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• W3152257382 abstract "To survive, cells sense their surroundings and adapt to enable homeostasis. Studies dissecting this process reveal organizational principles, including quality-control pathways, changes to organelle shape, and inter-organelle communication, that facilitate metabolic or developmental remodeling. In this issue, several reviews discuss these organelle homeostasis principles and how they are altered in disease. To survive, cells sense their surroundings and adapt to enable homeostasis. Studies dissecting this process reveal organizational principles, including quality-control pathways, changes to organelle shape, and inter-organelle communication, that facilitate metabolic or developmental remodeling. In this issue, several reviews discuss these organelle homeostasis principles and how they are altered in disease. To compartmentalize the amazing diversity of biochemical reactions necessary for life, eukaryotes developed organelles that partition subsets of metabolic processes. As life became more complex, these organelles became specialized, and some even gained diametrically opposed roles to maintain cell homeostasis. A classic example involves two metabolic organelles: the endoplasmic reticulum (ER) and lysosomes. As centers of anabolic and catabolic metabolism, the ER network acts as a platform for protein and lipid synthesis, whereas lysosomes receive biomaterials for degradation via membrane trafficking and autophagy. Thus, like many organelles, the ER and lysosomes exist in a constant state of metabolic tension. Their synthesis and degradation activities must be balanced to enable homeostasis and must be adjusted as changes in nutrient availability arise. Quality-control systems must ensure they and other organelles function as expected and can meet new challenges if the cell’s environment changes. This requires functional communication across the entire cellular organelle landscape. How such crosstalk is maintained and how it is regulated represent some of the last great questions of modern cell biology. In this focus issue of Developmental Cell, the mechanisms underlying how organelles maintain their own homeostasis, and communicate with each other to enable metabolic adaptations for the cell, are discussed. The reviews in this issue point to organizational principles for how organelles and cells sense and respond to metabolic, energetic, or developmental demands. They also indicate that diseases like cancers can hijack or alter cellular homeostasis programs for survival. Here, I will briefly discuss a few of these emerging principles and suggest that understanding them provides an opportunity to better study cellular homeostasis in both physiological and disease contexts. In nature, everything is made to be broken. To deal with this reality, eukaryotes developed systems to identify and degrade defective proteins and lipids, or even entire organelles. These pathways are essential to both cellular and organismal homeostasis. As Ng and colleagues discuss (Ng et al., 2021Ng M.Y.W. Wai T. Simonsen A. Quality control of the mitochondrion.Dev. Cell. 2021; 56 (this issue): 881-905Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar), mitochondria are an excellent model organelle to understand these diverse quality-control pathways. On the protein level, mitochondria are equipped with systems that monitor incoming nuclear-encoded proteins that must be imported into mitochondria. To ensure that only functional proteins enter mitochondria, and that they are imported into the proper mitochondrial sub-compartment, protein surveillance occurs at sites of import on the outer mitochondria membrane. One surveillance pathway is called the mitochondrial compromised protein response (mitoCPR) and was identified by the late (and great) Angelika Amon together with Hilla Weidberg. In situations in which protein import is malfunctioning or overwhelmed, yeast mitochondrial proteins accumulate on the outer surface, leading to synthesis of Cis1 and activating mitoCPR. Cis1 recruits the AAA-ATPase Msp1 to clogged import sites, where it extracts these proteins for proteasomal degradation (Weidberg and Amon, 2018Weidberg H. Amon A. MitoCPR—A surveillance pathway that protects mitochondria in response to protein import stress.Science. 2018; 360: eaan4146Crossref PubMed Scopus (142) Google Scholar). In a separate pathway for proteins that successfully enter mitochondria but need to be degraded later, mitochondria encode proteases such as the m-AAAs, which promote intra-mitochondrial proteostasis. Thus, mitochondria feature multiple quality-control pathways to maintain protein targeting and function. Although protein-focused quality-control systems promote mitochondrial homeostasis, mitochondria still gradually lose functional capacity, particularly during organismal aging. To combat this, cells developed another quality-control pathway that functions on the organelle level: mitophagy. This specialized form of macro-autophagy utilizes machinery that recognizes and targets defective mitochondria for lysosomal destruction. The kinase PINK1 and associated ubiquitin E3 ligase Parkin mediate a well-characterized form of mitophagy and can be activated when mitochondria lose membrane potential (Narendra et al., 2008Narendra D. Tanaka A. Suen D.