#peroxisomes

Basics of Cell Biology

Which of the following organelles is involved in detoxification?

Detoxification of endogenous metabolites and exogenous xenobiotics requires oxidative handling and compartmentalization to protect cellular components. Peroxisomes, single membrane organelles containing enzymes imported via peroxisomal targeting signals PTS1 C-terminal SKL tripeptide and PTS2 N-terminal recognized by shuttling receptors PEX5 and PEX7, house acyl-CoA oxidases that beta-oxidize very-long-chain fatty acids C22 and above and branched-chain fatty acids like phytanic acid generating acetyl-CoA for mitochondria plus hydrogen peroxide H2O2 as byproduct. Catalase, core component with heme prosthetic group and highly abundant crystal, rapidly dismutates H2O2 to water and oxygen preventing oxidative damage to lipids and DNA; absence or peroxisome biogenesis disorders such as Zellweger syndrome cause accumulation of VLCFA and neurological defects and liver dysfunction. Additionally D-amino acid oxidase, urate oxidase in non-primate organisms, and enzymes for plasmalogen ether lipid synthesis provide antimicrobial and membrane functions. Smooth ER complements via cytochrome P450 monooxygenase family CYP3A4, CYP2D6 hydroxylating xenobiotics increasing solubility, followed by conjugation via glucuronosyltransferases. Nucleus safeguards genome, Golgi processes glycans, lysosomes degrade polymers, but oxidative detoxification is hallmark of peroxisomes together with smooth ER collaboration.

Ref: Alberts et al., Molecular Biology of the Cell, 7th ed., Chapter 12: Peroxisomes and Detoxification.

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Cell Organelles

Which of the following statements is false regarding peroxisomes?

Peroxisomes are single-membrane organelles morphologically and functionally distinct from lysosomes despite both participating in degradative metabolism. Transmission electron microscopy shows spherical vesicles 0.1 to 1 micrometer with electron-dense crystalline cores composed of urate oxidase in rat or dense catalase aggregates in humans. Unlike double-membrane mitochondria and nucleus, peroxisomes are bounded by single phospholipid bilayer enriched in peroxisomal membrane proteins PMP70, ALDP, PEX11 isoforms and containing import translocon. Their matrix contains oxidative enzymes such as acyl-CoA oxidases, D-amino acid oxidase, L-pipecolic acid oxidase and catalase that generate and decompose hydrogen peroxide via dehydrogenation reactions, not classic acid hydrolases that cleave bonds at low pH using water. Biogenesis studies using live-cell imaging, vesicle budding assays and Sec16B colocalization demonstrate that pre-peroxisomal vesicles bud from specialized subdomains of endoplasmic reticulum carrying PEX3, PEX16 and PEX19, then fuse heterotypically and mature via growth and division mediated by PEX11 beta that elongates membrane and DRP1 and Fis1 that constrict and split. Therefore de novo formation coexists with growth and fission of pre-existing peroxisomes, firmly establishing ER contribution, while claim of exclusively containing hydrolytic enzymes reflects outdated confusion with lysosomes.

Ref: Smith & Aitchison, Cold Spring Harbor Perspect Biol 2013: Peroxisomes Originate from ER and Contain Oxidases.

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Cell Organelles

Which enzyme in peroxisomes detoxifies H₂O₂?

Because peroxisomal oxidases produce stoichiometric hydrogen peroxide during oxidation of fatty acids, urate, D-amino acids and polyamines, cells require robust detoxification to prevent oxidative damage to proteins, lipids and DNA. Catalase is the signature antioxidant enzyme residing in peroxisomal matrix, often forming electron-dense crystalline core visible by electron microscopy in rat liver. It is a 240 kDa heme-containing homotetramer that disproportionates hydrogen peroxide into water and molecular oxygen with extremely high turnover number near ten million molecules per second, one of fastest enzymes known, operating without additional cofactors and via compound I ferryloxo heme intermediate. Two molecules of H2O2 are consumed per catalytic cycle, protecting unsaturated ether lipids and peroxisomal proteins and limiting leakage to cytosol where glutathione peroxidase would be overwhelmed. Catalase is imported via noncanonical PTS1 recognized by PEX5 despite lacking classic SKL because of extended binding interface. Its activity complements cytosolic glutathione peroxidase, peroxiredoxins and mitochondrial superoxide dismutase in antioxidant network. Genetic catalase deficiency causes acatalasemia in Japan with mild phenotype due to redundancy, but peroxisome biogenesis failure impairs plasmalogen synthesis and causes severe neurologic disease.

Ref: Alberts et al., Molecular Biology of the Cell, 6th ed., Chapter 12: Peroxisomes and Catalase Function.

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Cell Organelles

What is the major function of peroxisomes?

Peroxisomes are ubiquitous single-membrane organelles present in most eukaryotes central to lipid metabolism, ROS balance, and signaling. Their hallmark metabolic function is beta-oxidation of very-long-chain fatty acids longer than 22 carbons, branched-chain fatty acids like phytanic acid requiring alpha-oxidation first, and polyunsaturated fatty acids that mitochondria cannot handle efficiently due to double bond positions. Unlike mitochondrial beta-oxidation coupled to electron transfer flavoprotein and respiratory chain to produce ATP, peroxisomal acyl-CoA oxidases, ACOX1, ACOX2, ACOX3, transfer electrons directly to molecular oxygen, generating hydrogen peroxide as byproduct. Enzymes include acyl-CoA oxidase, bifunctional protein with hydratase and dehydrogenase activities, and 3-ketoacyl-CoA thiolase. Acetyl-CoA and chain-shortened acyl-CoAs are then exported to mitochondria either as free acetate or via carnitine shuttle for complete oxidation to CO2. Peroxisomes also initiate ether phospholipid plasmalogen synthesis necessary for myelin, bile acid side chain oxidation, glyoxylate detoxification, and polyamine catabolism. Import of matrix proteins uses cytosolic receptors PEX5 recognizing C-terminal PTS1 SKL tripeptide and PEX7 recognizing N-terminal PTS2. Defective import causes Zellweger spectrum disorders with severe neurodevelopmental defects.

Ref: Wanders & Waterham, Annual Review of Biochemistry 2016: Peroxisome Biogenesis and Fatty Acid Beta-Oxidation.

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Cell Organelles

The major function of peroxisomes is:

Peroxisomes are single membrane oxidative organelles discovered by Rhodin and De Duve, numbering hundreds per cell, containing more than fifty enzymes producing and degrading hydrogen peroxide. Beta-oxidation of very long chain fatty acids greater than twenty two carbons, branched phytanic acid alpha-oxidation, bile acid intermediate shortening and ether lipid synthesis of plasmalogens providing antioxidant membranes and myelin components occur via enzymes acyl-CoA oxidase generating H2O2, bifunctional enzyme and thiolase. Catalase converts two H2O2 to water and oxygen detoxifying, also urate oxidase and D-amino acid oxidase produce peroxide. Import depends on peroxisomal targeting signals PTS1 tripeptide SKL at C terminus recognized by Pex5 receptor and PTS2 nonapeptide recognized by Pex7. Protein degradation via lysosomal hydrolases acidic, ATP synthesis mitochondrial inner membrane, nucleic acid processing nuclear. Defects in Pex genes cause Zellweger spectrum with accumulation of very long chain fatty acids, hypotonia and neuronal migration failure illustrating essential lipid metabolic and detoxification function distinct from energy metabolism.

Ref: Wanders Annu Rev Biochem; peroxisome beta-oxidation VLCFA catalase PTS1 PTS2 Pex import.

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