Fatty Acid Metabolism
Mitochondria and Much More
May 29, 2009
Edited by Roderick Capaldi, D.Phil.
Past issues are available for review in the archives.
Table of Contents
I. INTRODUCTION
II. MITOCHONDRIAL FATTY ACID OXIDATION
III. PEROXISOMAL FATTY ACID OXIDATION
IV. THE MITOCHONDRIAL-PEROXISOMAL CONNECTION: THERE’S MORE
V. FATTY ACID OXIDATION DISEASES
VI. FATTY ACID SYNTHESIS
VII. CONTROL OF LIPID METABOLISM: THE PPARs
VIII. FATTY ACID METABOLISM... EVEN MORE!
I. INTRODUCTION
Regular visitors to the MitoSciences website and readers of MitoNews will know that to-date our primary focus in both research and product development has been on Oxidative Phosphorylation. Recently we have added a new effort, to better understand and provide useful tools for studying Fatty Acid Metabolism.
Our motivation is not only that fatty acid oxidation and synthesis (see later) occur in mitochondria and we want to be able to screen mitochondrial functioning broadly, but also because understanding fatty acid metabolism is important for 1) being able to screen for all inborn errors of metabolism, 2) understanding the mechanism of, and treatment for, diabetes and metabolic syndrome, 3) cancer where up-regulation of key enzymes of fatty acid metabolism is an important part of cellular transformation, 4) inflammation, and 5) understanding the role of diet and exercise in all of these conditions.
This MitoNews provides a primer for those of you who, like me, thought that all there is to know on the topic is in text books such as Lehninger, and those who, like me, knew next to nothing about peroxisomes except that they must get proliferated as there are PPARs in cells. As I will review, fatty acid metabolism involves several different pathways in mitochondria, peroxisomes, endoplasmic reticulum and cytosol, under coordinated control to balance energy production with cell growth and associated cellular processes.
II. MITOCHONDRIAL FATTY ACID OXIDATION
Mitochondria have enzyme systems for processing long chain, medium chain and short chain lengths of most saturated and some unsaturated fatty acids. These are degraded in a cyclic set of reactions to produce acetyl CoAs. Energy is generated and stored both by providing electrons directly into the electron transfer chain e.g. via ETF-CoQ reductase which passes electrons to ubiquinone, and from product acetyl CoA by further processing by the Krebs cycle enzymes. Two excellent reviews of mitochondrial fatty acid oxidation are listed below.
Bartlett K, Eaton S. Eur J Biochem. 2004 Feb;271(3):462-9.
Mitochondrial beta-oxidation.
Chegary M. et al. Biochim Biophys Acta. 2009 May 21. [Epub ahead of print]
Mitochondrial long chain fatty acid beta-oxidation in man and mouse.
III. PEROXISOMAL FATTY ACID OXIDATION
Peroxisomes participate in alpha oxidation and beta oxidation of those very long chain fatty acids that cannot be taken up by mitochondria. The organelle also processes 3-methyl-branched chain fatty acids, dicarboxylic fatty acids, 2 methyl branched fatty acids, bile acid intermediates, eisosanoids and xenobiotic carboxylic acids. Recent proteomic studies indicate that peroxisomes in humans contain around 85 gene products, 50 of which are metabolic enzymes.
Reactions involved in "core or cyclic" fatty acid oxidation in peroxisomes are the same as in mitochondria but are catalyzed by proteins encoded on different genes. The products of this beta oxidation can be substrates for ether-phospholipid, cholesterol and bile salt synthesis, or they may exit after chain shortening and transferred to mitochondria for complete conversion to acetyl coAs.
Fatty acid oxidation in peroxisomes produces less energy than that in mitochondria because electrons removed by the flavin enzymes involved are transferred directly to molecular oxygen to form H2O2 (by the enzyme catalase) rather than being used up by the respiratory chain.
Two excellent reviews of peroxisomal fatty acid oxidation are:
Wanders RJ. et al. Biochem Soc Trans. 2001 May;29(Pt 2):250-67.
Peroxisomal fatty acid alpha- and beta-oxidation in humans: enzymology, peroxisomal metabolite transporters and peroxisomal diseases.
Schrader M, Fahimi HD. Histochem Cell Biol. 2008 Apr;129(4):421-40. Epub 2008 Feb 15.
The peroxisome: still a mysterious organelle.
For recent data on proteomics see:
Wiese S. et al. Mol Cell Proteomics. 2007 Dec;6(12):2045-57. Epub 2007 Sep 2.
Proteomics characterization of mouse kidney peroxisomes by tandem mass spectrometry and protein correlation profiling.
Pellicoro A. et al. Hepatology. 2007 Feb;45(2):340-8.