-F. Youle R.J. Parkin is recruited selectively to impaired mitochondria and promotes their autophagy.J. Cell Biol. 2008; 183: 795-803Crossref PubMed Scopus (2596) Google Scholar). Via this system, defective mitochondria are ubiquitinylated and are targeted for autophagic degradation via the canonical autophagy machinery. As with protein-level quality control, this pathway is specific, degrading only malfunctional mitochondria. Similar to mitochondria, the ER network also encodes mechanisms to degrade portions of itself and promote cell homeostasis. As Molinari discusses in their review (Molinari, 2021Molinari M. ER-phagy responses in yeast, plants and mammalian cells.Dev. Cell. 2021; 56 (this issue): 949-966Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar), ER-phagy is a specific type of autophagy triggered during various stress cues such as nutrient starvation. Numerous sub-types of ER-phagy exist and utilize distinct receptors that target regions of the ER for degradation. It is clear that ER-phagy can both function on the organelle length scale, to allow control of ER shape and size, and enable specific proteins in ER sub-domains to be captured and eventually turned over. Thus, surveillance and quality-control pathways enable proteins and organelles to maintain functionality for extended time periods. Erosion of these pathways contributes to numerous disease states including metabolic syndromes, as well as aging-related diseases like Huntington’s disease. In biology, structure reflects function. Organelles generally maintain particular morphologies to match their jobs, but these change in response to metabolic or developmental cues. Changes in organelle morphology enable functional adaptations and the maintenance of cell homeostasis. One classic example is that of mitochondria. As Ng and colleagues discuss (Ng et al., 2021Ng M.Y.W. Wai T. Simonsen A. Quality control of the mitochondrion.Dev. Cell. 2021; 56 (this issue): 881-905Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar) in response to changes in cellular energetics, mitochondria fragment or fuse together to fine-tune their metabolic activities. Mitochondrial cristae also proliferate to fine-tune the bioenergetics of the respiratory complexes localized on them. A less well-known, but still incredible, example of how organelle shape couples to function is a region of the ER network in some plants called the desmotubule. As Brandizzi explains in her review (Brandizzi, 2021Brandizzi F. Maintaining the structural and functional homeostasis of the plant endoplasmic reticulum.Dev. Cell. 2021; 56 (this issue): 919-932Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar), the plant ER often functions as a “super organelle” that traverses multiple cells via inter-cellular nanopores called plasmodesmata. The desmotubule is an ER tubule spanning these plasmodesmata, thus connecting the ER network between cells. It is possible that some entire plants contain a single, continuous ER via these desmotubule bridges, making plant ER systems perhaps the largest organelles on the planet! To match its complicated structure, the plant ER network is full of membrane-shaping proteins such as reticulons (Rtns), as well as lunapark (Lnp) and atlastin, which are associated with tubular three-way junctions and homotypic fusion, respectively. What are the functions of desmotubules? Because they innervate multiple cells through plasmodesmata, one potential role is to regulate the flow of metabolites between cells by tuning the plasmodesmata gap space. In this model, changes in turgor pressure between adjacent cells can displace or change the shape of a desmotubule and push it closer to the plasma membrane (PM) encircling the gap (in essence, adjusting the diameter of the plasmodesmata hole, and flow of materials between cells). As such, desmotubules and plasmodesmata are sites of close contact between the ER and PM, so called ER-PM contact sites also conserved in yeast and mammals as key regions for inter-organelle crosstalk. In line with this, C2 domain-containing proteins of the MCTP protein family have recently been proposed to act as desmotubule-PM tethering factors (Brault et al., 2019Brault M.L. Petit J.D. Immel F. Nicolas W.J. Glavier M. Brocard L. Gaston A. Fouché M. Hawkins T.J. Crowet J.