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Metabolic Interplay between Peroxisomes and Other Subcellular Organelles Including Mitochondria and the Endoplasmic Reticulum

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Wanders, Ronald J. A., Waterham, Hans R., Ferdinandusse, Sacha·2016·Frontiers in Cell and Developmental Biology
DOI 10.3389/fcell.2015.00083PMC PMC4729952
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Abstract

Peroxisomes are unique subcellular organelles which play an indispensable role in several key metabolic pathways which include: (1.) etherphospholipid biosynthesis; (2.) fatty acid beta-oxidation; (3.) bile acid synthesis; (4.) docosahexaenoic acid (DHA) synthesis; (5.) fatty acid alpha-oxidation; (6.) glyoxylate metabolism; (7.) amino acid degradation, and (8.) ROS/RNS metabolism. The importance of peroxisomes for human health and development is exemplified by the existence of a large number of inborn errors of peroxisome metabolism in which there is an impairment in one or more of the metabolic functions of peroxisomes. Although the clinical signs and symptoms of affected patients differ depending upon the enzyme which is deficient and the extent of the deficiency, the disorders involved are usually (very) severe diseases with neurological dysfunction and early death in many of them. With respect to the role of peroxisomes in metabolism it is clear that peroxisomes are dependent on the functional interplay with other subcellular organelles to sustain their role in metabolism. Indeed, whereas mitochondria can oxidize fatty acids all the way to CO2 and H2O, peroxisomes are only able to chain-shorten fatty acids and the end products of peroxisomal beta-oxidation need to be shuttled to mitochondria for full oxidation to CO2 and H2O. Furthermore, NADH is generated during beta-oxidation in peroxisomes and beta-oxidation can only continue if peroxisomes are equipped with a mechanism to reoxidize NADH back to NAD(+), which is now known to be mediated by specific NAD(H)-redox shuttles. In this paper we describe the current state of knowledge about the functional interplay between peroxisomes and other subcellular compartments notably the mitochondria and endoplasmic reticulum for each of the metabolic pathways in which peroxisomes are involved.

