] The omegasome is a cell organelle consisting of

lipid bilayer The lipid bilayer (or phospholipid bilayer) is a thin polar membrane made of two layers of lipid molecules. These membranes form a continuous barrier around all cell (biology), cells. The cell membranes of almost all organisms and many viruses a ...

membranes A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Membranes can be generally classified into synthetic membranes and biological membranes. B ...

enriched with

phosphatidylinositol 3-phosphate Phosphatidylinositol 3-phosphate (PI3P) is a phospholipid found in cell membranes that helps to recruit a range of proteins, many of which are involved in protein trafficking, to the membranes. It is the product of both the class II and III phosph ...

(abbreviated PI(3)P), and related to a process of

autophagy Autophagy (or autophagocytosis; from the Greek language, Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-depe ...

. It is a subdomain of the

endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

(ER), and has a morphology resembling the Greek capital letter Omega (Ω). Omegasomes are the sites from which phagophores (also called "isolation membranes") form, which are sack-like structures that mature into autophagosomes, and fuse with

lysosomes A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...

in order to degrade the contents of the autophagosomes. The formation of omegasomes depends on various factors, however in general, formation of omegasomes is increased as a response to starvation, and in some biochemical situations the presence of PI(3)P leads to the formation of omegasomes.

Discovery

Omegasomes were first discovered by researchers in 2008 as specialized structures that play a key role in the formation of autophagosomes, the central organelle in macroautophagy. In a study observing the movement and localization of double FYVE domain-containing protein 1 (DFCP1), a phosphatidylinositol 3-phosphate (PI(3)P) binding marker, researchers found that this protein would localize to a ring-shaped structure on the endoplasmic reticulum. Because of their ring-shaped morphology, which resembled the Greek capital letter Omega (Ω), researchers named these structures omegasomes. It was also found that omegasomes are enriched with PI(3)P, a phospholipid that plays an important role in membrane signaling and trafficking. PI(3)P is produced by class III phosphatidylinositol 3-kinase complexes (PI3KC3), primarily involving

Vps34 Class III PI 3-kinase is a subgroup of the enzyme family, phosphoinositide 3-kinase that share a common protein domain structure, substrate specificity and method of activation. There is only one known class III PI 3-kinase, Vps34, which is also th ...

and Beclin1, and researchers found that its recognition is crucial for the formation of omegasomes. Further examination of the omegasomes using live imaging indicated that there is a dynamic connection between the omegasomes and the endoplasmic reticulum, leading researchers to conclude that the omegasomes serve as an interface between the ER and autophagic machinery. The discovery of omegasomes has provided a missing link in the understanding of autophagosome

biogenesis Spontaneous generation is a Superseded scientific theories, superseded scientific theory that held that living creatures could arise from abiotic component, non-living matter and that such processes were commonplace and regular. It was Hypoth ...

and autophagy initiation and has opened the door to new avenues of research where autophagy may be involved. Subsequent studies have already revealed more about omegasome maturation, their interactions with other organelles, and their roles in more selective autophagy processes, such as

mitophagy Mitophagy is the selective degradation of mitochondria by autophagy. It often occurs to defective mitochondria following damage or stress. The process of mitophagy was first described in 1915 by Margaret Reed Lewis and Warren Harmon Lewis. Ashford ...

and xenophagy. Additionally, omegasomes will be of particular interest in future research of conditions such as cancer, neurodegenerative diseases, and various infections where autophagy plays an important role.

Structure

Omegasomes have a very distinct morphology, as they appear as ring-like or cup-shaped protrusions that resemble the Greek capital letter Omega. This unique structure is what gives omegasomes their name. These protrusions extend from the ER membrane, and the structures typically have a diameter of about 1.0 micrometers. DFCP1 can be used to visualize these structures as it binds to PI(3)P through its FYVE domains and accumulates at the omegasome formation site, outlining its shape. The formation of omegasomes is a very dynamic process that occurs within three minutes of autophagy induction. Before omegasome formation begins, the mechanistic target of rapamycin complex 1 (mTORC1) must be inactivated due to amino acid starvation or the activation of

AMP-activated protein kinase 5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cell ...

(AMPK) due to glucose starvation. The inactivation of mTORC1 leads to the activation of the UNC51-like kinase (ULK1) complex, and the activity of ULK1 promotes autophagy. ULK1 and PI3KC complexes are recruited to the ER and catalyze the production of PI(3)P, initiating the formation of omegasomes. The growth of the omegasome is sustained by the production of PI(3)P, and this step in omegasome formation is why they are so enriched with PI(3)P. Once formed, omegasomes serve as a scaffolding for the

nucleation In thermodynamics, nucleation is the first step in the formation of either a new Phase (matter), thermodynamic phase or Crystal structure, structure via self-assembly or self-organization within a substance or mixture. Nucleation is typically def ...

of phagophores, which are a precursor to autophagosomes.

Function

Omegasomes serve as an important intermediate in the formation of autophagosomes, which are the primary organelle in a process known as autophagy. Autophagy (from Greek words for "self" and "eating") is a process of digesting or degrading cytoplasmic molecules (

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

lipid Lipids are a broad group of organic compounds which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The functions of lipids include storing ...

sugars Sugar is the generic name for Sweetness, sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose, fructose, and galactose. Compound sugars, also called disaccharides ...

and

organelle In cell biology, an organelle is a specialized subunit, usually within a cell (biology), cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as Organ (anatomy), organs are to th ...

s).

