Fact-checked by Grok 2 weeks ago

Peroxisome

Peroxisomes are single-membrane-bound organelles found in nearly all eukaryotic cells, specialized for carrying out oxidative reactions that generate (H₂O₂) as a byproduct, which is subsequently decomposed by to prevent cellular damage. These organelles play essential roles in , including the β-oxidation of very long-chain fatty acids and the synthesis of plasmalogens, which constitute 80–90% of the phospholipids in sheaths. Additionally, peroxisomes contribute to processes, such as the oxidation of about 25% of ingested to in liver and cells, and in , they support and the for carbohydrate synthesis from fats. Beyond their core metabolic functions, peroxisomes are highly dynamic structures involved in (ROS) , immune signaling, and inter-organelle communication, such as through contact sites with the (ER) and mitochondria. Their biogenesis relies on peroxins (PEX proteins), like PEX5 for matrix protein import and PEX11β for fission and expansion, often initiating from ER-derived pre-peroxisomal vesicles, with all proteins synthesized in the and imported post-translationally. Dysfunctions in peroxisome assembly or function lead to peroxisome biogenesis disorders (PBDs), including Zellweger spectrum disorder (ZSD), characterized by severe neurological and developmental impairments due to impaired β-oxidation and synthesis, as well as X-linked (X-ALD), affecting approximately 1 in 17,000 births and causing neurodegeneration from very long-chain accumulation. Recent advances highlight peroxisomes' plasticity, including roles in antiviral defense via innate immune signaling and tissue-specific functions like retinal lipid metabolism and pancreatic ROS regulation, as well as peroxisome-mitochondria cooperation in managing cellular oxidative stress (as of July 2025) and peroxisomes' involvement in macrophage-mediated alveolar regeneration following severe respiratory viral infections (as of March 2025), underscoring their importance in maintaining cellular and organismal health across diverse physiological contexts.

Discovery and History

Early Observations

The initial observations of peroxisome-like structures, then termed microbodies, were made through electron microscopy studies in the mid-1950s. In 1954, Johannes Rhodin described these organelles as small, single-membrane-bound vesicles, approximately 0.5–1.0 μm in diameter, present in the proximal convoluted tubule cells of . Similar microbody structures were subsequently observed in liver cells by Rouiller and Bernhard in 1956, highlighting their granular matrix and association with cellular metabolism, though their function remained unclear at the time. Early biochemical investigations in the provided hints of a distinct subcellular compartment containing oxidative in liver. Studies on revealed that activity was enriched in particulate fractions of liver homogenates, suggesting localization to a membrane-bound structure separate from mitochondria or . Researchers such as A.H. Schein, E. Podber, and A.B. Novikoff demonstrated that this sedimented with other particulate components, indicating a potential involvement in , though the exact nature of the compartment was not yet defined. These microbodies were initially confused with lysosomes due to overlapping densities during , leading to co-purification in light mitochondrial fractions from rat liver. This similarity in behavior delayed recognition of peroxisomes as a unique until refined separation techniques in the 1960s, later formalized by , distinguished them based on enzymatic content.

Key Milestones and Naming

In 1966, and Pierre Baudhuin isolated and characterized peroxisomes from rat liver through subcellular fractionation and biochemical analysis, identifying them as distinct organelles containing oxidases that produce and that decomposes it. They proposed the name "peroxisomes" to reflect this oxidative role, distinguishing these structures from previously observed microbodies. During the 1970s and 1980s, key functional insights emerged, including the demonstration by Paul B. Lazarow and that rat liver peroxisomes catalyze the β-oxidation of fatty acids, a process distinct from mitochondrial β-oxidation and involving unique enzymes like acyl-CoA oxidase. In 1987, J. Gould and colleagues showed that , when expressed in mammalian cells, is targeted to peroxisomes via a C-terminal serine-lysine-leucine , establishing it as a valuable reporter for studying protein import mechanisms. The 1990s and 2000s marked significant progress in peroxisome biogenesis, with the identification of peroxins—proteins encoded by PEX genes essential for assembly and —through complementation studies in mutants and mammalian cells from patients with peroxisome biogenesis disorders. For instance, mutations in PEX genes such as PEX2 (cloned in 1992) and PEX5 (identified in 1995) were linked to , a severe peroxisomal disorder characterized by absent or dysfunctional peroxisomes, confirming the genetic basis of these conditions. Recent reviews in 2025 commemorated 70 years since Rhodin's initial electron microscopic observations of microbodies in 1954, underscoring peroxisomes' established metabolic roles while highlighting ongoing mysteries in their biogenesis, such as the precise mechanisms of membrane formation and protein .

Structure and Morphology

Physical Characteristics

Peroxisomes are typically spherical or ovoid organelles, though they can also adopt elongated forms, with diameters ranging from 0.1 to 1.0 μm. They are enclosed by a single that separates the organelle's dense matrix, containing metabolic enzymes and substrates, from the . This compact structure enables peroxisomes to efficiently compartmentalize oxidative reactions while maintaining flexibility in cellular environments. In mammalian s, peroxisomes number approximately 100 to more than 1,000 per cell, with abundance varying significantly by type to support specialized functions. For instance, liver cells contain higher peroxisome densities, often exceeding typical levels, to facilitate processes involving and . This variability ensures adaptive responses to metabolic demands across organs like and , where peroxisomes may range from 0.1 to 0.5 μm in size. Peroxisomes display notable morphological plasticity, altering shape and number in response to environmental cues or developmental stages. In certain tissues, they form tubular extensions up to several micrometers long, particularly under conditions. to fatty acids, such as , induces tubular forms and proliferation in cells, enhancing numbers for efficient substrate processing. Such changes also occur during cellular or , allowing peroxisomes to adapt dynamically without disrupting overall cellular architecture. Visualization of peroxisomes relies on advanced imaging techniques, including fluorescence microscopy with (GFP) fused to peroxisomal markers like PMP70, which highlights their distribution and dynamics in living cells. This method reveals peroxisomal movement and interactions, providing insights into their real-time behavior across cell types.

Membrane and Matrix Composition

The peroxisomal membrane is primarily composed of phospholipids, with phosphatidylcholine (PC) and phosphatidylethanolamine (PE) being the major species, accounting for approximately 36-45% and 47-50% of the total phospholipids in liver peroxisomes, respectively. is also present in the membrane, contributing to its biophysical properties, including modulation of fluidity and permeability to support lipid transport and organelle dynamics. Peroxisomal membrane proteins (PMPs) constitute a diverse group, including integral membrane proteins embedded in the and peripheral proteins associated with the membrane surface. Integral PMPs, such as PMP70 (also known as ABCD3), function as ATP-binding cassette transporters that facilitate the import of long-chain fatty acids into the peroxisome for . Peripheral PMPs, exemplified by Inp1p in , play roles in peroxisome inheritance and division by interacting with other membrane components without spanning the bilayer. The matrix of the peroxisome houses approximately 50 metabolic enzymes in mammalian cells, which perform oxidative reactions central to cellular . In some species, such as , the matrix may contain crystalline cores formed by . Key among these are , which decomposes (H₂O₂) generated during oxidative processes to prevent oxidative damage, and oxidases, which initiate the β-oxidation of fatty acids by producing H₂O₂ as a byproduct. , present in the peroxisomes of many non-primate mammals and other species, catalyzes the conversion of to , aiding in , though it is absent in humans and higher . Peroxisomal membranes exhibit a low protein-to-lipid ratio, which contributes to their biophysical properties such as fluidity and supports dynamics, while enables the dense packing of enzymes essential for efficient metabolic activity.

Biogenesis and Dynamics

Protein Import and Peroxins

Peroxisomal proteins are synthesized on free ribosomes in the and imported post-translationally into the , a process that allows even oligomeric and folded proteins to be translocated across the . This import is driven by specific peroxisomal targeting signals (PTSs) recognized by soluble receptors. The majority of proteins contain a C-terminal PTS1, typically a motif such as serine-lysine-leucine (SKL) or close variants like or AKL, which binds to the tetratricopeptide repeat of the receptor PEX5 in the . A smaller subset of proteins, including those involved in β-oxidation like , bear an N-terminal PTS2, a nonapeptide sequence (R/K)(L/V/I/Q)XX(L/V/I/H/Q)(L/S/G/A)X(H/Q)(L/A), which is recognized by the receptor PEX7, often in conjunction with PEX5 as a co-receptor. Membrane proteins destined for the peroxisomal utilize a distinct mPTS, typically an α-helical cluster of basic and hydrophobic residues, which interacts with the chaperone PEX19 for targeting and insertion. The import machinery assembles at the peroxisomal membrane to facilitate cargo translocation. Cytosolic PEX5- complexes dock at the peroxisomal import pore via interactions between PEX5 and the integral membrane peroxins PEX13 and PEX14, forming a transient translocon that allows the receptor and cargo to . Similarly, PTS2 cargoes bound to PEX7-PEX5 dock through PEX7's interaction with PEX14 and PEX5's binding to PEX13. For membrane proteins, PEX19 delivers mPTS-bearing proteins to PEX3 at the peroxisomal membrane, where they are inserted independently of matrix import pathways. This machinery is composed of peroxins, a of conserved proteins essential for peroxisome biogenesis; 36 peroxins (PEX1 through PEX36) have been identified across eukaryotes, with PEX s distributed across chromosomes, such as PEX1 on 7q21.2. Receptor recycling is critical for sustained import and involves an ATP-dependent ubiquitination cycle. Upon cargo release in the matrix, PEX5 is monoubiquitinated at a conserved cysteine residue by the E2 ubiquitin-conjugating enzyme PEX4 and the E3 ligase complex PEX10-PEX12-PEX2, marking it for extraction. The AAA+ ATPases PEX1 and PEX6, recruited to the membrane via PEX26, then unfold and retrotranslocate ubiquitinated PEX5 to the cytosol in an ATP-hydrolyzing process, enabling receptor deubiquitination and reuse. This cycle ensures efficient protein flux and prevents receptor accumulation on the organelle. The overall import process is strictly ATP-dependent, with hydrolysis powering receptor ubiquitination, retrotranslocation, and potentially cargo threading through the pore, distinguishing it from co-translational pathways in other organelles.

Formation, Growth, and Division

Peroxisomes can form de novo from pre-peroxisomal vesicles that bud from both the () and mitochondria, which then fuse to generate mature organelles. This pathway involves the peroxins PEX3, PEX16, and PEX19, which are essential for assembling the initial peroxisomal membrane. PEX3 and PEX16 localize to the ER membrane, where they recruit PEX19 to facilitate vesicle budding and maturation into functional peroxisomes, while mitochondrial-derived vesicles contribute additional components such as certain PMPs. In addition to de novo synthesis, peroxisomes proliferate through a fission model that encompasses growth, elongation, and division. During growth, peroxisomes expand by incorporating lipids and proteins synthesized in the ER and other cellular compartments, increasing their membrane surface area. Elongation is driven by PEX11 family proteins, particularly PEX11β, which remodel the peroxisomal membrane into tubular structures. Division then occurs via constriction and scission, mediated by the dynamin-related protein DRP1, which is recruited to the peroxisomal membrane by receptors such as FIS1 and PEX11β. This process ensures equitable distribution of peroxisomes within the cell and responds to metabolic demands. Peroxisome formation, growth, and division are tightly regulated by environmental and metabolic cues. Fatty acids act as ligands for the PPARα, which induces expression of genes involved in peroxisome proliferation, including those encoding PEX11 and enzymes for . This regulatory mechanism links peroxisome dynamics to , promoting organelle expansion under conditions of high load. Recent findings from 2025 highlight the role of (PKC) in enhancing PEX11β-dependent ; PKC activation increases peroxisome-ER contact sites, facilitating and biogenesis through inactivation of GSK3β. During , peroxisomes are partitioned between daughter cells to maintain . In symmetric , peroxisomes distribute relatively evenly via microtubule-based and association with the . However, in asymmetric divisions, such as those in s, partitioning can be uneven; older or functionally distinct peroxisomes marked by may be selectively retained in the stem cell to preserve self-renewal capacity, while newer ones are allocated to differentiating progeny, as observed in mammary and epidermal stem cells (as of April 2025). This selective inheritance influences cellular fate and tissue organization.

