate the activity of key enzymes in gluconeogenesis and glycolysis directly through acetylation. Overall, both the AR and Tip60 are master metabolic regulators that mediate cellular energy metabolism in prostate cancer, providing a framework for the development of novel therapeutic targets in androgen-dependent prostate cancer. Full article

(This article belongs to the Special Issue Energy Metabolism in Health and Disease)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Energy Metabolism in Health and Disease

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Published Papers (8 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI