- Review
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Reevaluating Golgi fragmentation and its implications in wound repair
Cell Regeneration volume 13, Article number: 4 (2024)
Abstract
The Golgi Apparatus (GA) is pivotal in vesicle sorting and protein modifications within cells. Traditionally, the GA has been described as a perinuclear organelle consisting of stacked cisternae forming a ribbon-like structure. Changes in the stacked structure or the canonical perinuclear localization of the GA have been referred to as “GA fragmentation”, a term widely employed in the literature to describe changes in GA morphology and distribution. However, the precise meaning and function of GA fragmentation remain intricate. This review aims to demystify this enigmatic phenomenon, dissecting the diverse morphological changes observed and their potential contributions to cellular wound repair and regeneration. Through a comprehensive analysis of current research, we hope to pave the way for future advancements in GA research and their important role in physiological and pathological conditions.
Background
The Golgi apparatus (GA) is a cytoplasmic structure primarily located near the nucleus and is present in virtually all cell types (Bentivoglio 1999; Han et al. 2013). It comprises stacked cisternae, including the cis, medial, and trans compartments (Linstedt 1999; Lowe 2011; Nakamura et al. 2012). In mammalian cells, these GA stacks are interconnected laterally, forming a ribbon structure on the perinuclear region (Klumperman 2011) (Fig. 1A). The GA plays a crucial role in regulating intracellular transport processes. Newly synthesized proteins from the endoplasmic reticulum (ER) concentrate near the GA for sorting and undergo protein modifications, such as glycosylation, leading to the formation of secretory granules directed toward the plasma membrane (PM) (Jamieson and Palade 1967; Palade 1975).
The maintenance of efficient anterograde and retrograde transport between the ER and GA is essential for sustaining the structural integrity of the GA cisternae (Fig. 2). For instance, the inhibition of Arf1 GTPase activation has been shown to preserve the stacked GA structure during the mitotic phase (Altan-Bonnet et al. 2003, 2006; Xiang et al. 2007). Conversely, treatment with Brefeldin A (BFA), inhibiting COP II vesicle transport from the ER to GA by locking Arf1 in a GDP state (Chardin and McCormick 1999), disrupts the balance between anterograde and retrograde transport, leading to GA dispersal and retrieval to the ER (Sciaky et al. 1997). Besides the importance of ER-GA transport in maintaining GA integrity, GA resident proteins also contribute to maintaining cisternal adhesion, thereby ensuring the integrity of the GA structure (Tang et al. 2010). Consequently, the diverse distributions of GA in various cell types raise intriguing questions about the underlying mechanisms and their functional implications.
The non-perinuclear distribution of GA is commonly referred to as fragmented GA and has been observed in various organism fields (Jackson 2009; Wooding and Pelham 1998) (Table 1) (Fig. 1B-E). In the case of Pichia pastoris (P. pastoris), although the GA exhibits a fragmented appearance while still maintaining a stacked structure, it is neither ribbon-like nor localized to the perinuclear region (Mogelsvang et al. 2003; Suda and Nakano 2012) (Fig. 1B). In Saccharomyces cerevisiae (S. cerevisiae), the GA does not form stacked cisternae as observed in mammalian cells. Instead, it exists as a non-perinuclear membrane structure, with the cis, medial, and trans cisternae evenly distributed in the cytosol (Fig. 1D). This is a distinct GA morphology and distribution in P. pastoris and S. cerevisiae are believed to have evolved from different ancestors, contributing to their unique characteristics (Papanikou and Glick 2009). Interestingly, adult Caenorhabditis elegans (C. elegans) epidermal cell (hyp7) also exhibits a non-perinuclear distribution of the GA (Zhu et al. 2016). Simultaneous observation of markers for the cis, medial, and trans cisternae in C. elegans reveals the presence of stacks structures (Meng et al. 2023).
Non-canonical GA distributions are also observed in mammalian muscle cells, neurons, and urothelial cells (Table 1). Skeletal muscle cells are multi-nucleated and display a non-perinuclear distribution of the GA. These non-perinuclear GA in neurons and skeletal muscle cells can be visualized using markers such as MANII and TGN38 (Quassollo et al. 2015). It is noteworthy that these non-perinuclear GA are generally smaller in size compared to the perinuclear GA. The term “Golgi outpost” (GOP) is commonly used to describe the non-perinuclear GA in both neuronal and muscle cells that are located far away from the nucleus (Valente and Colanzi 2015; Valenzuela et al. 2020). GOP is generated from the somatic GA through a sequential process involving tubulation, elongation, and fission (Quassollo et al. 2015). The fragmented GA in the urothelial cell can be observed in both normal and cancerous cells, where the structure of the fragmented GA varies with disease progression (Table 1). The GA structure and its regulation have recently been extensively reviewed elsewhere (Li et al. 2019; Lowe 2011; Makhoul et al. 2019; Martinez-Menarguez et al. 2019). This review focuses on the dynamic regulation of fragmented GA in various physiological and pathological conditions, emphasizing its role in regulating cellular wound repair and regeneration.
GA fragmentation under normal physiological conditions
The GA undergoes a remarkable transformation during cell division, where its signature stacked cisternae unravel into ribbon-like structures, eventually forming scattered vesicles. This process, known as mitotic GA fragmentation or disassembly, is essential for ensuring the equal distribution of the GA to the daughter cells (Altan-Bonnet et al. 2006; Colanzi and Sütterlin 2013). Mitotic GA fragmentation involves the breakdown of cisternal stacks and the lateral connection, resulting in tubule-vesicular structures distributed evenly in the cytosol (Lucocq and Warren 1987; Sutterlin et al. 2002). Ribbon unlinking, a process regulated by Brefeldin A ADP-Ribosylation Substrate (BARS) and the phosphorylation of GA structural proteins GRASP55 and GRASP65, plays a crucial role in this phenomenon (Mascanzoni et al. 2022; Valente and Colanzi 2015).