Core Metabolic Functions

Fatty Acid β-Oxidation

Peroxisomal β-oxidation represents a specialized metabolic pathway within peroxisomes that initiates the breakdown of certain fatty acids, contrasting with the more general mitochondrial β-oxidation by handling longer and branched substrates. Very long-chain fatty acids are activated to acyl-CoA esters in the cytosol by acyl-CoA synthetases such as ACSVL1, then imported into the peroxisomal matrix via ABC transporters like ABCD1 for degradation. The core cycle consists of four sequential steps: dehydrogenation to form a trans-2-enoyl-CoA, hydration to L-3-hydroxyacyl-CoA, further dehydrogenation to 3-ketoacyl-CoA, and thiolysis to yield acetyl-CoA (or propionyl-CoA for odd-chain or branched substrates) and a shortened acyl-CoA ester. This process shortens the fatty acid chain by two carbons per cycle but is incomplete, typically stopping at medium-chain lengths (C6–C8), after which the products are exported to mitochondria for final oxidation via carnitine-dependent shuttles like carnitine octanoyltransferase. Unlike mitochondria, peroxisomes lack an electron transport chain, so energy from the initial dehydrogenation is not captured as ATP but instead reduces molecular oxygen directly to hydrogen peroxide (H₂O₂). The H₂O₂ byproduct is managed by peroxisomal catalase to prevent oxidative damage. The pathway's substrate specificity targets very long-chain fatty acids (VLCFAs, chain length >C22, such as C24:0 and C26:0), which cannot be efficiently processed by mitochondrial enzymes, as well as branched-chain fatty acids like —derived from dietary sources and first shortened via peroxisomal α-oxidation to pristanic acid before β-oxidation—and bile acid intermediates such as trihydroxycoprostanoyl-CoA (THCA) and dihydroxycholestanoic acid (DHCA), which are converted from C27 to C24 forms. These substrates accumulate if peroxisomal function is impaired, highlighting the pathway's essential role in lipid homeostasis. Key enzymes include three acyl-CoA oxidases: for straight-chain s (including VLCFAs and polyunsaturated fatty acids like ), for 2-methyl branched-chain s (e.g., pristanoyl-CoA) and intermediates, and for additional branched substrates like pristanoyl-CoA, though its expression is limited in humans. Hydration and dehydrogenation are catalyzed by multifunctional proteins, such as MFP1 (or HSD17B4) for straight-chain substrates and MFP2 for branched-chain ones, which integrate enoyl-CoA hydratase and 3-hydroxyacyl-CoA activities. Thiolysis is performed by peroxisomal , including ACAA1 (also known as A) for straight-chain cleavage and SCPx for branched-chain products, often yielding propionyl-CoA. Auxiliary enzymes like AMACR racemize (2R)-methylacyl-CoAs to the (2S)- required for β-oxidation, ensuring efficient processing of branched substrates. Regulation of peroxisomal β-oxidation occurs primarily through transcriptional control by the PPARα, which, upon activation, forms a heterodimer with RXRα and binds to peroxisome proliferator response elements (PPREs) in promoter regions of target genes such as ACOX1, EHHADH (encoding MFP1), and ACAA1. In the liver, fibrates like and fenofibrate serve as synthetic PPARα ligands, inducing 10- to 20-fold increases in β-oxidation enzyme expression and activity, alongside peroxisome proliferation. This upregulation enhances catabolism in response to lipid overload, with coactivators like PGC-1α amplifying the response.

Other Lipid and Detoxification Pathways

Peroxisomes play a crucial role in the biosynthesis of ether lipids, particularly , which are vital for membrane structure and function in mammalian cells. The initial steps of plasmalogen synthesis occur in the peroxisomal matrix, where (DHAP) is first acylated by DHAP acyltransferase (GNPAT), also known as :dihydroxyacetonephosphate acyltransferase, to form acyl-DHAP. This is followed by the action of alkyl-DHAP synthase (AGPS), which exchanges the acyl group for a long-chain , yielding alkyl-DHAP, the precursor for ether lipids. These peroxisome-specific reactions ensure the exclusive production of ether-linked phospholipids, with subsequent steps completing the pathway in the . Defects in GNPAT or AGPS lead to severe reductions in plasmalogen levels, as seen in rhizomelic chondrodysplasia punctata, highlighting their indispensable role. In addition to ether lipid synthesis, peroxisomes contribute to bile acid production through the oxidation of cholesterol-derived intermediates. The peroxisomal acyl-CoA oxidase 2 (ACOX2), a branched-chain , catalyzes the initial step in the β-oxidation of C27 precursors, shortening their side chains to form mature C24 essential for digestion and . This process involves the sequential action of ACOX2, the multifunctional type 2 (MFE2), and , all localized in peroxisomes, to convert intermediates like 3α,7α,12α-trihydroxy-5β-cholestanoyl-CoA into cholic acid derivatives. Mutations in ACOX2 result in the accumulation of toxic C27 intermediates, causing liver dysfunction and emphasizing peroxisomes' specialized role in this pathway, distinct from mitochondrial oxidation. Peroxisomes also facilitate through the of various metabolites, including and . D-aspartate oxidase, a flavin-dependent , oxidizes D-aspartate and other D-amino acids in the peroxisomal matrix, generating as a and aiding in the clearance of these compounds, particularly in and tissues. Similarly, L-pipecolic acid metabolizes L-pipecolic acid, a derivative, to piperidine-6-carboxylic acid, contributing to breakdown and preventing , with elevated pipecolic acid levels observed in peroxisomal disorders like . In , urate further supports by converting to , a more soluble product, thus mitigating risks, though this is absent in humans. Peroxisomes are involved in polyamine oxidation, where N¹-acetylpolyamine oxidase (PAOX), a flavin-containing enzyme, catabolizes acetylated spermine and spermidine, producing (ROS) that influence cellular signaling and stress responses. This peroxisomal activity links homeostasis to ROS generation, with PAOX contributing to the regulation of levels during and in mammalian tissues. Dysregulation of this pathway can exacerbate ROS-mediated damage, underscoring its role in maintaining metabolic balance.

