Cellular inclusions are substances found inside cells that are not bounded by their own membrane and are not considered active, living components of the cell’s machinery. They range from stored nutrients like glycogen and fat droplets to pigment granules, crystals, and even aggregated proteins associated with disease. Unlike organelles such as mitochondria or the endoplasmic reticulum, inclusions generally lack the internal architecture that would qualify them as permanent working parts of the cell, though that boundary has gotten blurrier as researchers learn more about how some of these structures behave.
Energy and Nutrient Storage
The most familiar cellular inclusions are the ones that store fuel. Glycogen granules are dense clusters of branched glucose chains found primarily in liver and muscle cells. Each granule functions as its own self-contained metabolic unit, packed with both the stored sugar and the enzymes needed to break it down or build it back up. When your blood sugar drops or your muscles need quick energy during exercise, glycogen granules are the first reserve your body taps.1PubMed Central. The dynamic life of the glycogen granule The structure of these granules varies between tissues: liver glycogen particles tend to be larger and more complex than those in skeletal muscle, reflecting the liver’s role in feeding glucose back into the bloodstream for other organs to use.2PubMed. Comparative structural analyses of purified glycogen particles from rat liver, human skeletal muscle and commercial preparations
Lipid droplets are the other major energy inclusion. Found in virtually every cell type, these are tiny spheres of neutral fat suspended in the watery interior of the cell, almost like oil droplets in a vinaigrette. They store energy much more densely than glycogen and also serve as reservoirs of raw material for building new membranes. Lipid droplets were long dismissed as inert blobs, but research has shown they are metabolic hubs in their own right, interacting with mitochondria and other organelles.3PubMed Central. Lipid Droplet Biogenesis In fat cells, lipid droplets can grow so large they dominate the entire cell interior. In other cell types, they are much smaller and more numerous, turning over rapidly to supply fatty acids wherever they are needed.
Pigment Granules
Some inclusions are visible to the naked eye, or at least under a basic microscope, because they carry color. Melanin granules in skin cells are probably the best-known pigment inclusion. They absorb ultraviolet light and protect DNA from sun damage. Hemosiderin is an iron-containing pigment that forms when the body breaks down old red blood cells and needs to store the leftover iron safely. The iron in hemosiderin is locked into a less reactive form, which prevents it from generating harmful free radicals. Cells called macrophages often take up both hemosiderin and melanin at the same time, sometimes even packing both pigments into the same intracellular compartment.4PubMed. A case of non-selective phagocytosis of hemosiderin and melanin of dermal histiocytes in stasis dermatitis This storage role extends beyond mammals. In developing sea lamprey larvae, certain cells sequester iron specifically to prevent toxicity, storing it as hemosiderin until the metal can be safely eliminated.5Tissue and Cell. Intracellular distribution of iron (and associated elements) in various cell types of larvae and juveniles of the sea lamprey (Petromyzon marinus)
Lipofuscin is a pigment inclusion that accumulates with age, earning it the nickname “age pigment” or “wear-and-tear pigment.” It forms when oxidized fats and proteins get cross-linked into clumps that the cell’s recycling systems cannot break down. The process starts with oxidative damage to fatty acids in cellular membranes. The resulting reactive molecules bond to nearby proteins and lipids, creating tangled aggregates that pile up inside the cell’s lysosomes.6PubMed Central. Lipofuscin accumulation in aging and neurodegeneration: a potential “timebomb” overlooked in Alzheimer’s disease For years, lipofuscin was considered a harmless byproduct of aging. More recent work challenges that view: when researchers isolated authentic lipofuscin from human heart tissue and exposed cells to it, the material boosted damaging free radical production, disrupted lysosome function, and triggered a form of inflammatory cell death at surprisingly low concentrations.7PubMed. The age pigment lipofuscin causes oxidative stress, lysosomal dysfunction, and pyroptotic cell death That finding has implications for how we think about aging in the brain and heart, where lipofuscin can accumulate heavily in long-lived cells that rarely divide.