Mitotic kinases, such as polo-like kinase and Cdk1, drive the phosphorylation of GRASP65, leading to the fragmentation of the GA (Sengupta and Linstedt 2010) (Fig. 2). GRASP55 phosphorylation, regulated by MAP kinase, also results in GA unstacking, forming structures termed “Golgi Blobs” (Colanzi and Sutterlin 2013). Importantly, the fragmentation of the GA during mitosis is reversible, initiating GA reassembly after cell division. NSF (N-ethylmaleimide-sensitive factor)-mediated membrane fusion re-forms the tubular-reticular elements of the GA, eventually restoring cisternae. The phosphorylation of VCIP135 by CDK1, reversed at the end of mitosis, activates p97/p47 and promotes GA reassembly (Valente and Colanzi 2015). Additionally, the dephosphorylation of GRASP55 by mTORC1 (Nuchel et al. 2021) and GRASP65 by PP2A contribute to the reassembly of GA stacks (Fig. 2).
GA fragmentation is traditionally associated with accelerated transport but impaired glycosylation (Haukedal et al. 2023). However, GA fragmentation induced by the depletion of GRASP55 and GRASP65 proteins resulted in accelerated transport while impairing the cell surface glycosylation (Ahat et al. 2022; Xiang et al. 2013). In Alzheimer’s disease (AD), Cdk5-induced GA fragmentation mediated by GRASP65 protein promotes amyloid precursor protein trafficking (Zhang and Wang 2020). In addition, under neuronal excitation, these fragmented GA contribute to the glycosylation of the newly synthesized proteins from the ER to promote secretion (Govind et al. 2021). GA fragmentation is observed in these protrusions, indicating GA fragmentation in the cell-cell communications (Kreft et al. 2022) (Table 1).
The GA undergoes significant changes in both structure and function under various stress conditions, such as DNA damage, energy and nutrient deprivation, abiotic stress, oxidative stress, aging, and pro-apoptotic conditions (Li et al. 2019). These alterations can occur through microtubule disorganization, altered protein phosphorylation, or degradation of key Golgi structural proteins. Additionally, the GA interacts with numerous signaling molecules, suggesting its potential role in sensing and transmitting stress signals within the cell (Alvarez-Miranda et al. 2015).
For example, in the process of apoptosis, the GA undergoes irreversible fragmentation, a phenomenon distinct from the reversible fragmentation observed during mitosis. Morphological changes in GA during apoptosis include swelling, loss of its ribbon-like structure, and the failure to maintain the perinuclear distribution (He et al. 2020). Caspase2 and Caspase3 are key players in GA fragmentation during apoptosis, inducing cleavage of resident proteins such as GM130, p115, and Golgin160 (Chiu et al. 2002). The cleavage results in the dispersal of the GA, contributing to the distinctive morphological changes observed during apoptosis. Importantly, GA fragmentation occurs during apoptosis before the cytoskeleton rearrangements (Mukherjee et al. 2007), setting it apart temporally from the regulatory mechanism of fragmented GA in cancer progression. Understanding the relationship between GA morphology and apoptosis could provide insights into why certain cell types retain a fragmented GA, though the beneficial role of this altered GA structure in preventing cell death remains poorly understood.
GA fragmentation under pathological conditions
GA fragmentation has emerged as a distinctive feature in cancer progression and is recognized as a hallmark of the malignancy (Petrosyan 2015). Specific cancer cells, such as HT-29 colon tumor cells and SU.86.86 pancreatic cancer cells, exhibit a fragmented GA morphology (Bui et al. 2021; Kellokumpu et al. 2002) (Table 1). Under normal circumstances, GA undergoes fragmentation during the G2 phase of the cell cycle and restores its stacked perinuclear ribbon structure after mitosis. However, in malignancy, cancer cells maintain the fragmented GA morphology during the G2 phase, indicating an aberrant cellular state (Corda et al. 2012).
The motor protein NMIIA, localized in the cytosol and the GA, regulates vesicular trafficking within the cell (Togo and Steinhardt 2004). Inhibition of NMIIA using blebbistatin or siRNA has restored GA morphology in HT-29 colon tumor cells (Petrosyan and Cheng 2013) (Table 1), suggesting NMIIA-dependent regulation in GA fragmentation during cancer progression. Additionally, Petrosyan and Cheng showed that GA fragmentation induced by COP II inhibition (knockdown or BFA treatment) is also NMIIA-dependent (Fig. 2). While NMIIA emerges as a promising candidate for cancer therapy, further validation is required, as NMIIA is not exclusively localized to the GA, necessitating an exploration of potential side effects associated with its inhibition. Despite morphological evidence showing fragmented GA in multiple cell lines, the molecular mechanism underlying the relationship between GA fragmentation and cancer progression remains poorly understood.
Efforts have been invested in inducing GA fragmentation as a strategy to trigger cancer cell death. Inhibition of the Golgin protein GM130 impaired gastric cancer cell angiogenesis and metastasis capability (Zhao et al. 2015). GM130 degradation, mediated by the 26S proteasome, induced GA dispersal and cell death in myeloma cells, indicating a protective role for GM130 in maintaining GA structure (Eisenberg-Lerner et al. 2020). However, conflicting outcomes were reported, as a clinical study found elevated GM130 expression in lung adenocarcinoma patients, revealing its protective effect on patient survival (Li et al. 2022). These conflicting reports underscore the complexity of the relationship between GA fragmentation and cellular fate, emphasizing the need for a comprehensive understanding of the changes in GA morphology.
GA fragmentation is not only a feature observed in cancer but also in neurodegenerative diseases, including AD, amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD) (Haase and Rabouille 2015). In neurons, the GA plays a crucial role in regulating anterograde trafficking to release neurotransmitters (Martinez-Menarguez et al. 2019). The fragmented morphology of the GA is predominantly observed in hyperexcitable neurons and neuronal hyperactivity, such as in ALS (Thayer et al. 2013; Weskamp et al. 2020). Unlike the irreversible GA fragmentation seen in apoptosis, GA fragmentation induced by neuronal hyperactivity causing diseases is reversible when neuronal activity returns to normal. In AD, CDK5 overactivation leads to the phosphorylated GM130 and GRASP65, resulting in a GA fragmentation (Liu et al. 2019). Interestingly, nicotine intake has been shown to protect against certain neuronal diseases, such as AD and PD (Piao et al. 2009), and can induce GA fragmentation through α4β2 receptors, which have a high affinity for nicotine. Remarkably, despite the fragmented GA morphology, cargo can still be transported through this GA fragmentation (Govind et al. 2021).
