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Metabolic Interplay between Peroxisomes and Other Subcellular Organelles Including Mitochondria and the Endoplasmic Reticulum
Open accessAbstract
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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“All of these metabolites must be transferred into mitochondria for full β-oxidation into CO2 and H2O because peroxisomes lack a Krebs’ cycle [162].”
From Revisiting the Pathogenesis of X-Linked Adrenoleukodystrophy (2025) · cites this paper as [162]
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“One dynamic metabolic process that peroxisomes participate in 552 is the degradation of fatty acids that cannot occur in the mitochondria, in specific (1) very553 long chain fatty acids with at least 22 carbons; (2) branched-chain fatty acids; (3) bile acid 554 intermediates such as di- and trihydroxycholestanoic acid…”
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BackgroundAutophagy and Redox Homeostasis in Parkinson’s: A Crucial Balancing Act
Jiménez-Moreno, N., & Lane, J. D. (2020) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2020/8865611 · Cited by 26
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Flux analysis of inborn errors of metabolism
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BackgroundPeroxisome-Deficiency and HIF-2α Signaling Are Negative Regulators of Ketohexokinase Expression
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“Moreover, mitochondrial respiration is also critical to reoxidize NADH formed in peroxisomes and maintain peroxisomal β-oxidation (Wanders et al., 2015).”
BackgroundUnloosing the Gordian knot of peroxisome formation
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Peroxisomes of the Brain: Distribution, Functions, and Associated Diseases
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“In particular, peroxisomes contain large number of ROS-producing enzymes such as acyl-CoA oxidases (Wanders et al., 2015), and they also have a large network of antioxidants that protect organelles from oxidative damage.”
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Peroxisome Deficiency in Cochlear Hair Cells Causes Hearing Loss by Deregulating BK Channels
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Autophagy in the mammalian nervous system: a primer for neuroscientists
Suomi, F., & McWilliams, T. G. (2019) · Neuronal Signaling · doi:10.1042/ns20180134 · Cited by 18
Puri, K., Lal, N., Shang, R., Ghosh, S., Flibotte, S., Dyer, R., Hussein, B., & Rodrigues, B. B. (2019) · Journal of the American Heart Association · doi:10.1161/jaha.119.014022 · Cited by 19
Daniele, L. L., Caughey, J., Volland, S., Sharp, R. C., Dhingra, A., Williams, D. S., Philp, N. J., & Boesze-Battaglia, K. (2019) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00185.2019 · Cited by 16
Zhang, M., Wei, J., He, C., Sui, L., Jiao, C., Zhu, X., & Pan, X. (2024) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-024-00669-4 · Cited by 20
Cha, H.-R., Kim, J.-S., Ryu, J., & Cho, H. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26157342 · Cited by 18
“Protein oxidation can induce activity loss and/or protein unfolding along with a tendency to promote intracellular and extracellular protein oligomerization and aggregation [18].”
Wegrzyn, A. B., Herzog, K., Gerding, A., Kwiatkowski, M., Wolters, J. C., Dolga, A. M., van Lint, A. E. M., Wanders, R. J. A., Waterham, H. R., & Bakker, B. M. (2020) · FEBS Journal · doi:10.1111/febs.15292 · Cited by 17
Self-citationMa, Y., Wang, M., Guo, S., Li, T., Liu, X., & Zhao, L. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.1048728 · Cited by 17
“, C26-AC) reflects the disruption of fatty acid metabolism outside the mitochondria, primarily associated with impaired metabolism of the peroxisome as well as the endoplasmic reticulum (Wanders et al., 2016).”
BackgroundPorukala, M., & Vinod, P. K. U. (2023) · Scientific Reports · doi:10.1038/s41598-023-31315-2 · Cited by 18
Ganguli, G., Pattanaik, K. P., Jagadeb, M., & Sonawane, A. (2020) · Cellular Microbiology · doi:10.1111/cmi.13214 · Cited by 17
Potential Involvement of Peroxisome in Multiple Sclerosis and Alzheimer’s Disease
Zarrouk, A., Nury, T., Hajj, H. I. E., Gondcaille, C., Andreoletti, P., Moreau, T., Cherkaoui‐Malki, M., Berger, J., Hammami, M., Lizard, G., et al. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-60204-8_8 · Cited by 20
Colasuonno, F., Marioli, C., Tartaglia, M., Bertini, E., Compagnucci, C., & Moreno, S. (2022) · Biomedicines · doi:10.3390/biomedicines10061329 · Cited by 17
Pradhan, S. S., Rao, K. R., Manjunath, M., Saiswaroop, R., Patnana, D. P., Kanikaram, S. P., Choudhary, B., & Sivaramakrishnan, V. (2023) · 3 Biotech · doi:10.1007/s13205-023-03525-y · Cited by 16
“Peroxisomes are the sites of fatty acid degradation and unsaturated fatty acid biosynthesis in all organisms including yeast (Wanders et al. 2016; Schrader et al. 2016).”
BackgroundKashyap, I., Deb, R., Battineni, A., & Nagotu, S. (2023) · Molecular Genetics and Genomics · doi:10.1007/s00438-023-02059-5 · Cited by 16
“1; Schrader et al. 2015; Wanders et al. 2015).”
BackgroundRetinal pigment epithelium lipid metabolic demands and therapeutic restoration
Nolan, N. D., Jenny, L. A., Wang, N., & Tsang, S. H. (2021) · Taiwan Journal of Ophthalmology · doi:10.4103/tjo.tjo_31_21 · Cited by 16
“[13] While two similar pathways for fatty acid β‐oxidation exist[14] (peroxisome‐mediated and mitochondria‐mediated), evidence suggests that there is a preference for the mitochondrial pathway in the RPE as the peroxisomal pathway fails to yield ATP.”