Human and rat bile acid-CoA:amino acid N-acyltransferase are liver-specific peroxisomal enzymes: implications for intracellular bile salt transport.
IV. THE MITOCHONDRIAL-PEROXISOMAL CONNECTION: THERE’S MORE
There are other features of peroxisomes that link them to mitochondria. This organelle has recently been shown to undergo fusion and fission processes much like mitochondria, using many similar proteins and some of the same proteins (e.g DRP1) . This feature is well reviewed by Schrader and Fahimi (reference above). Recent interesting studies have shown that there are mitochondrially-derived vesicles that can fuse with the peroxisomes to deliver cargo back and forth between the two organelles.
Andrade-Navarro MA. et al. Curr Opin Cell Biol. 2009 May 5. [Epub ahead of print]
Mitochondrial vesicles: an ancient process providing new links to peroxisomes.
V. FATTY ACID OXIDATION DISEASES
Inborn errors of fatty acid metabolism are common and involve proteins of both mitochondria and peroxisomes. These are covered in Wanders et al. and Schrader and Fatami (see above). For an additional more recent review of mitochondrial fatty acid oxidation disorders, see:
Gregersen N. et al. J Inherit Metab Dis. 2008 Oct;31(5):643-57. Epub 2008 Oct 7.
Mitochondrial fatty acid oxidation defects--remaining challenges.
VI. FATTY ACID SYNTHESIS
Synthesis of saturated fatty acids is a relatively simple (in terms of the number of enzymes involved) and a well understood process that occurs in the cytosol. The key enzymes are ACC (acetyl CoA carboxylase) and fatty acid synthase. A good review of the process is provided by the article below, which discusses a particularly important new focus, the role of up-regulation of fatty acid synthesis in cancer.
Mashima T, Seimiya H, Tsuruo T. Br J Cancer. 2009 May 5;100(9):1369-72. Epub 2009 Apr 7.
De novo fatty-acid synthesis and related pathways as molecular targets for cancer therapy.
Conversion of saturated to unsaturated fatty acids occurs in the endoplasmic reticulum and involves the enzyme stearoyl-CoA desaturase. Studies of this enzyme have revealed considerable insight into the overall regulation of lipid metabolism as reviewed below.
Dobrzyn A, Dobrzyn P. J Physiol Pharmacol. 2006 Nov;57 Suppl 10:31-42.
Stearoyl-CoA desaturase--a new player in skeletal muscle metabolism regulation.
One important recent development is now conclusive evidence that there is fatty acid synthesis in mitochondria. This process is malonyl-CoA-dependent and it functions primarily to produce lipoic acid.
The work of Stuart Smith and colleagues has provided good detail of the enzymes involved, including a multi-enzyme fatty acid synthase:
Zhang L, Joshi AK, Smith S. J Biol Chem. 2003 Oct 10;278(41):40067-74. Epub 2003 Jul 25.
Cloning, expression, characterization, and interaction of two components of a human mitochondrial fatty acid synthase. Malonyltransferase and acyl carrier protein.
VII. CONTROL OF LIPID METABOLISM: THE PPARs
One of the most exciting areas of research into fatty acid metabolism over the last few years has been in identifying the role of PPARs (alpha, beta, and gamma) in the overall control of the process, and the resulting development of drugs to treat later onset diseases involving disrupted fatty acid metabolism, namely diabetes, metabolic syndrome and obesity. An overview is provided by the 2 reviews below.
Takahashi S, Tanaka T, Sakai J. Endocr J. 2007 Jun;54(3):347-57. Epub 2007 Apr 3.
New therapeutic target for metabolic syndrome: PPARdelta.
Kleiner S. et al. J Biol Chem. 2009 May 12. [Epub ahead of print]
PPARdelta agonism activates fatty acid oxidation via PGC-1alpha but does not increase mitochondrial gene expression and function.
VIII. FATTY ACID METABOLISM... EVEN MORE!
A complete review of aspects of lipid metabolism should include studies of the catabolism of polyunsaturated fatty acids including omega fatty acids and their conversion into molecules important for cellular immunity. Also missing from this summary is reference to conversion of fatty acids to ketone bodies which occurs in mitochondria. These topics will be the subject of another MitoNews, but first you need the background, so start with the reviews listed here.
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New Products:
MetaPath™ Fatty Acid Oxidation 4-Plex Microplate Array (MSX41)
MetaPath™ Fatty Acid Oxidation 4-Plex Dipstick Array (MSX31)
These new multiplexing assays from MitoSciences allow for the simultaneous measurement of 4 key proteins in either high-throughput (microplate) or rapid and simple (dipstick) platforms. These new arrays are the first of many new multiplex assays that will soon be released by MitoSciences, covering not only fatty acid oxidation and fatty acid synthesis, but many other metabolic pathways as well.
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