The function of GA fragmentation stem cell activation and wound repair
The GA undergoes repositioning and fragmentation during key cellular processes, such as cell differentiation. Various stem cell types, including myoblast, urothelial stem cells, and neural stem cells, initially maintain a perinuclear GA cluster anchored by microtubules, which undergo significant shifts as they mature. For instance, myoblast reposition their GA from a perinuclear position to an even distributed configuration as they differentiate into myotubes, with the repositioning being actin-dependent and driven by Myosin VI (Lu et al. 2001; Percival and Froehner 2007). Similarly, neural stem cells initially have perinuclear GA. During development, radial glial cells (RG) undergo apical-basal repositioning in various contexts, including Drosophila quiescent neural stem cells reactivation (Gujar et al. 2023) and neurogenesis from induced pluripotent stem cell (iPSC) (Scharaw et al. 2023). These dynamic changes in GA positioning and morphology raise intriguing questions about their potential role in stem cell contributions to wound healing. For example, Scharaw et al. reported that iPSCs regulate the morphology and orientation of the GA to match the niche Paneth cells (Scharaw et al. 2023), suggesting a potential mechanism for targeted protein delivery within stem cell niches.
Moreover, the ability of stem cells to switch between quiescent and proliferative states is fundamental for tissue homeostasis. Adult neural stem cells (NSCs), primarily in a quiescent state, can be awakened by physiological cues such as injury or nutritional shifts (Urbán et al. 2019). Drosophila larval brain NSCs, also known as neuroblasts, serve as a powerful model to study the mechanisms governing quiescence and reactivation in vivo. These neuroblasts enter a quiescence state post-embryogenesis and resume proliferation after larval hatching, triggered by dietary amino acids. Their reactivation relies on an evolutionarily conserved insulin growth factor (IGF) signaling pathway and microtubule-rich extensions. Recent studies suggest that the GA and its outposts (GOP) can act as a microtubule-organizing center (MTOC) in quiescent NSCs (Valenzuela et al. 2020), with Golgi-resident GTPase ARF1 and its guanine nucleotide exchange factor (GEF) Sec71 playing a pivotal role in promoting NSC reactivation and regeneration (Gujar et al. 2023). These findings highlight the essential role of GA in regeneration after injury in vivo.
The GA also plays a crucial role in wound repair in vitro, potentially by ensuring the targeted delivery of essential proteins and lipids. Upon induction of a wound, the GA acts as a conductor of cell polarity, facilitating precise trafficking of key proteins, guiding cell migration, and orchestration the wound closure (Bisel et al. 2013; Darido and Jane 2013; Yadav et al. 2009) (Fig. 3A). Depletion of GA organization-related proteins such as Golgin160 or GMAP210 disrupts the GA perinuclear distribution, impacting polarized trafficking mechanisms crucial for directed protein delivery during wound healing. Importantly, it is observed that there is no enrichment of Vesicular Stomatitis Virus G protein (VSV-G) towards the wound in these cells after scratching the wound (Yadav et al. 2009). Unlike the microtubule-dependent GA fragmentation observed during cell division, GA remodeling in migrating cells is actin-dependent (Valente and Colanzi 2015), as observed in a scratch wounding assay in astrocytes, where CDC-42 activation at the leading edge promotes GA reorientation and polarization towards the wound (Fig. 3A). Thus, these results highlight the importance of GA fragmentation in cellular wound repair. Understanding how stem cells regulate GA morphology and orientation in response to injury signals could offer novel therapeutic strategies for enhancing tissue wound repair and regeneration.
The function of GA fragmentation in plasma membrane repair
The plasma membrane is a critical barrier protecting the cell from external factors. Any form of physical, chemical, or biological damage threatens cell survival. Skeletal muscle injury during exercise, radiation-induced injury to the cutaneous epithelial cell, microbial-induced damage, ischemia, and other factors can compromise its integrity, jeopardizing cell survival (Ammendolia et al. 2021). In response to these threats, cells must activate the repair processes to ensure cell survival. Any defect in the PM repair is associated with diseases such as muscular dystrophy, cardiovascular diseases, and neuronal diseases.
When the plasma membrane is damaged, various mechanisms contribute to the repair process, including membrane tension, endocytosis, exocytosis, patch, and membrane shedding (Xu et al. 2023). The specific repair mechanisms employed depend on the cell type, wound type, and size (Cai et al. 2009; Jimenez et al. 2014). Following repair, membrane remodeling occurs, involving alterations in membrane components to restore their proximity to the undamaged PM (Ammendolia et al. 2021). Modifying and controlling PM repair signaling and mechanisms is crucial to maintain homeostasis and prevent pathological development. Notably, overactivation of the repair mechanism has been observed in cancer cells, showing a high ability to protect against the immune cell attack or during metastasis (Dias and Nylandsted 2021). However, whether the GA functions in repairing the damaged membrane remains largely unknown.
We use adult C. elegans hyp7 cell (large syncytium epidermal cell with 139 nuclei) as an in vivo model investigating the membrane wound response and repair (Chisholm and Hsiao 2012; Ma et al. 2021; Xu et al. 2022). Recently, we observed the GA is evenly distributed throughout the hyp7 cell (Table 1). Upon PM damage, the GA is recruited to the wound site, suggesting potential de-novo assembly at the wound site (Fig. 3B). This recruitment is supported by the evidence that inhibition of ER-GA anterograde transport blocks GA recruitment (Meng et al. 2023). Significantly, inhibition of GA recruitment to the wound site also hinders wound repair, leading to high animal lethality after membrane damage, highlighting the importance of GA in membrane repair in C. elegans epidermal cell (Meng et al. 2023).