Crystals and Specialized Protein Inclusions
Some inclusions take the form of actual crystals inside cells. Charcot-Leyden crystals form from a protein abundant in eosinophils, a type of white blood cell involved in allergic and parasitic responses. When eosinophils break down in inflamed tissue, the released protein readily crystallizes into distinctive needle-like or diamond-shaped structures. Finding these crystals in tissue samples or sputum has historically been a marker for diseases involving heavy eosinophil activity, such as asthma or parasitic infections. Interestingly, these crystals appear to be essentially unique to humans; when researchers compared the protein sequence across mammals, only a few nonhuman primate species had enough similarity to potentially form them, and even there, key differences in the crystal-forming regions may prevent crystallization.8PubMed. Charcot-Leyden crystals: do they exist in veterinary species? A case report and literature review
Reinke crystals are another example. These rod-shaped or rhomboid inclusions appear in Leydig cells, the testosterone-producing cells in the testes. Their exact function remains unclear, but they are considered a hallmark of normally developed adult Leydig cells in humans. They can form both in the cytoplasm and in the nucleus, which suggests their appearance depends mainly on how concentrated the relevant protein becomes rather than on any specific cellular compartment. Variations in how tissue samples are processed can affect whether Reinke crystals show up under the microscope, a detail that matters when pathologists are trying to diagnose Leydig cell tumors.9PubMed. Reinke crystals: Hallmarks of adult Leydig cells in humans
Inclusions in Bacteria
Cellular inclusions are not limited to animal or plant cells. Bacteria produce a wide variety of intracellular storage bodies and specialized compartments that blur the line between inclusion and organelle. One of the best-studied examples is polyhydroxyalkanoates, or PHAs, which are polyester granules that bacteria build up when nutrients are imbalanced, for instance when carbon is abundant but nitrogen or phosphorus is scarce.10PubMed. Bacterial polyhydroxyalkanoate granules: biogenesis, structure, and potential use as nano-/micro-beads in biotechnological and biomedical applications These granules serve as carbon and energy reserves, but research shows they also boost bacterial survival under stress conditions like heat, cold, UV exposure, and osmotic pressure.11PubMed. Involvement of polyhydroxyalkanoates in stress resistance of microbial cells: Biotechnological consequences and applications
Gas vesicles are a more exotic bacterial inclusion. Produced by many cyanobacteria and salt-loving archaea, these hollow, gas-filled protein shells allow cells to regulate their buoyancy in water. By inflating or collapsing gas vesicles, aquatic microorganisms can float up toward light for photosynthesis or sink to deeper, nutrient-rich layers. In some species, gas vesicle production is controlled by cell-to-cell communication signals and ramps up when oxygen levels are low, helping bacteria migrate to the water’s surface.12PubMed Central. Quorum sensing-controlled buoyancy through gas vesicles: Intracellular bacterial microcompartments for environmental adaptation
Magnetosomes push the concept even further. Certain bacteria that live in aquatic sediments build chains of nanometer-scale magnetic crystals inside their cells, essentially constructing an internal compass needle. These magnetic particles align the bacterium with Earth’s magnetic field, guiding it along field lines toward the oxygen-poor zones of sediment where it thrives.13PubMed Central. A Compass To Boost Navigation: Cell Biology of Bacterial Magnetotaxis Magnetosomes are membrane-bounded, which puts them in a grey zone between classic inclusions and true organelles, but they are routinely discussed alongside other bacterial inclusions because of how they formed evolutionarily.
Carboxysomes and Bacterial Microcompartments
Some bacterial inclusions are not just passive storage but active metabolic chambers. Carboxysomes, found in cyanobacteria and some other photosynthetic bacteria, are protein-shelled compartments that concentrate the enzyme Rubisco and the carbon dioxide it needs to fix carbon. By enclosing these components in a semipermeable protein shell, carboxysomes create a local environment where COâ‚‚ levels are far higher than in the surrounding cell, dramatically improving the efficiency of carbon fixation.14PubMed Central. Rubisco proton production can drive the elevation of CO(2) within condensates and carboxysomes Researchers have been working to engineer these compartments, for instance by incorporating helper proteins that reactivate Rubisco when it gets jammed by inhibitory molecules, further boosting the carbon-fixing ability of synthetic carboxysomes.15PubMed Central. Incorporation of Functional Rubisco Activases into Engineered Carboxysomes to Enhance Carbon Fixation This work has attracted attention from synthetic biologists interested in improving photosynthesis in crops or developing carbon-capture biotechnology.