Inter-Organelle Interactions

Physical Contacts and Tethering

Peroxisomes establish direct membrane contact sites (MCSs) with various s, enabling structural proximity that supports organelle biogenesis and maintenance. These contacts typically maintain inter-membrane distances of 10-30 nm, as revealed by techniques such as direct stochastic optical reconstruction microscopy (dSTORM) and stimulated emission depletion (STED) nanoscopy, which overcome the diffraction limit to visualize nanoscale interactions. Endoplasmic reticulum (ER)-peroxisome contacts play a central role in peroxisome biogenesis and . Peroxins PEX3 and PEX16 mediate these interfaces by facilitating the ER-dependent trafficking of peroxisomal proteins (PMPs); PEX16 recruits PEX3 to the ER, where it initiates pre-peroxisomal formation and subsequent fission into mature peroxisomes. This process ensures constant supply of PMPs and from the ER for peroxisome growth and division. Complementing these biogenesis roles, the tethering complex formed by VAPs (VAPA/B) on the ER and ACBD5 on peroxisomes anchors the organelles, promoting expansion through exchange such as phospholipids and . Disruption of this VAP-ACBD5 interaction, as shown by co-immunoprecipitation and depletion studies, reduces peroxisome-ER colocalization and increases peroxisome mobility, underscoring its necessity for stability. Mitochondria-peroxisome interfaces resemble mitochondria-associated membranes (MAMs) and involve mitofusins MFN1 and MFN2 alongside PEX11. MFN2, enriched at these sites, promotes peroxisome clustering with mitochondria by their outer membranes, with overexpression enhancing contact frequency as observed in fluorescence microscopy assays. PEX11 contributes to contact initiation, potentially in an ER-dependent manner, facilitating for inter-organelle proximity. In neuronal contexts, recent studies highlight dynamic regulation of these contacts; for instance, under like exposure, peroxisome-mitochondria associations increase in cortical neurons to bolster balance, while GDAP1 mediates to influence mitochondrial dynamics in neuropathologies. Peroxisomes also form contacts with lipid droplets (LDs) to mobilize stored s. In mammalian cells, M1 spastin, a membrane-bound on LDs, tethers them to peroxisomes via interaction with the peroxisomal transporter ABCD1, recruiting ESCRT-III components (IST1 and CHMP1B) to potentially induce LD membrane tubulation and facilitate release for peroxisomal uptake. This mechanism, evidenced by increased LD-peroxisome colocalization upon spastin overexpression, ensures efficient handover. In , peroxisomes extend tubular protrusions to contact oil bodies (plant LDs), delivering lipases like SDP1 directly to the surface for breakdown, illustrating a conserved strategy for LD-peroxisome interfacing. Peroxisomes form membrane contact sites with lysosomes, which are crucial for lipid metabolism, particularly cholesterol transport. These contacts, maintaining close inter-membrane proximity, are mediated by lysosomal synaptotagmin VII binding to phosphatidylinositol 4,5-bisphosphate on peroxisomes, enabling the non-vesicular transfer of cholesterol from lysosomes to peroxisomes for subsequent oxidation and bile acid synthesis. Disruption of these sites impairs cellular cholesterol homeostasis, highlighting their physiological significance.

Metabolic Crosstalk and Signaling

Peroxisomes engage in extensive metabolite shuttling with mitochondria, particularly during β-oxidation of very long-chain fatty acids, where the resulting is exported to mitochondria for entry into the tricarboxylic acid cycle and complete oxidation to generate ATP. This process is facilitated by physical tethers between the organelles, enabling efficient transfer without diffusion through the . Additionally, NADH produced in peroxisomal β-oxidation must be reoxidized to NAD⁺ to sustain the pathway, with peroxisomes relying on mitochondrial interactions to maintain NAD⁺/NADH ratios that influence overall cellular redox balance and prevent buildup. Dysregulation of this shuttling can lead to metabolic imbalances, as seen in conditions where peroxisomal NAD⁺ is compromised, highlighting the interdependence of these organelles in energy metabolism. Peroxisomes also contribute to cellular signaling through (ROS), which serve as messengers in inflammatory pathways. Peroxisomal ROS, generated during β-oxidation and reactions, can activate the by promoting its assembly and downstream release, such as IL-1β, thereby linking metabolic activity to innate immune responses. This signaling is modulated by peroxisome proliferator-activated receptors (PPARs), particularly PPARα and PPARγ, which upon ligand activation regulate peroxisome proliferation, enhance β-oxidation enzyme expression, and promote , including controlled proliferation in response to overload. PPAR signaling thus integrates peroxisomal function with broader transcriptional control of metabolism and growth, ensuring under varying nutritional states. Recent advances have illuminated peroxisomes' role in interactions, with 2025 studies revealing how bacterial effectors hijack these organelles for replication. For instance, secretes an effector protein that recruits peroxisomes to its replication , exploiting peroxisomal lipids and enzymes to support bacterial growth and evade host defenses. This manipulation underscores peroxisomes' vulnerability in contexts, potentially altering host metabolic signaling. Peroxisomes further influence autophagy regulation, where phosphorylation of the import receptor PEX5 serves as a key control point. ATM kinase, recruited to peroxisomes, phosphorylates PEX5 in response to ROS, triggering its ubiquitination and selective degradation via , which in turn modulates overall . This PEX5-mediated process links peroxisomal turnover to , as upregulated pexophagy can deplete shared autophagy resources, limiting mitochondrial clearance and affecting cellular quality control. Such interconnections highlight peroxisomes' regulatory role in balancing .

Physiological Roles and Emerging Functions

Reactive Oxygen Species Management

Peroxisomes serve as major intracellular sites for the generation of (ROS), primarily through enzymatic reactions involved in oxidative metabolism. During β-oxidation, oxidase 1 (ACOX1) catalyzes the initial desaturation step, directly producing (H₂O₂) as a byproduct. Additionally, superoxide anions (O₂⁻) arise from electron leakage in the peroxisomal , particularly during NADH reoxidation. These ROS are integral to peroxisomal function but require tight regulation to prevent cellular damage. To neutralize these ROS, peroxisomes employ robust antioxidant systems, with (CAT) as the primary . efficiently decomposes H₂O₂ via the reaction: $2 \mathrm{H_2O_2} \rightarrow 2 \mathrm{H_2O} + \mathrm{O_2} This process occurs at high rates within the peroxisomal matrix, where CAT is highly concentrated. Supporting CAT, peroxiredoxin 5 (PRDX5) and peroxidases reduce H₂O₂ and other peroxides using or as electron donors, acting as backups during peak ROS production. These mechanisms collectively maintain low steady-state ROS levels, preventing diffusion out of the and subsequent . The high abundance of catalase in peroxisomes represents an evolutionary adaptation to their oxidative metabolic role, enabling efficient ROS without compromising energy-yielding reactions. This balance is crucial for cellular , as peroxisomes handle a significant portion of cellular H₂O₂ flux. Dysregulation leading to excess ROS from peroxisomes has been implicated in aging processes, where impaired capacity accelerates macromolecular damage and lifespan shortening. Recent studies highlight protective networks, such as those stimulated by monounsaturated fatty acids (MUFAs), which enhance peroxisome- droplet interactions to reduce lipid oxidation and mitigate oxidative burden.