Moreover, we identified ZC8.6, a GA-resident PI4Kα, and PPK-1, a PtdkIns4P5K, as crucial players in the PM repair process and highlighted their contribution to the generation of PtdIns4P to Phosphatidylinositol 4,5-bisphosphate (PtdIns4,5P2) at the wound site. GA recruitment facilitates polarized secretion toward the wounded PM, providing necessary membranes and PtdIns4P to restore the PtdIns4,5P2 level in the damaged PM (Meng et al. 2023). This finding is consistent with the requirement of RAB-6.2 for the transport of PtdIns4P to the damaged PM (Meng et al. 2023). Given the presence of similar GA structures in various cell types, such as skeletal muscle and cancer cells with fragmented GA, it is worth investigating whether GA translocation occurs in response to membrane damage and facilitates repair in muscle and cancer cells. Furthermore, understanding the translocation of GA may shed light on the mechanisms underlying the evasion of cell protective mechanisms observed in certain cancer cells during T cell attack and metastasis.
The biological significance of GA’s contribution to the PM PtdIns4,5P2 was overshadowed by the PM PtdIns4P pool in a study conducted using the tsA-201 cell line (Dickson et al. 2014). Yet in adult C. elegans hyp7, GA provides a PtdIns4P pool for PtdIns4,5P2 generation during PM damage. This could be due to the translocation capability of the adult C. elegans hyp7 non-perinuclear GA (Meng et al. 2023), yet not ruling out the different mechanisms to restore PtdIns4,5P2 under damaged PM condition. Therefore, investigating mechanisms in skeletal muscle injury and exploring the similarities in PM repair mechanisms among cells with similar GA morphologies present intriguing areas of study.
However, the role of GA in PM repair, particularly in skeletal muscle cells and carcinogenesis, has received limited attention. Skeletal muscle PM is frequently subjected to mechanical and chemical damage, which triggers repair mechanisms involving Annexins, dysferlin, SNAREs, and inflammatory signaling pathways (Allen et al. 2008; Demonbreun et al. 2016). Notably, Plasma membrane repair involves the requirement of a membrane source to restore the membrane integrity. Membrane fusion and patching are two of the proposed membrane repair machinery that require SNARE complex to complete (Andrews and Corrotte 2018). In C. elegans, the SYX-2/RIC-4/SEC-22 SNARE complex can promote membrane repair by facilitating membrane fusion (Shao et al. 2023). In the context of carcinogenesis, the GA morphology of cancer cells may show uncanonical distribution. Understanding the GA morphology in cancer cells and its impact on PM repair machinery remains an understudied aspect, holding potential insights into cancer cell resistance and evasion of cell death. The translocation of GA in this context could unveil unconventional perspectives on the organelle’s involvement in PM repair and polarized transport regulation during injury.
Conclusions
Despite a general understanding of GA, its observation in diverse cell types, organisms, pathological conditions, or experimentally induced “fragmentation” reveals distinct patterns of GA distribution and morphology (Mogelsvang et al. 2003; Papanikou and Glick 2009; Petrosyan 2015; Petrosyan and Cheng 2013). This diversity raises the question of why different causes of GA fragmentation lead to varied GA morphologies. In contrast to the well-defined mechanism of mitochondrial fragmentation, which is conserved and serves a common biological function, the definition of GA fragmentation remains conflicted (Kleele et al. 2021).
Several key aspects must be addressed to establish a gold standard for defining GA fragmentation corresponding to a function. Firstly, the identification of inducers of fragmentation is essential. Secondly, a detailed examination of changes in GA morphology is required, including aspects such as ribbon unlinking, reduced stack number, cisternal fragmentation, or alterations in GA distribution. Lastly, understanding how the function of GA fragmentation, including changes in transport, cell polarity, protein modifications, and other cellular processes. Addressing these questions will enhance our understanding of GA fragmentation, its mechanisms, and its functional consequences, contributing to a more comprehensive understanding of the role of GA in cellular processes and disease progression.
On the other hand, the term “fragmentation” cannot be universally applied to all instances of GA morphological changes. Consider whether it involves ribbon unlinking, loss of stacked GA structure, or alteration in subcellular distribution for accurate GA morphology definition. Moreover, determining whether these changes in GA morphology promote cell survival, as observed in cancer progression, or lead to harm, as in apoptotic cells, is crucial. For example, the word “translocation” or “re-localization” could better describe the loss of GA perinuclear distribution (Khuntia et al. 2022), while “depolarization” may better describe the incapability of GA to face one direction for targeted transport (Jiang et al. 2017).
While changes in GA morphology are often linked with disease pathogenesis (cancer and neurodegenerative), some specific cell types, like skeletal muscle cells, yeast, and adult C. elegans hyp7 cells, naturally exhibit non-perinuclear or non-canonical GA morphologies. Understanding why these cell types retain such morphologies deserves further investigation. Additionally, the assessment of GA fragmentation must be improved based solely on morphology to determine a biological condition (Makhoul et al. 2019). Employing more sophisticated assays to evaluate the function of GA fragmentation is essential. Given that GA is involved in trafficking and protein modification, exploring whether GA morphology can serve as a parameter to determine the nature, fate, and diagnostic potential is intriguing. Clear classification of GA morphology changes can provide new insights and make breakthroughs in understanding the field’s unresolved physiological and pathological mechanisms.
Availability of data and materials
Not applicable.