Pathological Inclusions in Human Disease
Not all inclusions are helpful or even neutral. In several major diseases, the accumulation of abnormal protein aggregates inside cells is a defining feature. Lewy bodies, dense clumps of the protein alpha-synuclein found inside neurons, are the pathological hallmark of Parkinson’s disease and related conditions. Under the microscope, a classic Lewy body has a dense core surrounded by a lighter halo. Staining studies reveal that the outer ring of a Lewy body is heavily tagged with ubiquitin, a small protein that normally marks damaged molecules for disposal, while the dense core often lacks this tag, suggesting the cell tried and failed to clear the material.16PubMed. New aspects of the pathology of neurodegenerative disorders as revealed by ubiquitin antibodies
Neurofibrillary tangles, made of abnormally modified tau protein, are the signature inclusion of Alzheimer’s disease. In most brain regions, Lewy bodies and neurofibrillary tangles tend to appear in different neurons even when both are present. But in the amygdala, a brain region involved in emotion and memory, both types of inclusion frequently show up inside the same neuron. This overlap suggests that amygdala neurons may be especially vulnerable to the protein aggregation processes behind both diseases.17PubMed. Convergence of Lewy bodies and neurofibrillary tangles in amygdala neurons of Alzheimer’s disease and Lewy body disorders
Mallory bodies are another disease-associated inclusion, found in liver cells. They are abnormal clumps of keratin-like intermediate filament proteins that appear in alcoholic liver disease, certain drug reactions, and some metabolic disorders. Early immunofluorescence work showed that Mallory bodies contain a pathological form of material similar to the keratins found in skin, indicating a profound disruption of the cell’s internal skeleton.18PubMed Central. Formation and involution of Mallory bodies (“alcoholic hyalin”) in murine and human liver revealed by immunofluorescence microscopy with antibodies to prekeratin Their presence in a liver biopsy is a strong diagnostic clue for chronic alcohol-related damage, though they can appear in other conditions too.
Viral Inclusion Bodies
When viruses hijack a cell, they often create their own inclusions. Viral inclusion bodies are compartments where the virus concentrates its genetic material and replication machinery, shielded from the host cell’s immune sensors. For negative-strand RNA viruses and certain DNA viruses, these structures are essential for efficient replication. They sequester viral components away from the cell’s antiviral defenses and keep everything needed for viral assembly in close proximity.19PubMed Central. Morphogenesis and functional organization of viral inclusion bodies
Many of these viral factories are not surrounded by a membrane. Instead, they form through liquid-liquid phase separation, the same physical process by which oil and water spontaneously separate. Measles virus, for example, creates cytoplasmic inclusion bodies when two of its proteins, the nucleoprotein and the phosphoprotein, reach high enough concentrations to trigger phase separation. The result is a liquid-like droplet inside the cell that behaves much like a membraneless organelle, fusing, dripping, and exchanging contents with the surrounding cytoplasm.20PubMed Central. Measles Virus Forms Inclusion Bodies with Properties of Liquid Organelles The most famous viral inclusion body may be the Negri body, the diagnostic hallmark of rabies. These too are membraneless replication compartments where rabies virus concentrates its genome and proteins.21PubMed Central. Negri bodies and other virus membrane-less replication compartments Before modern molecular testing, finding Negri bodies in brain tissue was the standard way to confirm a rabies diagnosis.
Stress Granules and Phase-Separated Condensates
The discovery that many inclusions form through liquid-liquid phase separation has reshaped how biologists think about what counts as an inclusion versus what counts as an organelle. Stress granules are a prime example. When a cell encounters heat shock, oxygen deprivation, or viral infection, it stalls the translation of many of its messenger RNA molecules. These stalled messages, along with associated proteins, spontaneously condense into visible granules in the cytoplasm.22PubMed Central. Principles and Properties of Stress Granules The granules are temporary: once the stress passes, they dissolve and the stored messages can be translated again. Processing bodies, or P-bodies, are a related but distinct type of condensate. Unlike stress granules, P-bodies are present in cells all the time and are involved in the routine sorting, storage, and degradation of mRNA.23PubMed. Composition and function of stress granules and P-bodies in plants
Both structures form via phase separation, the same principle behind viral inclusion bodies and many other membraneless compartments. The general idea is that certain proteins and RNA molecules, when they reach a critical concentration, spontaneously demix from the surrounding cytoplasm into a concentrated droplet, much the way salad dressing separates into layers when left to sit.24PubMed. Liquid phase condensation in cell physiology and disease This mechanism turns out to be remarkably common. It underlies everything from how cells organize their DNA-repair machinery to how neurons keep signaling molecules concentrated at synapses. Whether these condensates should be called “inclusions” in the classic sense is an open semantic question, but they share the fundamental property of being non-membrane-bounded accumulations of material inside the cell.