Roles in Immunity, Neuronal Function, and Beyond

Peroxisomes play a pivotal role in innate immunity, particularly in the survival and function of , which are essential for pulmonary defense. In , peroxisomes facilitate the of very-long-chain fatty acids and other , preventing that could otherwise compromise cellular integrity. A 2025 study demonstrated that peroxisomal β-oxidation is crucial for maintaining mitochondrial fitness in these cells, enabling their homeostatic development, self-renewal, and resistance to lipid overload in the lipid-rich alveolar environment. Without functional peroxisomes, exhibit impaired mitochondrial respiration and increased susceptibility to , underscoring their necessity for immunity. Pathogenic bacteria, such as , exploit peroxisomes to promote intracellular replication and evade host defenses. Legionella secretes an effector protein that actively recruits peroxisomes to its replication , facilitating nutrient acquisition and modulation of host to support . This hijacking, detailed in a 2025 investigation, enhances the pathogen's ability to manipulate peroxisomal functions, including oxidation, thereby subverting immune responses in infected macrophages. In neuronal physiology, peroxisomes exhibit dynamic localization and function, particularly in axons and dendrites, where they support myelination and axonal integrity. Peroxisomes are trafficked along to distal neurites, adjusting their distribution in response to cellular demands; under basal conditions, they predominate in the and proximal dendrites but redistribute during . Their biogenesis and , mediated by proteins like PEX11β, DRP1, and MFF, ensure adequate numbers for lipid synthesis essential to myelin sheath formation. Peroxisomes synthesize s—ether phospholipids critical for myelin stability—and their dysfunction leads to reduced plasmalogen levels, demyelination, and axonal degeneration observed in conditions like . Peroxisomes also interact closely with mitochondria in neurons, forming membrane contact sites that facilitate lipid transfer and redox balance, with up to 80% of peroxisomes engaging mitochondria in neurites. These interactions protect against ; for instance, arsenic-induced stress increases peroxisome-mitochondria contacts, mitigating neuronal damage. In neurodegeneration, such as Alzheimer's and Parkinson's diseases, disrupted peroxisomal-mitochondrial tethering elevates and very-long-chain fatty acids, exacerbating neuronal loss—a link highlighted in a 2025 review. Beyond immunity and neuronal roles, peroxisomes contribute to aging protection through integrated lipid networks. They maintain cellular homeostasis by cooperating with and lipid droplets at membrane contact sites, such as those involving ACBD5-VAPB tethers, to regulate β-oxidation and synthesis. In aging tissues like the , peroxisomal abundance and protein expression decline, correlating with impaired balance and increased vulnerability to stress; interventions like supplementation restore peroxisomal function, enhancing longevity pathways. A 2024 review emphasized these networks' protective effects against age-related metabolic dysregulation. Advances in have leveraged peroxisomes for production, engineering yeast compartments to boost efficiency. In Pichia pastoris, relocating the to peroxisomes enabled α-bisabolene synthesis—a precursor to bisabolane —from alone, yielding 1.1 g/L via fed-batch fermentation, a 69% improvement over cytosolic approaches. Proteomic optimization identified bottlenecks, such as overexpressing EfmvaE, increasing peroxisomal output by 72%. These 2024 developments highlight peroxisomes' potential as factories for precursors. Therapeutically, peroxisomes represent promising targets for and neurodegeneration interventions. Agonists of peroxisome proliferator-activated receptors (PPARs), such as those activating PPARα/γ, reduce by enhancing peroxisomal and suppressing signaling in models of . Chemical chaperones like 4-phenylbutyrate (4-PBA) restore peroxisomal biogenesis, alleviating demyelination and in preclinical neurodegeneration studies. A 2025 analysis positioned peroxisomes as key regulators of innate immunity via MAVS signaling, suggesting targeted modulation could mitigate viral-induced and in .

Associated Diseases

Peroxisome Biogenesis Disorders

Peroxisome biogenesis disorders (PBDs) are a group of rare, autosomal recessive genetic conditions resulting from in PEX genes, which peroxins essential for peroxisome and function. These defects lead to absent or dysfunctional peroxisomes, disrupting multiple metabolic pathways and causing multisystem involvement. The most prevalent PBDs fall within the Zellweger spectrum disorders (ZSD), encompassing a continuum of severity from severe (ZS) to milder forms like neonatal (NALD) and infantile . ZSD primarily arises from mutations in PEX1 or PEX6 genes, which impair the import of peroxisomal matrix proteins and result in a near-complete absence of functional peroxisomes. Affected individuals exhibit profound , seizures, dysmorphic facial features, severe liver dysfunction, and progressive neurological deterioration, often leading to death in early infancy for the most severe cases. Neonatal adrenoleukodystrophy (NALD), an intermediate ZSD variant, shares overlapping features such as and but typically presents with later onset and somewhat prolonged survival, though still with significant developmental delays and multi-organ failure. Another distinct PBD is rhizomelic chondrodysplasia punctata type 1 (RCDP1), caused by PEX7 mutations that selectively disrupt import of peroxisomal targeting signal 2 (PTS2) proteins, leading to rhizomelic shortening of proximal limbs, congenital cataracts, skeletal dysplasia, and , with survival often extending into childhood or adolescence. The pathophysiology of PBDs stems from impaired peroxisomal functions, including defective β-oxidation of very long-chain fatty acids (VLCFAs) and , reduced synthesis of (ether phospholipids crucial for stability), and diminished production of (DHA), an essential for neuronal health. These metabolic derangements cause VLCFA accumulation in tissues, particularly and adrenal glands, triggering , , and demyelination, while deficiency exacerbates neuronal migration defects and white matter abnormalities. Diagnosis relies on biochemical assays, such as elevated plasma VLCFA levels (e.g., increased C26:0 and C26:1 ratios) and reduced erythrocyte levels, complemented by to identify PEX mutations; these markers are detectable from birth and do not correlate directly with disease severity. Current treatments for PBDs are primarily symptomatic and supportive, focusing on nutritional supplementation (e.g., DHA to address deficiency) and management of complications like seizures or . Bile acid therapy with cholic acid has shown efficacy in reducing toxic C27-bile acid intermediates and improving liver function in ZSD patients, with long-term use demonstrating biochemical stabilization and potential survival benefits. Emerging therapeutic strategies include targeting specific PEX mutations, such as AAV-based retinal for PEX1-deficient ZSD to restore visual function, currently in preclinical and early clinical development as of 2025. Additionally, pharmacological approaches like (HDAC) inhibitors are under investigation to enhance peroxisome biogenesis by upregulating peroxin expression and stabilizing proteins like PEX5, offering promise for restoring partial peroxisomal function in cellular models of PBDs.