Abbreviations
- AD:
-
Alzheimer’s Disease
- ALS:
-
Amyotrophic Lateral Sclerosis
- aRG:
-
Apical radial glia
- BFA:
-
Brefeldin A
- bRG:
-
Basal radial glia
- C. elegans :
-
Caenorhabditis elegans
- COPI:
-
Coat protein complex I
- COPII:
-
Coat protein complex II
- ER:
-
Endoplasmic reticulum
- GA:
-
Golgi Apparatus
- GAAP:
-
Golgi apparatus anti-apoptotic proteins
- GOP:
-
Golgi Outpost
- GRASP:
-
Golgi reassembly stacking protein
- MTOC:
-
Microtubule organizing center
- NMIIA:
-
Non-muscle myosin IIA
- NSF:
-
N-ethylmaleimide sensitive fusion protein
- PD:
-
Parkinson’s Disease
- PM:
-
Plasma membrane
- P. pastoris :
-
Pichia pastoris
- PtdIns4P:
-
Phosphatidylinositol 4-phosphate
- PtdkIns4P5K:
-
Phosphatidylinositol 4-phosphate-5-kinase
- PtdIns4,5P2 :
-
Phosphatidylinositol 4,5-bisphosphate
- RNAi:
-
RNA interference
- S. cerevisiae :
-
Saccharomyces cerevisiae
- siRNA:
-
Short interfering RNA
- SNARE:
-
Soluble N-ethylmalemide-sensitive-factor attachment protein receptor
- tER:
-
Transitional endoplasmic reticulum
- VSV-G:
-
Vesicular stomatitis virus G protein
References
Ahat E, Song Y, Xia K, Reid W, Li J, Bui S, Zhang F, Linhardt RJ, Wang Y. GRASP depletion-mediated Golgi fragmentation impairs glycosaminoglycan synthesis, sulfation, and secretion. Cell Mol Life Sci. 2022;79:199. https://doi.org/10.1007/s00018-022-04223-3.
Allen DG, Lamb GD, Westerblad H. Skeletal muscle fatigue: cellular mechanisms. Physiol Rev. 2008;88:287–332. https://doi.org/10.1152/physrev.00015.2007.
Altan-Bonnet N, Phair RD, Polishchuk RS, Weigert R, Lippincott-Schwartz J. A role for Arf1 in mitotic Golgi disassembly, chromosome segregation, and cytokinesis. Proc Natl Acad Sci U S A. 2003;100:13314–9. https://doi.org/10.1073/pnas.2234055100.
Altan-Bonnet N, Sougrat R, Liu W, Snapp EL, Ward T, Lippincott-Schwartz J. Golgi inheritance in mammalian cells is mediated through endoplasmic reticulum export activities. Mol Biol Cell. 2006;17:990–1005. https://doi.org/10.1091/mbc.e05-02-0155.
Altun ZF, Hall DH. Epithelial system, hypodermis. In WormAtlas. 2009. https://doi.org/10.3908/wormatlas.1.13.
Alvarez-Miranda EA, Sinnl M, Farhan H. Alteration of Golgi structure by stress: a link to neurodegeneration? Front Neurosci. 2015;9:435. https://doi.org/10.3389/fnins.2015.00435.
Ammendolia DA, Bement WM, Brumell JH. Plasma membrane integrity: implications for health and disease. BMC Biol. 2021;19:71. https://doi.org/10.1186/s12915-021-00972-y.
Andrews NW, Corrotte M. Plasma membrane repair. Curr Biol. 2018;28:R392–7. https://doi.org/10.1016/j.cub.2017.12.034.
Bentivoglio M. The discovery of the Golgi apparatus. J Hist Neurosci. 1999;8:202–8. https://doi.org/10.1076/jhin.8.2.202.1833.
Bisel B, Calamai M, Vanzi F, Pavone FS. Decoupling polarization of the Golgi apparatus and GM1 in the plasma membrane. PLoS One. 2013;8:e80446. https://doi.org/10.1371/journal.pone.0080446.
Bui S, Mejia I, Diaz B, Wang Y. Adaptation of the Golgi apparatus in cancer cell invasion and metastasis. Front Cell Dev Biol. 2021;9:806482. https://doi.org/10.3389/fcell.2021.806482.
Cai C, Masumiya H, Weisleder N, Matsuda N, Nishi M, Hwang M, Ko JK, Lin P, Thornton A, Zhao X, et al. MG53 nucleates assembly of cell membrane repair machinery. Nat Cell Biol. 2009;11:56–64. https://doi.org/10.1038/ncb1812.
Chardin P, McCormick F. Brefeldin A: the advantage of being uncompetitive. Cell. 1999;97:153–5. https://doi.org/10.1016/S0092-8674(00)80724-2.
Chisholm AD, Hsiao TI. The Caenorhabditis elegans epidermis as a model skin. I: development, patterning, and growth. Wiley Interdiscip Rev Dev Biol. 2012;1:861–78. https://doi.org/10.1002/wdev.79.
Chiu R, Novikov L, Mukherjee S, Shields D. A caspase cleavage fragment of p115 induces fragmentation of the Golgi apparatus and apoptosis. J Cell Biol. 2002;159:637–48. https://doi.org/10.1083/jcb.200208013.
Colanzi A, Sutterlin C. Signaling at the Golgi during mitosis. Methods Cell Biol. 2013;118:383–400. https://doi.org/10.1016/B978-0-12-417164-0.00023-9.
Colanzi A, Sütterlin C. Signaling at the Golgi during mitosis. Methods Anal Golgi Complex Funct. 2013;118:383–400. https://doi.org/10.1016/B978-0-12-417164-0.00023-9.
Corda D, Barretta ML, Cervigni RI, Colanzi A. Golgi complex fragmentation in G2/M transition: an organelle-based cell-cycle checkpoint. IUBMB Life. 2012;64:661–70. https://doi.org/10.1002/iub.1054.
Darido C, Jane SM. Golgi feels its own wound. Adv Wound Care (New Rochelle). 2013;2:87–92. https://doi.org/10.1089/wound.2011.0352.
Day KJ, Casler JC, Glick BS. Budding Yeast Has a Minimal Endomembrane System. Dev Cell. 2018;44:56–72.e54. https://doi.org/10.1016/j.devcel.2017.12.014.
Demonbreun AR, Quattrocelli M, Barefield DY, Allen MV, Swanson KE, McNally EM. An actin-dependent annexin complex mediates plasma membrane repair in muscle. J Cell Biol. 2016;213:705–18. https://doi.org/10.1083/jcb.201512022.
Dias C, Nylandsted J. Plasma membrane integrity in health and disease: significance and therapeutic potential. Cell Discov. 2021;7(1):4. https://doi.org/10.1038/s41421-020-00233-2.
Dickson EJ, Jensen JB, Hille B. Golgi and plasma membrane pools of PI(4)P contribute to plasma membrane PI(4,5)P2 and maintenance of KCNQ2/3 ion channel current. Proc Natl Acad Sci U S A. 2014;111:E2281–2290. https://doi.org/10.1073/pnas.1407133111.