How Cells Clean Up Inclusions
Cells do not just accumulate inclusions passively. They actively manage them through a process called selective autophagy, in which specific cellular cargo is tagged, enclosed in a double-membrane compartment, and delivered to lysosomes for breakdown. Lipid droplets, protein aggregates, and even damaged organelles like mitochondria can all be targeted for autophagic clearance.25PubMed Central. Selective autophagy in cardiometabolic disease When the system works well, inclusions that are no longer needed or that have become harmful get recycled efficiently. When it fails, as happens increasingly with age, the result is buildup. Lipofuscin accumulation is a direct consequence of this failure: the cross-linked material resists lysosomal digestion, and as more of it piles up, it actually impairs lysosome function further, creating a vicious cycle.
This cleanup system is one reason pathological inclusions like Lewy bodies and neurofibrillary tangles are so devastating. The protein aggregates in these inclusions are partly tagged with ubiquitin, meaning the cell recognized them as problematic, but the aggregates overwhelm or resist the disposal machinery. Understanding why autophagy fails in these contexts is one of the most active areas of neurodegeneration research.
Inclusions as Diagnostic Markers
Pathologists have used inclusions as diagnostic clues for well over a century. The presence and character of inclusion bodies in tissue samples can point toward specific diseases, infections, or toxic exposures.26Biomedical and Pharmacology Journal. Inclusion Bodies Negri bodies in brain tissue once served as the gold standard for rabies. Mallory bodies in a liver biopsy suggest chronic alcohol damage. Charcot-Leyden crystals in sputum signal heavy eosinophilic inflammation.
But inclusions are not always as specific as they might seem. Pancreatic inclusions, for example, were historically linked to boric acid poisoning, with early forensic pathologists treating their presence as near-proof of boric acid toxicity. Later work found that these same inclusions could appear in cases of severe gastroenteritis with no boric acid exposure at all. Under the electron microscope, the inclusions turned out to represent a generic autophagic cell-breakdown process rather than a poison-specific response.27Forensic Science. Pancreatic inclusions and its relation to boric acid poisoning: review of the literature and report of a case That kind of finding is a good reminder that inclusions are often signs of cellular stress rather than signatures of one particular cause.
Industrial and Biotechnology Uses
The same bacterial PHA granules that serve as energy reserves in nature have attracted serious commercial interest as biodegradable plastics. Because PHAs are polyesters produced from renewable carbon sources, they can substitute for petroleum-based plastics in packaging, medical implants, and other applications where environmental persistence is a problem.28PubMed Central. Natural Polyhydroxyalkanoates-An Overview of Bacterial Production Methods Researchers have been optimizing bacterial fermentation processes to increase PHA yields, and some companies already produce PHA-based materials at industrial scale, though cost remains a barrier to widespread adoption.
Beyond biodegradable plastics, the inclusion bodies that form when bacteria are engineered to produce recombinant proteins have become a resource in their own right. When a bacterium is forced to churn out large quantities of a foreign protein, the protein often misfolds and aggregates into dense intracellular clumps. For decades, these aggregates were considered a nuisance, requiring laborious unfolding and refolding steps to recover functional protein. But advances in understanding how proteins behave inside inclusion bodies have led to streamlined recovery methods, and the bodies themselves are finding new uses as slow-release drug delivery vehicles, scaffolds for tissue engineering, and nanoparticle-like carriers in biomedical applications.29PubMed. Bacterial Inclusion Bodies: A Treasure Trove of Bioactive Proteins What was once a waste product of protein manufacturing is now considered a versatile biotechnological material.