Enzyme-Specific Deficiencies

Enzyme-specific deficiencies in peroxisomes arise from mutations in genes encoding individual peroxisomal enzymes or transporters, leading to impaired specific metabolic functions despite intact organelle biogenesis. These disorders contrast with peroxisome biogenesis disorders by affecting targeted pathways, such as fatty acid oxidation or bile acid synthesis, resulting in accumulation of toxic substrates and diverse clinical manifestations ranging from neurological impairment to adrenal insufficiency. X-linked adrenoleukodystrophy (X-ALD) is the most common peroxisomal enzyme-specific disorder, caused by mutations in the ABCD1 gene encoding the peroxisomal membrane transporter ALDP, which facilitates the import of very long-chain fatty acids (VLCFAs) into peroxisomes for β-oxidation. This defect leads to progressive accumulation of VLCFAs in tissues, particularly in the and adrenal glands, manifesting in two primary forms: the childhood cerebral form, characterized by rapid demyelination, behavioral changes, and vision/, and adrenomyeloneuropathy (AMN), an adult-onset disorder with progressive paraparesis and sensory loss. The cerebral form affects about 35-40% of male patients and is often fatal within a decade if untreated, while AMN predominates in adulthood with in up to 70% of cases. Diagnosis relies on elevated plasma VLCFA levels, confirmed by . Acyl-CoA oxidase deficiency, specifically the straight-chain acyl-CoA oxidase 1 (ACOX1) variant, results from mutations in the ACOX1 gene, disrupting the initial step of peroxisomal VLCFA β-oxidation and causing accumulation of very long-chain fatty acids and . This rare autosomal recessive disorder typically presents in infancy with , seizures, developmental delay, dysmorphic features such as and , and progressive , often leading to death in early childhood. MRI shows cerebral white matter abnormalities. Unlike classic , it involves VLCFA accumulation but spares phytanoyl-CoA hydroxylase. Only a handful of cases have been reported, with via elevated VLCFAs and phytanic acid in plasma and fibroblasts. Other notable enzyme-specific deficiencies include alpha-methylacyl-CoA racemase (AMACR) deficiency, caused by mutations in the AMACR gene, which encodes an enzyme essential for of pristanoyl-CoA and bilisomal intermediates in peroxisomal and branched-chain . This leads to accumulation of pristanic acid, C27- intermediates, and , resulting in a with adult-onset sensory motor neuropathy, pigmentary , and elevated cholestanol levels; pediatric cases may present with liver dysfunction and . Diagnosis involves biochemical profiling showing specific metabolite elevations, with fewer than 20 families reported worldwide. Therapeutic approaches for these deficiencies remain limited but evolving. For X-ALD, Lorenzo's oil—a mixture of oleic and erucic acids—partially normalizes VLCFA levels in asymptomatic boys but shows mixed results in preventing neurological progression, with no benefit in advanced cerebral cases per randomized trials. Hematopoietic stem cell transplantation (HSCT) is the standard for early-stage cerebral X-ALD in boys under 10, stabilizing or reversing demyelination in over 80% of cases when performed presymptomatically via MRI screening. Lentiviral vector-based gene therapy elivaldogene autotemcel (SKYSONA) received FDA approval in 2022 for slowing neurologic progression in boys aged 4-17 with early, active cerebral X-ALD. As of 2024, long-term data show major disability-free survival in most treated patients after six years, with reduced VLCFA levels. However, as of August 2025, FDA labeling was updated to reflect a 15% risk of hematologic malignancies in clinical trial patients, restricting use to individuals without suitable hematopoietic stem cell transplantation options or donors. CRISPR-based editing approaches remain in preclinical stages for broader application. For acyl-CoA oxidase and AMACR deficiencies, management is supportive, including phytanic acid-restricted diets and monitoring for complications, with no disease-modifying therapies approved yet.

Genetics and Regulation

PEX Genes and Mutations

The encodes peroxins, proteins essential for peroxisome biogenesis, including the formation of the membrane, matrix protein import, and . In humans, there are at least 14 core PEX genes (PEX1 through PEX14), with additional genes such as PEX16, PEX19, and PEX22 contributing to these processes. These genes are highly conserved across eukaryotes, reflecting the fundamental role of peroxisomes in cellular . In model organisms, orthologs of PEX genes facilitate studies of peroxisome biogenesis. In (), the corresponding genes are known as (peroxisome assembly) genes, such as PAS10 (ortholog of PEX5) and PAS1 (ortholog of PEX3), which share functional similarities in and assembly. , including , possess orthologs like AtPEX1 and AtPEX6, which support peroxisomal functions adapted to plant-specific metabolism, such as lipid mobilization during seed germination. In , orthologs such as dmPex1 and dmPex3 enable genetic screens to model peroxisomal defects, revealing conserved roles in development and stress response. Mutations in PEX genes underlie peroxisome biogenesis disorders (PBDs), with PEX1 being the most frequently affected, accounting for approximately 70% of cases in the (ZSD), a subset of PBDs. In PEX1, the majority of pathogenic variants are missense , with the recurrent G843D (c.2528G>A) alteration representing a hypomorphic hotspot that partially retains protein function; other hotspots cluster in exons 13 and 15, often at CpG dinucleotides prone to transitions. For PEX6, which encodes an AAA- partnering with PEX1 in receptor for protein , defects commonly target the domain, disrupting and leading to impaired peroxisomal assembly. PEX6 comprise about 10-15% of PBD cases, frequently involving missense changes that reduce protein . Resources like PeroxisomeDB catalog PEX gene variants, integrating genomic, proteomic, and functional from humans and model organisms to track spectra and ortholog . The prevalence of ZSD, primarily driven by PEX gene , is estimated at 1 in 50,000 live births worldwide.