Eisenberg-Lerner A, Benyair R, Hizkiahou N, Nudel N, Maor R, Kramer MP, Shmueli MD, Zigdon I, Cherniavsky Lev M, Ulman A, et al. Golgi organization is regulated by proteasomal degradation. Nat Commun. 2020;11:409. https://doi.org/10.1038/s41467-019-14038-9.
Govind AP, Jeyifous O, Russell TA, Yi Z, Weigel AV, Ramaprasad A, Newell L, Ramos W, Valbuena FM, Casler JC, et al. Activity-dependent Golgi satellite formation in dendrites reshapes the neuronal surface glycoproteome. Elife. 2021;10:e68910. https://doi.org/10.7554/eLife.68910.
Gujar MR, Gao Y, Teng X, Deng QN, Lin KY, Tan YS, Toyama Y, Yang HY. Golgi-dependent reactivation and regeneration of quiescent neural stem cells. Dev Cell. 2023;58:1933. https://doi.org/10.1016/j.devcel.2023.07.010.
Haase G, Rabouille C. Golgi fragmentation in ALS motor neurons. New mechanisms targeting microtubules, tethers, and transport vesicles. Front Neurosci. 2015;9:448. https://doi.org/10.3389/fnins.2015.00448.
Han HM, Bouchet-Marquis C, Huebinger J, Grabenbauer M. Golgi apparatus analyzed by cryo-electron microscopy. Histochem Cell Biol. 2013;140:369–81. https://doi.org/10.1007/s00418-013-1136-3.
Haukedal H, Corsi GI, Gadekar VP, Doncheva NT, Kedia S, de Haan N, Chandrasekaran A, Jensen P, Schionning P, Vallin S, et al. Golgi fragmentation - one of the earliest organelle phenotypes in Alzheimer’s disease neurons. Front Neurosci. 2023;17:1120086. https://doi.org/10.3389/fnins.2023.1120086.
He Q, Liu H, Deng S, Chen X, Li D, Jiang X, Zeng W, Lu W. The Golgi apparatus may be a potential therapeutic target for apoptosis-related neurological diseases. Front Cell Dev Biol. 2020;8:830. https://doi.org/10.3389/fcell.2020.00830.
Jackson CL. Mechanisms of transport through the Golgi complex. J Cell Sci. 2009;122:443–52. https://doi.org/10.1242/jcs.032581.
Jamieson JD, Palade GE. Intracellular transport of secretory proteins in the pancreatic exocrine cell. I. Role of the peripheral elements of the Golgi complex. J Cell Biol. 1967;34:577–96. https://doi.org/10.1083/jcb.34.2.577.
Jiang P, Li Y, Poleshko A, Medvedeva V, Baulina N, Zhang Y, Zhou Y, Slater CM, Pellegrin T, Wasserman J, et al. The protein encoded by the CCDC170 breast cancer gene functions to organize the Golgi-microtubule network. EBioMedicine. 2017;22:28–43. https://doi.org/10.1016/j.ebiom.2017.06.024.
Jimenez AJ, Maiuri P, Lafaurie-Janvore J, Divoux S, Piel M, Perez F. ESCRT machinery is required for plasma membrane repair. Science. 2014;343:1247136. https://doi.org/10.1126/science.1247136.
Kellokumpu S, Sormunen R, Kellokumpu I. Abnormal glycosylation and altered Golgi structure in colorectal cancer: dependence on intra-Golgi pH. FEBS Lett. 2002;516:217–24. https://doi.org/10.1016/S0014-5793(02)02535-8.
Khuntia P, Rawal S, Marwaha R, Das T. Actin-driven Golgi apparatus dispersal during collective migration of epithelial cells. Proc Natl Acad Sci U S A. 2022;119:e2204808119. https://doi.org/10.1073/pnas.2204808119.
Kleele T, Rey T, Winter J, Zaganelli S, Mahecic D, Perreten Lambert H, Ruberto FP, Nemir M, Wai T, Pedrazzini T, et al. Distinct fission signatures predict mitochondrial degradation or biogenesis. Nature. 2021;593:435–9. https://doi.org/10.1038/s41586-021-03510-6.
Klumperman J. Architecture of the mammalian Golgi. Cold Spring Harb Perspect Biol. 2011;3(7):a005181. https://doi.org/10.1101/cshperspect.a005181.
Kreft ME, Mironov AA, Hudoklin S. The Golgi complex: an organelle that determines urothelial cell biology in health and disease. Histochem Cell Biol. 2022;158:229–40. https://doi.org/10.1007/s00418-022-02121-0.
Li J, Ahat E, Wang Y. Golgi structure and function in health, stress, and diseases. Results Probl Cell Differ. 2019;67:441–85. https://doi.org/10.1007/978-3-030-23173-6_19.
Li LF, Chen YB, Liao W, Yu QM, Lin H, Shi YQ, Zhang L, Fu GQ, Wang ZY, Li X, et al. Associations of IFT20 and GM130 protein expressions with clinicopathological features and survival of patients with lung adenocarcinoma. BMC Cancer. 2022;22(1):809. https://doi.org/10.1186/s12885-022-09905-6.
Linstedt AD. Stacking the cisternae. Curr Biol. 1999;9:R893–896. https://doi.org/10.1016/S0960-9822(00)80077-9.
Liu JY, He JL, Huang Y, Xiao H, Jiang Z, Hu ZP. The Golgi apparatus in neurorestoration. J Neurorestoratol. 2019;7:116–28. https://doi.org/10.26599/JNR.2019.9040017.
Lowe M. Structural organization of the Golgi apparatus. Curr Opin Cell Biol. 2011;23:85–93. https://doi.org/10.1016/j.ceb.2010.10.004.
Lu ZM, Joseph D, Bugnard E, Zaal KJM, Ralston E. Golgi complex reorganization during muscle differentiation: visualization in living cells and mechanism. Mol Biol Cell. 2001;12:795–808. https://doi.org/10.1091/mbc.12.4.795.