Macroautophagy Autophagy (or autophagocytosis; from the Greek , , meaning "self-devouring" and , , meaning "hollow") is the natural, conserved degradation of the cell that removes unnecessary or dysfunctional components through a lysosome-dependent regulated ...

is the main autophagic pathway, used primarily to eradicate damaged cell organelles such as

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

, ribosomes, etc., which helps in supplying amino acids and energy to the cells, and maintains longevity. Omegasomes, enriched with PI(3)P and PI(3)P-binding proteins, are positioned on the ER to serve as a scaffolding for the nucleation of phagophores, a double-membraned sequestering structure that matures into an autophagosome. Additionally, omegasomes attract the effectors needed to target PI3P, while also ensuring that the autophagosomal membranes fuse with the double membrane vesicles and promote autophagosome formation. ATG9 vesicles, which come from the Golgi apparatus, have been proposed as the membrane seed for the phagophore formation, and the contact between the omegasome and the phagophore are initiated by these ATG9-positive seed vesicles. The omegasome remains present at the opening of the sack-like phagophore while items destined for degradation by macroautophagy are loaded into the phagophore. There are specific receptor proteins that recruit items to the phagophore. The phagophore expands to accommodate the items, until the omegasome is closed to produce the roughly spherical autophagosome. DFCP1's

ATPase ATPases (, Adenosine 5'-TriPhosphatase, adenylpyrophosphatase, ATP monophosphatase, triphosphatase, ATP hydrolase, adenosine triphosphatase) are a class of enzymes that catalyze the decomposition of ATP into ADP and a free phosphate ion or ...

activity is believed to play a role in detaching the mature autophagosome from the omegasome, and autophagocytosis associated protein Atg3 and other proteins appear to be required as well. Additionally, collections of thin tubules at the junction between omegasome and phagophore and actin appear to be involved. Ultimately, omegasomes play a vital role in autophagy, and the omegasome regulation of this pathway provides a smooth transition of autophagosome formation and enrichment of nutrients in the cells.

Clinical relevance

Neurodegenerative diseases

One of the most prominent areas of clinical relevance for omegasomes is in

neurodegenerative disease A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, mul ...

s such as

Alzheimer’s disease Alzheimer's disease (AD) is a neurodegenerative disease and the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems wit ...

, Parkinson’s disease, Huntington’s disease, and

Amyotrophic Lateral Sclerosis Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND) or—in the United States—Lou Gehrig's disease (LGD), is a rare, Terminal illness, terminal neurodegenerative disease, neurodegenerative disorder that results i ...

. The accumulation of misfolded, aggregated proteins is a hallmark feature of neurodegenerative diseases. Autophagy is a key mechanism that allows cells to degrade and remove these toxic proteins, and because of the essential role that omegasomes play in autophagy, defective omegasome function, which is being investigated for several diseases, can impair the autophagy process. The impairment of autophagy can lead to an accumulation of these harmful proteins, contributing to neuronal death and disease progression.

Alzheimer’s Disease (AD)

One of the characteristic features of Alzheimer’s disease is the accumulation of plaques (formed by clumped amyloid beta proteins, bits of degenerating neurons, and other cell debris) and

neurofibrillary tangle Neurofibrillary tangles (NFTs) are intracellular aggregates of hyperphosphorylated tau protein that are most commonly known as a primary Biomarker (medicine), biomarker of Alzheimer's disease. Their presence is also found in numerous other disea ...

s (primarily made up of hyperphosphorylated

tau protein The tau proteins (abbreviated from tubulin associated unit) form a group of six highly soluble protein isoforms produced by alternative splicing from the gene ''MAPT'' (microtubule-associated protein tau). They have roles primarily in maintainin ...

s). These plaques and tangles interfere with the communication between nerve cells and cause cell damage and death. It is uncertain of the exact role that autophagy plays in AD pathogenesis, but evidence suggests that AD-related proteins may be selectively degraded through the autophagy process, known as aggregaphy, and that impairment or reduction of this process may play a role in AD development and progression. Because of this, regulation of the autophagy pathway could be a viable method for modulating the formation of protein aggregates associated with AD and is being explored as a potential therapeutic strategy for the treatment of AD.

Parkinson's Disease (PD)

Some of the characteristic features of Parkinson’s disease are the degeneration of

dopaminergic neurons Dopaminergic cell groups, DA cell groups, or dopaminergic nuclei are collections of neurons in the central nervous system that synthesize the neurotransmitter dopamine. In the 1960s, dopaminergic neurons or ''dopamine neurons'' were first identi ...

in the

substantia nigra The substantia nigra (SN) is a basal ganglia structure located in the midbrain that plays an important role in reward and movement. ''Substantia nigra'' is Latin for "black substance", reflecting the fact that parts of the substantia nigra a ...

and the accumulation of

Lewy bodies Lewy bodies are the inclusion bodies – abnormal aggregations of protein – that develop inside neurons affected by Parkinson's disease (PD), the Lewy body dementias (Parkinson's disease dementia and dementia with Lewy bodies (DLB)) ...

, abnormal clumps of misfolded

α-synuclein Alpha-synuclein (aSyn) is a protein that in humans is encoded by the ''SNCA'' gene. It is a neuronal protein involved in the regulation of synaptic vesicle trafficking and the release of neurotransmitters. Alpha-synuclein is abundant in the bra ...

proteins in the brain. The loss of dopaminergic neurons leads to a decrease in dopamine production that results in motor impairment, and the accumulation of Lewy bodies can cause the disruption of normal brain cell function, interference with

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

release, and eventually cell death. The aggregation of α-synuclein proteins that lead to the formation of Lewy bodies is caused by an impairment in the autophagy pathway. Overexpression of α-synuclein has been associated with a disruption of autophagy initiation in some cases of PD, possibly through mislocalization of ATG9 that may impair omegasome formation. With omegasome formation inhibited, autophagosome initiation is disrupted, impairing the overall autophagy process, which reduces the removal of α-synuclein and allows disease progression. Targeting the autophagy-lysosomal pathway could be a possible therapeutic strategy for treating PD.

References

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