Transcriptional and Post-Translational Control

The of peroxisome biogenesis and function primarily involves the alpha (PPARα), which forms a heterodimer with the (RXR). This complex binds to peroxisome proliferator response elements (PPREs) in the promoter regions of target genes upon activation by ligands, such as very long-chain fatty acids (VLCFAs) and polyunsaturated fatty acids (PUFAs). Key targets include PEX11α, which promotes peroxisome proliferation by facilitating membrane fission, and ACOX1, encoding oxidase 1, the rate-limiting in peroxisomal β-oxidation of . This ligand-induced activation enhances peroxisomal lipid metabolism and biogenesis in response to elevated levels, particularly in liver and other metabolically active tissues. Post-translational modifications further fine-tune peroxisome dynamics and protein import. A 2025 study revealed that protein kinase C (PKC) activation promotes peroxisome biogenesis by phosphorylating PEX11b at serine 53, enhancing peroxisome-endoplasmic reticulum (ER) contact sites and fission events. Additionally, ubiquitination of the import receptor PEX5 serves as a critical quality control mechanism; monoubiquitination at cysteine 11 (in humans) or lysine residues facilitates PEX5 recycling via the PEX1/PEX6 ATPase complex, while polyubiquitination under stress targets defective PEX5 or entire peroxisomes for proteasomal degradation or pexophagy. Feedback loops involving (ROS) integrate peroxisomal function with cellular . Peroxisomes generate ROS during β-oxidation, which activates the NRF2; in turn, NRF2 upregulates antioxidant enzymes, mitigating oxidative damage. Circadian rhythms also modulate peroxisome abundance in the liver, where PPARα expression oscillates daily, peaking during to coordinate rhythmic oxidation and peroxisomal proliferation. Environmental cues, such as , repress peroxisomal activity through hypoxia-inducible factor 1 (HIF-1), which downregulates PPARα expression. This adaptive response limits ROS production under low-oxygen conditions, prioritizing glycolytic metabolism over oxidative pathways.

Evolutionary Origins

Proposed Mechanisms of Origin

The evolutionary origin of peroxisomes remains a topic of , with multiple hypotheses proposed based on biochemical, genetic, and phylogenetic evidence. The predominant model posits that peroxisomes arise from the (ER), integrating them into the broader rather than as an independent endosymbiotic entity. This ER-derived mechanism is supported by observations that key peroxins, such as PEX3 and PEX16, initially localize to the ER in both and mammalian cells, where they facilitate the budding of pre-peroxisomal vesicles containing peroxisomal membrane proteins (PMPs). For instance, in peroxisome-deficient mutant cells, reintroduction of PEX16 or PEX3 triggers the formation of new peroxisomes directly from ER-derived structures, as demonstrated by electron microscopy and showing vesicular intermediates budding from the ER. This process involves non-vesicular transfer and membrane contact sites between the ER and nascent peroxisomes, underscoring the organelle's dependence on ER-derived and proteins for initial assembly. An alternative endosymbiotic hypothesis suggests that peroxisomes originated from engulfed , based on their possession of oxidases and for management, akin to mitochondrial functions, and their ability to import proteins post-translationally. Proponents argued this similarity implied a shared bacterial ancestry, with peroxisomes potentially evolving as a specialized compartment from an ancient symbiont. However, this view has been largely challenged by proteomic analyses revealing that 39–58% of peroxisomal proteins, including all core biogenesis factors (peroxins), are of eukaryotic origin and recruited from cytosolic or pools, with no evidence of a dedicated peroxisomal or bacterial phylogenetic signatures in key enzymes. Phylogenetic trees of peroxisomal enzymes further indicate gradual recruitment from host eukaryotic pathways, such as the ER-associated degradation (ERAD) machinery for peroxins like PEX1 and PEX5, rather than wholesale endosymbiotic transfer. A model proposes that peroxisomes form through the heterotypic of distinct pre-peroxisomal vesicle populations derived from the , assembling a complete import machinery only after merging. In mutants lacking factors like PEX1 or PEX6, pre-peroxisomal vesicles accumulate separately—one carrying docking components (PEX13, PEX14) and the other complex (PEX2, PEX10, )—preventing protein import until occurs, as shown by split-GFP assays and biochemical . Similar vesicle dynamics have been observed in mammalian s, where exit of PMPs leads to intermediate vesicles that fuse to generate mature peroxisomes, supported by from pex3/pex19 double mutants restoring peroxisomes via remnant . This model complements the ER-derived pathway by explaining how modular vesicle pools contribute to maturation. Recent perspectives, informed by advances in membrane contact site and as of 2024, emphasize peroxisomes' full into the eukaryotic , rejecting strict endosymbiosis in favor of an ER-centric evolutionary trajectory. Dynamic ER-peroxisome contacts, mediated by adaptors like ACBD5-VAPB, enable lipid transfer essential for peroxisome membrane expansion, while of PMPs at these sites drives vesicle budding and fusion. These findings, drawn from high-resolution imaging in diverse eukaryotes, suggest peroxisomes evolved as a specialized ER offshoot for oxidative metabolism, with biogenesis pathways conserved across and , highlighting their role in early eukaryotic compartmentalization without requiring symbiotic events.

Comparative Aspects Across Eukaryotes

Peroxisomes exhibit remarkable functional and structural diversity across eukaryotic kingdoms, adapting to the metabolic needs of different organisms while maintaining core roles in and (ROS) detoxification. In animals, particularly mammals, peroxisomes are highly specialized for β-oxidation of very long-chain fatty acids (VLCFAs, typically C22–C26), which cannot be fully processed in mitochondria, and they contain high levels of to decompose generated during these reactions. This emphasis on VLCFA catabolism and robust antioxidant defense distinguishes mammalian peroxisomes from those in other lineages, though peroxisomes are generally present in , with variations in abundance or function in certain species. In plants, peroxisomes play a pivotal role in the , enabling the conversion of stored s into carbohydrates during seedling germination through , a absent in . Plant peroxisomes also feature multiple paralogs of peroxin (PEX) genes, such as duplicated PEX5 variants with distinct cargo specificities, which facilitate specialized protein import and adapt to developmental stages like in leaves or mobilization in seeds. These paralogs enhance peroxisomal versatility, supporting diverse metabolic fluxes unique to photosynthetic organisms. Fungal and yeast peroxisomes demonstrate dynamic proliferation in response to oleate, a fatty acid that induces massive organelle biogenesis to support β-oxidation and growth on alternative carbon sources. Their protein import machinery is comparatively simpler for PTS2-targeted proteins, relying on co-receptors like PEX20 family members without the extensive recycling of the PTS2 receptor PEX7 seen in mammals; instead, PEX7 is often degraded post-import, streamlining the process for rapid adaptation to nutrient shifts. Among protists, glycosomes represent a specialized peroxisomal variant in kinetoplastids like trypanosomes, where they compartmentalize glycolytic enzymes to sequester toxic intermediates, differing from canonical peroxisomes by prioritizing over lipid oxidation. These organelles serve as evolutionary intermediates, bridging general peroxisomal functions in ROS management with the acquisition of anabolic pathways, as evidenced by their presence in parasitic life cycles where energy demands fluctuate dramatically.