Lucocq JM, Warren G. Fragmentation and partitioning of the Golgi apparatus during mitosis in HeLa cells. EMBO J. 1987;6:3239–46. https://doi.org/10.1002/j.1460-2075.1987.tb02641.x.
Ma YC, Xie J, Wijaya CS, Xu SH. From wound response to repair - lessons from C. elegans. Cell Regen. 2021;10:5. https://doi.org/10.1186/s13619-020-00067-z.
Makhoul C, Gosavi P, Gleeson PA. Golgi dynamics: the morphology of the mammalian Golgi apparatus in health and disease. Front Cell Dev Biol. 2019;7:112. https://doi.org/10.3389/fcell.2019.00112.
Manjithaya R, Anjard C, Loomis WF, Subramani S. Unconventional secretion of Pichia pastoris Acb1 is dependent on GRASP protein, peroxisomal functions, and autophagosome formation. J Cell Biol. 2010;188:537–46. https://doi.org/10.1083/jcb.200911149.
Martinez-Menarguez JA, Tomas M, Martinez-Martinez N, Martinez-Alonso E. Golgi fragmentation in neurodegenerative diseases: is there a common cause? Cells. 2019;8(7):748. https://doi.org/10.3390/cells8070748.
Mascanzoni F, Iannitti R, Colanzi A. Functional coordination among the Golgi complex, the centrosome and the microtubule cytoskeleton during the cell cycle. Cells. 2022;11(3):354. https://doi.org/10.3390/cells11030354.
Meng X, Wijaya CS, Shao Q, Xu S. Triggered Golgi membrane enrichment promotes PtdIns(4,5)P2 generation for plasma membrane repair. J Cell Biol. 2023;222(8):e202303017. https://doi.org/10.1083/jcb.202303017.
Mogelsvang S, Gomez-Ospina N, Soderholm J, Glick BS, Staehelin LA. Tomographic evidence for continuous turnover of Golgi cisternae in Pichia pastoris. Mol Biol Cell. 2003;14:2277–91. https://doi.org/10.1091/mbc.e02-10-0697.
Mukherjee S, Chiu R, Leung SM, Shields D. Fragmentation of the Golgi apparatus: an early apoptotic event independent of the cytoskeleton. Traffic. 2007;8:369–78. https://doi.org/10.1111/j.1600-0854.2007.00542.x.
Nakamura N, Wei JH, Seemann J. Modular organization of the mammalian Golgi apparatus. Curr Opin Cell Biol. 2012;24:467–74. https://doi.org/10.1016/j.ceb.2012.05.009.
Neumann U. Protein Transport in Plant Cells: In and Out of the Golgi. Ann Bot. 2003;92:167–80. https://doi.org/10.1093/aob/mcg134.
Nuchel J, Tauber M, Nolte JL, Morgelin M, Turk C, Eckes B, Demetriades C, Plomann M. An mTORC1-GRASP55 signaling axis controls unconventional secretion to reshape the extracellular proteome upon stress. Mol Cell. 2021;81:3275–3293.e3212. https://doi.org/10.1016/j.molcel.2021.06.017.
Palade G. Intracellular aspects of the process of protein synthesis. Science. 1975;189:347–58. https://doi.org/10.1126/science.1096303.
Papanikou E, Glick BS. The yeast Golgi apparatus: insights and mysteries. FEBS Lett. 2009;583:3746–51. https://doi.org/10.1016/j.febslet.2009.10.072.
Percival JM, Froehner SC. Golgi complex organization in skeletal muscle: a role for Golgi-mediated glycosylation in muscular dystrophies? Traffic. 2007;8:184–94. https://doi.org/10.1111/j.1600-0854.2006.00523.x.
Petrosyan A. Onco-Golgi: is fragmentation a gate to cancer progression? Biochem Mol Biol J. 2015;1(1):16. https://doi.org/10.21767/2471-8084.100006.
Petrosyan A, Cheng PW. A non-enzymatic function of Golgi glycosyltransferases: mediation of Golgi fragmentation by interaction with non-muscle myosin IIA. Glycobiology. 2013;23:690–708. https://doi.org/10.1093/glycob/cwt009.
Piao WH, Campagnolo D, Dayao C, Lukas RJ, Wu J, Shi FD. Nicotine and inflammatory neurological disorders. Acta Pharmacol Sin. 2009;30:715–22. https://doi.org/10.1038/aps.2009.67.
Quassollo G, Wojnacki J, Salas DA, Gastaldi L, Marzolo MP, Conde C, Bisbal M, Couve A, Caceres A. A RhoA signaling pathway regulates dendritic Golgi outpost formation. Curr Biol. 2015;25:971–82. https://doi.org/10.1016/j.cub.2015.01.075.
Ralston E, Ploug T, Kalhovde J, Lømo T. Golgi Complex, Endoplasmic Reticulum Exit Sites, and Microtubules in Skeletal Muscle Fibers Are Organized by Patterned Activity. J Neurosci. 2001;21:875–83. https://doi.org/10.1523/JNEUROSCI.21-03-00875.2001.
Rosquete MR, Davis DJ, Drakakaki G. The Plant Trans-Golgi Network: Not Just a Matter of Distinction. Plant Physiol. 2018;176:187–98. https://doi.org/10.1104/pp.17.01239.
Scharaw S, Sola-Carvajal A, Belevich I, Webb AT, Das S, Andersson S, Pentinmikko N, Villablanca EJ, Goldenring JR, Jokitalo E, Coffey RJ, Katajisto P. Golgi organization is a determinant of stem cell function in the small intestine. bioRxiv. 2023. https://doi.org/10.1101/2023.03.23.533814.
Sciaky N, Presley J, Smith C, Zaal KJ, Cole N, Moreira JE, Terasaki M, Siggia E, Lippincott-Schwartz J. Golgi tubule traffic and the effects of brefeldin A visualized in living cells. J Cell Biol. 1997;139:1137–55. https://doi.org/10.1083/jcb.139.5.1137.
Sengupta D, Linstedt AD. Mitotic inhibition of GRASP65 organelle tethering involves Polo-like kinase 1 (PLK1) phosphorylation proximate to an internal PDZ ligand. J Biol Chem. 2010;285:39994–40003. https://doi.org/10.1074/jbc.M110.189449.