BackgroundTrade-offs and design principles in the spatial organization of catalytic particles
Hinzpeter, F., Tostevin, F., Büchner, A., & Gerland, U. (2021) · Nature Physics · doi:10.1038/s41567-021-01444-4 · Cited by 17
“These superstructures also function synergistically and some have been found to spatially colocalize [21–23].”
BackgroundTakashima, S., Takemoto, S., Toyoshi, K., Ohba, A., & Shimozawa, N. (2021) · Molecular Genetics and Metabolism · doi:10.1016/j.ymgme.2021.05.002 · Cited by 15
A broadly conserved fungal alcohol oxidase ( AOX ) facilitates fungal invasion of plants
Westrick, N. M., Park, S. C., Keller, N. P., et al. (2022) · Molecular Plant Pathology · doi:10.1111/mpp.13274 · Cited by 15
“Synergistic activity between peroxisomes and mitochondria to facilitate fatty acid biosynthesis has been studied in animal systems and it is additionally possible that AOX is also driving similar activity in fungi (Wanders et al., 2016).”
BackgroundMartin, W. P., Nair, M., Chuah, Y. H. D., Malmodin, D., Pedersen, A., Abrahamsson, S., Hutter, M., Abdelaal, M., Elliott, J. A., Fearon, N. M., et al. (2022) · Clinical Science · doi:10.1042/cs20220205 · Cited by 16
“…Kidney and liver are the the two organs with the highest abundance of peroxisomes [100], and the the marked induction of genes relating to peroxisomal FAO in renal and hepatic tissue following DMT suggests that peroxisomal activation may be an important element of the therapeutic response [105].”
Transmembrane protein 135 regulates lipid homeostasis through its role in peroxisomal DHA metabolism
Landowski, M., Bhute, V. J., Grindel, S. H., Haugstad, Z., Gyening, Y. K., Tytanic, M., Brush, R. S., Moyer, L. J., Nelson, D. W., Davis, C. R., et al. (2023) · Communications Biology · doi:10.1038/s42003-022-04404-7 · Cited by 15
Redox system and ROS-related disorders in peroxisomes
Kim, H., Hwang, J., Park, C., & Park, R. (2024) · Free Radical Research · doi:10.1080/10715762.2024.2427088 · Cited by 17
“Peroxisomes directly contact with eR for ether phospholipid synthesis and cholesterol trafficking, which facilitates cholesterol localization from peroxisomes to eR [125,126].”
Omotoso, G. O., Mutholib, N. Y., Abdulsalam, F. A., & Bature, A. (2020) · Anatomy & Cell Biology · doi:10.5115/acb.19.160 · Cited by 15
“Endoplasmic reticulum has also been implicated in the generation of ROS, as a redox interplay exists between the trio of mitochondria, endoplasmic reticulum, and peroxisomes in their involvement in ROS production [47].”
BackgroundIntracellular communication between lipid droplets and peroxisomes: the Janus face of PEX19
Schrul, B., & Schliebs, W. (2018) · Biological Chemistry · doi:10.1515/hsz-2018-0125 · Cited by 14
Negro, M., Cerullo, G., Parimbelli, M., Ravazzani, A., Feletti, F., Berardinelli, A. L., Cena, H., & D’Antona, G. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.704290 · Cited by 15
Peroxisomal ERK mediates Akh/glucagon action and glycemic control
Li, J., Dang, P., Li, Z., Zhao, T., Cheng, D., Pan, D., Yuan, Y., & Song, W. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113200 · Cited by 13
Zhu, F., Li, X., Wen, J., & Zhang, L. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.4c05028 · Cited by 13
Zhou, J., & Wang, X. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107387 · Cited by 13
Large-Scale Modeling Approach Reveals Functional Metabolic Shifts during Hepatic Differentiation
Poupin, N., Corlu, A., Cabaton, N. J., Dubois‐Pot‐Schneider, H., Canlet, C., Person, E., Bruel, S., Frainay, C., Vinson, F., Maurier, F., et al. (2018) · Journal of Proteome Research · doi:10.1021/acs.jproteome.8b00524 · Cited by 15
PEX13 is required for thermogenesis of white adipose tissue in cold-exposed mice
Park, W. Y., Park, J., Lee, S., Song, G., Nam, I.-K., Ahn, K. S., Choe, S., & Um, J. (2021) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2021.159046 · Cited by 13
PEX19 Coordinates Neutral Lipid Storage in Cells in a Peroxisome-Independent Fashion
Lyschik, S., Lauer, A. A., Roth, T., et al. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.859052 · Cited by 12
Zhou, D., & Zhu, L. (2025) · Water Research · doi:10.1016/j.watres.2025.124242 · Cited by 12
Sun, S., Gu, Y., Wang, J., Chen, C., Han, S., & Che, H. (2021) · Journal of Immunology Research · doi:10.1155/2021/7483865 · Cited by 12
“The peroxisome is a subcellular organelle found in most organs and acts as a secondary site for FAO [13].”
Sharing the wealth: The versatility of proteins targeted to peroxisomes and other organelles
Bittner, E., Stehlik, T., & Freitag, J. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.934331 · Cited by 12
“, during the biosynthesis of ether lipids (Wanders et al., 2016).”
Background
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.
- 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)
- 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
- gold
- doi.org
- 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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