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Figures

Figure 1 Schematic diagram showing the functional interplay between peroxisomes and mitochondria in the beta-oxidation of fatty acids in peroxisomes. See text for detailed discussion.
Figure 1 Schematic diagram showing the functional interplay between peroxisomes and mitochondria in the beta-oxidation of fatty acids in peroxisomes. See text for detailed discussion.CC BY · PubMed Central
Figure 2 Etherphospolipid biosynthesis and the important role of peroxisomes and the endoplasmic reticulum. (A) Schematic representation of the peroxisome and the enzymes and transporters involved in the peroxisomal synthesis of alkyl-DHAP. (B) Schematic representation of the peroxisome and the enzymes and transporters involved in the peroxisomal synthesis of alkyl-DHAP with special emphasis on the sub-peroxisomal localization of GNPAT and AGPS as peripheral peroxisomal membrane proteins joined together in a functional complex. (C) Overview of the reactions catalyzed by the three intraperoxisomal enzymes involved in etherphospholipid synthesis including GNPAT, AGPS, and ACSVL1 (SLC27A2). G3P, glycerol-3-phosphate; DHAP, dihydroxyacetonephosphate; GNPAT, glyceronephosphate O-acyltransferase; AGPS, alkyl-glyceronephosphate synthase; FAR1, fatty acyl-CoA reductase 1.
Figure 2 Etherphospolipid biosynthesis and the important role of peroxisomes and the endoplasmic reticulum. (A) Schematic representation of the peroxisome and the enzymes and transporters involved in the peroxisomal synthesis of alkyl-DHAP. (B) Schematic representation of the peroxisome and the enzymes and transporters involved in the peroxisomal synthesis of alkyl-DHAP with special emphasis on the sub-peroxisomal localization of GNPAT and AGPS as peripheral peroxisomal membrane proteins joined together in a functional complex. (C) Overview of the reactions catalyzed by the three intraperoxisomal enzymes involved in etherphospholipid synthesis including GNPAT, AGPS, and ACSVL1 (SLC27A2). G3P, glycerol-3-phosphate; DHAP, dihydroxyacetonephosphate; GNPAT, glyceronephosphate O-acyltransferase; AGPS, alkyl-glyceronephosphate synthase; FAR1, fatty acyl-CoA reductase 1.CC BY · PubMed Central
Figure 3 Peroxisomes, fatty acid beta-oxidation and the human deficiencies of peroxisomal beta-oxidation. (A) Schematic diagram depicting the substrates known to be oxidized in peroxisomes exclusively and the transporters and enzymes involved in their degradation (see text for detailed information). (B) Schematic diagram depicting the substrates known to be oxidized in peroxisomes exclusively and the transporters and enzymes involved in their degradation and the human deficiencies in the peroxisomal beta-oxidation pathway so far identified (see text for more information).
Figure 3 Peroxisomes, fatty acid beta-oxidation and the human deficiencies of peroxisomal beta-oxidation. (A) Schematic diagram depicting the substrates known to be oxidized in peroxisomes exclusively and the transporters and enzymes involved in their degradation (see text for detailed information). (B) Schematic diagram depicting the substrates known to be oxidized in peroxisomes exclusively and the transporters and enzymes involved in their degradation and the human deficiencies in the peroxisomal beta-oxidation pathway so far identified (see text for more information).CC BY · PubMed Central
Figure 4 Schematic diagram depicting the peroxisomal enzymes involved in the degradation of very long-chain fatty acids (VLCFAs), pristanic acid, di- and trihydroxycholestanoic acid, and long-chain dicarboxylic acids. See text for detailed information.
Figure 4 Schematic diagram depicting the peroxisomal enzymes involved in the degradation of very long-chain fatty acids (VLCFAs), pristanic acid, di- and trihydroxycholestanoic acid, and long-chain dicarboxylic acids. See text for detailed information.CC BY · PubMed Central
Figure 5 Functional interplay between peroxisomes and mitochondria with respect to the reoxidation of NADH produced within the peroxisomal beta-oxidation system. (A) S. cerevisiae (see text for detailed information). (B): H. sapiens. PYR, pyruvate; LAC, lactic acid; LDH, lactate dehydrogenase; GOT, glutamate oxaloacetate transaminase; ASP, L-aspartate, GLUT, L-glutamate; 2OG, 2-oxoglutarate; MDH1, mitochondrial malate dehydrogenase.
Figure 5 Functional interplay between peroxisomes and mitochondria with respect to the reoxidation of NADH produced within the peroxisomal beta-oxidation system. (A) S. cerevisiae (see text for detailed information). (B): H. sapiens. PYR, pyruvate; LAC, lactic acid; LDH, lactate dehydrogenase; GOT, glutamate oxaloacetate transaminase; ASP, L-aspartate, GLUT, L-glutamate; 2OG, 2-oxoglutarate; MDH1, mitochondrial malate dehydrogenase.CC BY · PubMed Central
Figure 6 Functional interplay between peroxisomes and mitochondria in the oxidation of C26:0. See text for detailed information. ALDP, adrenoleukodystrophy protein; TE, acyl-CoA thioesterase; CrOT, carnitine octanoyltransferase; CrAT, carnitine acetyltransferase; CACT, mitochondrial carnitine: acylcarnitine translocase.
Figure 6 Functional interplay between peroxisomes and mitochondria in the oxidation of C26:0. See text for detailed information. ALDP, adrenoleukodystrophy protein; TE, acyl-CoA thioesterase; CrOT, carnitine octanoyltransferase; CrAT, carnitine acetyltransferase; CACT, mitochondrial carnitine: acylcarnitine translocase.CC BY · PubMed Central
Figure 7 Schematic diagram showing the key role of peroxisomes in the formation of C22:6 n-3. Doxosahexaenoic acid is synthesized from C18:3 n-3 which first undergoes a number of elongation and desaturation steps in the endoplasmic reticulum to produce C24:6-CoA which is then transported to the peroxisome and imported via a mechanism not yet resolved. Within peroxisomes C24:6-CoA undergoes one cycle of beta-oxidation to produce the corresponding C22:6-CoA which can then be exported out of the peroxisome for subsequent incorporation into lipids in the endoplasmic reticulum or may undergo additional sequential rounds of oxidation in peroxisomes and mitochondria. See text for more detailed information.
Figure 7 Schematic diagram showing the key role of peroxisomes in the formation of C22:6 n-3. Doxosahexaenoic acid is synthesized from C18:3 n-3 which first undergoes a number of elongation and desaturation steps in the endoplasmic reticulum to produce C24:6-CoA which is then transported to the peroxisome and imported via a mechanism not yet resolved. Within peroxisomes C24:6-CoA undergoes one cycle of beta-oxidation to produce the corresponding C22:6-CoA which can then be exported out of the peroxisome for subsequent incorporation into lipids in the endoplasmic reticulum or may undergo additional sequential rounds of oxidation in peroxisomes and mitochondria. See text for more detailed information.CC BY · PubMed Central
Figure 8 Schematic diagram showing the unique and important role of peroxisomes in the formation of the primary bile acids cholic acid and deoxycholic acid. See text for detailed information.
Figure 8 Schematic diagram showing the unique and important role of peroxisomes in the formation of the primary bile acids cholic acid and deoxycholic acid. See text for detailed information.CC BY · PubMed Central
Figure 9 Functional interplay between mitochondria and peroxisomes in the alpha-oxidation of phytanic acid. See text for detailed information.
Figure 9 Functional interplay between mitochondria and peroxisomes in the alpha-oxidation of phytanic acid. See text for detailed information.CC BY · PubMed Central
Figure 10 The detoxification of glyoxylate in peroxisomes as catalyzed by the enzyme alanine glyoxylate aminotransferase (AGXT).
Figure 10 The detoxification of glyoxylate in peroxisomes as catalyzed by the enzyme alanine glyoxylate aminotransferase (AGXT).CC BY · PubMed Central

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  1. Novikoff, 1964, The endoplasmatic reticulum in the golgi zone and its relation to microbodies, golgi apparatus and autophagic vacuoles in rat livers, J. Microsc., 3, 187

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Metadata

Authors
Wanders, R. J. A., Waterham, H. R., & Ferdinandusse, S.
Affiliations
Amsterdam UMC Location University of Amsterdam (NL)
Corresponding author
Wanders, Ronald J. A.
ORCID
Venue
Frontiers in Cell and Developmental Biology
Publisher
Frontiers Media SA
Published
2016-01-28
Volume
3
Pages
83-83
ISSN
2296-634X (ISSN-L)
DOI
10.3389/fcell.2015.00083
PMC
PMC4729952
OpenAlex
W2262335045
Cited by
366
References
88
Citations by year
2026: 25 · 2025: 36 · 2024: 43 · 2023: 31 · 2022: 56 · 2021: 39 · 2020: 50 · 2019: 30 · 2018: 29 · 2017: 24 · 2016: 2
FWCI
2.91
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Cell and Developmental Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Pure Amsterdam UMC (acceptedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • European Commission (316723)
  • Hersenstichting (F2012(1)-102)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
Keywords
peroxisomes, fatty acid beta-oxidation, NADH reoxidation, bile acid synthesis, glyoxylate metabolism, amino acid catabolism

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