Shao Q, Wijaya CS, Wang S, Meng X, Yuan C, Ma C, Xu S. The SNARE complex formed by RIC-4/SEC-22/SYX-2 promotes C. elegans epidermal wound healing. Cell Rep. 2023;42:113349. https://doi.org/10.1016/j.celrep.2023.113349.
Suda Y, Nakano A. The yeast Golgi apparatus. Traffic. 2012;13:505–10. https://doi.org/10.1111/j.1600-0854.2011.01316.x.
Sutterlin C, Hsu P, Mallabiabarrena A, Malhotra V. Fragmentation and dispersal of the pericentriolar Golgi complex is required for entry into mitosis in mammalian cells. Cell. 2002;109:359–69. https://doi.org/10.1016/S0092-8674(02)00720-1.
Tang D, Yuan H, Wang Y. The role of GRASP65 in Golgi cisternal stacking and cell cycle progression. Traffic. 2010;11:827–42. https://doi.org/10.1111/j.1600-0854.2010.01055.x.
Taverna E, Mora-Bermudez F, Strzyz PJ, Florio M, Icha J, Haffner C, Norden C, Wilsch-Brauninger M, Huttner WB. Non-canonical features of the Golgi apparatus in bipolar epithelial neural stem cells. Sci Rep. 2016;6:21206. https://doi.org/10.1038/srep21206.
Thayer DA, Jan YN, Jan LY. Increased neuronal activity fragments the Golgi complex. Proc Natl Acad Sci U S A. 2013;110:1482–7. https://doi.org/10.1073/pnas.1220978110.
Togo T, Steinhardt RA. Nonmuscle myosin IIA and IIB have distinct functions in the exocytosis-dependent process of cell membrane repair. Mol Biol Cell. 2004;15:688–95. https://doi.org/10.1091/mbc.e03-06-0430.
Urbán N, Blomfield IM, Guillemot F. Quiescence of adult mammalian neural stem cells: a highly regulated rest. Neuron. 2019;104:834–48. https://doi.org/10.1016/j.neuron.2019.09.026.
Valente C, Colanzi A. Mechanisms and regulation of the mitotic inheritance of the Golgi complex. Front Cell Dev Biol. 2015;3:79. https://doi.org/10.3389/fcell.2015.00079.
Valenzuela A, Meservey L, Nguyen H, Fu MM. Golgi outposts nucleate microtubules in cells with specialized shapes. Trends Cell Biol. 2020;30:792–804. https://doi.org/10.1016/j.tcb.2020.07.004.
Weskamp K, Tank EM, Miguez R, McBride JP, Gomez NB, White M, Lin Z, Gonzalez CM, Serio A, Sreedharan J, et al. Shortened TDP43 isoforms upregulated by neuronal hyperactivity drive TDP43 pathology in ALS. J Clin Invest. 2020;130:1139–55. https://doi.org/10.1172/JCI130988.
Wooding S, Pelham HR. The dynamics of golgi protein traffic visualized in living yeast cells. Mol Biol Cell. 1998;9:2667–80. https://doi.org/10.1091/mbc.9.9.2667.
Xiang Y, Seemann J, Bisel B, Punthambaker S, Wang Y. Active ADP-ribosylation factor-1 (ARF1) is required for mitotic Golgi fragmentation. J Biol Chem. 2007;282:21829–37. https://doi.org/10.1074/jbc.M611716200.
Xiang Y, Zhang X, Nix DB, Katoh T, Aoki K, Tiemeyer M, Wang Y. Regulation of protein glycosylation and sorting by the Golgi matrix proteins GRASP55/65. Nat Commun. 2013;4:1659. https://doi.org/10.1038/ncomms2669.
Xie Z, Hur SK, Zhao L, Abrams CS, Bankaitis VA. A Golgi Lipid Signaling Pathway Controls Apical Golgi Distribution and Cell Polarity during Neurogenesis. Dev Cell. 2018;44:725–740.e724. https://doi.org/10.1016/j.devcel.2018.02.025.
Xu S, Li S, Bjorklund M, Xu S. Mitochondrial fragmentation and ROS signaling in wound response and repair. Cell Regen. 2022;11:38. https://doi.org/10.1186/s13619-022-00141-8.
Xu S, Yang TJ, Xu S, Gong YN. Plasma membrane repair empowers the necrotic survivors as innate immune modulators. Semin Cell Dev Biol. 2023. https://doi.org/10.1016/j.semcdb.2023.08.001.
Yadav S, Puri S, Linstedt AD. A primary role for Golgi positioning in directed secretion, cell polarity, and wound healing. Mol Biol Cell. 2009;20:1728–36. https://doi.org/10.1091/mbc.e08-10-1077.
Zhang X, Wang Y. Nonredundant roles of GRASP55 and GRASP65 in the Golgi apparatus and beyond. Trends Biochem Sci. 2020;45:1065–79. https://doi.org/10.1016/j.tibs.2020.08.001.
Zhao J, Yang C, Guo S, Wu Y. GM130 regulates epithelial-to-mesenchymal transition and invasion of gastric cancer cells via snail. Int J Clin Exp Pathol. 2015;8:10784–91.
Zhu M, Wu G, Li YX, Stevens JK, Fan CX, Spang A, Dong MQ. Correction: Serum- and glucocorticoid-inducible kinase-1 (SGK-1) plays a role in membrane trafficking in Caenorhabditis elegans. PLoS One. 2016;11:e0163398. https://doi.org/10.1371/journal.pone.0163398.
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We thank Dr.Xinan Meng for reading and comments on the manuscript.
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This work was supported in part by the National Key R&D Program of China (2021YFA1101002, 2021YFA1300302), and by the National Natural Science Foundation of China (92254303).
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Wijaya, C.S., Xu, S. Reevaluating Golgi fragmentation and its implications in wound repair. Cell Regen 13, 4 (2024). https://doi.org/10.1186/s13619-024-00187-w
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DOI: https://doi.org/10.1186/s13619-024-00187-w