Related Organelles

Glyoxysomes in Plants

Glyoxysomes represent a specialized subclass of peroxisomes uniquely adapted in the storage tissues, such as or cotyledons, of germinating oilseed to mobilize stored for conversion into carbohydrates during early development. This process is essential for sustaining growth before the onset of , as seeds rely on triacylglycerol reserves broken down via β-oxidation to produce , which is then shunted into the within glyoxysomes. The enables the net synthesis of succinate from two molecules of , providing precursors for and allowing carbon conservation that would otherwise be lost as CO₂ in the tricarboxylic acid (TCA) cycle. Central to this pathway are two key enzymes exclusive to glyoxysomes: isocitrate lyase, which cleaves isocitrate into succinate and glyoxylate, and malate synthase, which combines glyoxylate with to yield malate. These enzymes bypass the decarboxylating steps of the cycle ( and α-ketoglutarate dehydrogenase), facilitating the anaplerotic replenishment of TCA intermediates and the production of four-carbon compounds for sugar biosynthesis. In species like castor bean (Ricinus communis), these enzymes constitute a significant portion of glyoxysomal protein, underscoring their role in efficient lipid-to-sugar conversion. Glyoxysomes undergo a dynamic developmental transition post-germination, as seedlings emerge from and initiate greening. In this phase, enzymes such as isocitrate lyase and malate synthase are progressively downregulated, while photorespiratory enzymes like hydroxypyruvate reductase are imported, transforming glyoxysomes directly into leaf peroxisomes to support carbon reassimilation during . This repurposing ensures metabolic adaptation from heterotrophic utilization to autotrophic . The glyoxylate cycle in glyoxysomes holds critical agronomic significance for oilseed crops, including soybean, sunflower, and rapeseed, where efficient lipid mobilization drives seedling establishment and stand uniformity in the field. Mutants deficient in isocitrate lyase, such as Arabidopsis thaliana icl alleles, exhibit severe post-germinative growth defects on lipid-rich media, failing to elongate hypocotyls or develop roots without exogenous sucrose, thereby confirming the pathway's indispensability for survival on stored reserves. Similarly, malate synthase knockouts display arrested development and reduced gluconeogenic flux, emphasizing potential breeding targets to enhance vigor in lipid-dependent crops under suboptimal conditions.

Microbodies in Other Organisms

In kinetoplastid protists, such as those in the genus , glycosomes represent specialized microbodies that compartmentalize the initial stages of , including the first seven enzymatic steps from glucose to 3-phosphoglycerate. This sequestration is crucial for the survival of the bloodstream form of , where the parasite relies almost exclusively on for ATP production in the glucose-rich mammalian host environment. Without glycosomal compartmentation, the rapid "turbo design" of trypanosomal could lead to toxic accumulation of phosphorylated intermediates, such as phosphates reaching up to 100 mM, disrupting cellular ; instead, the impermeable glycosomal membrane maintains distinct ATP/ and NAD+/NADH pools, enabling efficient and rapid reactivation upon glucose replenishment. Glycosomes, numbering 65–250 per cell and occupying about 4% of the cytoplasmic volume, are biogenesisally related to peroxisomes via shared peroxins like PEX1, underscoring their evolutionary adaptation for metabolic protection in these parasites. In filamentous ascomycete fungi, Woronin bodies serve as peroxisome-derived structures that function as dynamic plugs to seal septal pores, preventing cytoplasmic loss during hyphal injury. These dense-core organelles, primarily composed of the HEX1 protein which harbors a peroxisomal targeting signal-1 (PTS1), accumulate near septa in species like Neurospora crassa and Magnaporthe grisea, rapidly docking to plug pores against turgor pressures exceeding 0.7 MPa. This sealing mechanism is essential for hyphal integrity and survival under stress, such as mechanical damage or nutrient deprivation, with mutants lacking functional Woronin bodies exhibiting up to 4.5-fold higher rates of hyphal death and impaired pathogenesis in plant hosts. Unlike typical peroxisomes involved in lipid metabolism, Woronin bodies prioritize structural roles, highlighting microbody specialization in fungal multicellularity within the Pezizomycotina subphylum. Hydrogenosomes, found in certain anaerobic eukaryotes like trichomonad protists and some fungi, are double-membrane-bound microbodies that generate ATP and molecular (H₂) via pyruvate oxidation under oxygen-limited conditions, bypassing typical mitochondrial . These organelles produce H₂ through activity, coupling it to reduction and supporting in hosts like the human pathogen . Their evolutionary relation to peroxisomes remains debated; while early studies noted similarities in single-membrane topology and potential shared targeting signals like SKL motifs, subsequent analyses emphasize a mitochondrial origin, with hydrogenosomes retaining mitochondrial hallmarks such as a transmembrane gradient and no activity typical of peroxisomes. This distinction positions hydrogenosomes as modified mitochondria rather than peroxisomal variants, though both types reflect broader diversity in adapting to anaerobiosis. Microbody diversity across eukaryotes reveals evolutionary plasticity, with peroxisomes and related structures often absent in certain anaerobic lineages due to the loss of oxidative metabolic demands. For instance, peroxisomes are missing in anaerobic protists such as Giardia intestinalis, Entamoeba histolytica, and Trichomonas vaginalis, where reduced peroxins (e.g., PEX3 and PEX19) preclude biogenesis, reflecting secondary adaptations to oxygen-poor niches like the vertebrate gut. However, exceptions like the anaerobic amoeba Mastigamoeba balamuthi retain peroxisome-like vesicles with 14 core peroxins, performing non-oxidative roles in acyl-CoA and nucleotide metabolism, suggesting that microbody loss is not universal in anaerobes but tied to specific lifestyle constraints. Evolutionarily, peroxisomes, glycosomes, and Woronin bodies share a common ancestry as single-membrane compartments derived from the endoplasmic reticulum, while hydrogenosomes derive from mitochondria, enabling diversification and linking to oxidative or reductive pathways in aerobic or anaerobic ancestors.