-M. et al.Multiple C2 domains and transmembrane region proteins (MCTPs) tether membranes at plasmodesmata.EMBO Rep. 2019; 20: e47182Crossref PubMed Scopus (34) Google Scholar). Another example of inter-organelle crosstalk in cell homeostasis is the construction and maintenance of the plant cell wall. As Hoffmann and colleagues discuss (Hoffmann et al., 2021Hoffmann N.K.S. Samuels A.L. McFarlane H. Subcellular coordination of plant cell wall synthesis.Dev. Cell. 2021; 56 (this issue): 933-948Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar), building the plant cell wall requires multiple organelle systems that execute a division of labor to manufacture and transport wall components to the extracellular space. In the Golgi, matrix polysaccharides are synthesized and ultimately packaged into vesicles sent to the cell surface. Cellulose is also required but is manufactured “locally” at the PM via cellulose synthases. Together, these processes enable the cell wall to be constructed but also to change in response to external stimuli. One such cue is from plant-microbe interactions. Here, plant pathogens stimulate local cell wall production to fortify plants from damage. Thus, organelles and inter-organelle contacts exhibit unique shapes and functions that enable them to promote cell and organismal homeostasis. In my lab, we study the physical expansion of the yeast ER-lysosome contact site, called the nucleus-vacuole junction (NVJ), as it relates to cell homeostasis. NVJ expansion directly correlates with nutritional stress. The NVJ expands into a large disc-like platform during low-nutrient subsistence to promote metabolic adaptation via the promotion of micro-autophagy, enhancing lipid droplet biogenesis, and the selective recruitment of metabolic enzymes (Hariri et al., 2018Hariri H. Rogers S. Ugrankar R. Liu Y.L. Feathers J.R. Henne W.M. Lipid droplet biogenesis is spatially coordinated at ER-vacuole contacts under nutritional stress.EMBO Rep. 2018; 19: 57-72Crossref PubMed Scopus (73) Google Scholar; Kvam et al., 2005Kvam E. Gable K. Dunn T.M. Goldfarb D.S. Targeting of Tsc13p to nucleus-vacuole junctions: a role for very-long-chain fatty acids in the biogenesis of microautophagic vesicles.Mol. Biol. Cell. 2005; 16: 3987-3998Crossref PubMed Scopus (58) Google Scholar). This is a simple example of how an inter-organelle contact can act as a “metabolic barometer,” visibly changing in response to stress and enabling metabolic remodeling for survival. NVJ expansion is thus one pro-survival behavior and can even be used to predict cell fate following extended nutrient starvation (Wood et al., 2020Wood N.E. Kositangool P. Hariri H. Marchand A.J. Henne W.M. Nutrient signaling, stress response, and inter-organelle communication are non-canonical determinants of cell fate.Cell Rep. 2020; 33: 108446Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar). Cells are tailored to sense and adapt to changes in environmental conditions. Cancer cells exploit such evolutionarily developed survival programs to proliferate even under harsh metabolic conditions, such as within tumors. These survival strategies also make treatments that target cancer cells more challenging. As Miller and Thorburn discuss (Miller and Thorburn, 2021Miller D.R. Thorburn A. Autophagy and organelle homeostasis in cancer.Dev. Cell. 2021; 56 (this issue): 906-918Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar), numerous cancer cell types have developed strategies to hijack survival pathways. One specific example is mitophagy, which cancer cells can activate to maintain the high functional integrity of mitochondrial metabolism that is necessary for cell proliferation. Active mitophagy also prevents the release of pro-apoptotic factors such as cytochrome c from mitochondria and thus serves as a potent pro-survival strategy. However, it should be noted that general autophagy may also have anti-cancer roles. For example, genetic inhibition of ATG5 or ATG7 in tumor-prone mouse models caused an increase in tumor incidence, suggesting that autophagy is actually protective against some cancer progression (Strohecker et al., 2013Strohecker A.M. Guo J.Y. Karsli-Uzunbas G. Price S.M. Chen G.J. Mathew R. McMahon M. White E. Autophagy sustains mitochondrial glutamine metabolism and growth of BrafV600E-driven lung tumors.Cancer Discov. 2013; 3: 1272-1285Crossref PubMed Scopus (287) Google Scholar). Thus, autophagy can either promote or inhibit survival of cancer cells in different contexts, making its therapeutic targeting more challenging. Like mitochondria, alterations in lysosome function are also reported to be either helpful or harmful to cancer cells. Lysosomes can promote cancer cell drug resistance when they sequester anti-cancer drugs and prevent them from entering into the cytoplasm (Zhitomirsky and Assaraf, 2016Zhitomirsky B. Assaraf Y.G. Lysosomes as mediators of drug resistance in cancer.Drug Resist. Updat. 2016; 24: 23-33Crossref PubMed Scopus (230) Google Scholar). Conversely, malfunctioning lysosomes can become leaky and spill toxic hydrolases into the cytoplasm. Mutations that affect lysosome membrane integrity are thus detrimental to cancer cell survival. Similarly, lysosomes are platforms for sensing and generating basic metabolites like amino acids, and their dysfunction may reduce cell growth. Thus, loss of lysosome homeostasis can reduce cancer cell fitness, pointing to anti-cancer strategies that focus on perturbing lysosome function in metabolism. A third organelle whose homeostasis is altered in cancers is the lipid droplet (LD). As reservoirs for energy-rich fatty acids, LDs often accumulate in cancer cells following the upregulation of fatty acid synthesis to support cell growth (Menard et al., 2016Menard J.A. Christianson H.C. Kucharzewska P. Bourseau-Guilmain E. Svensson K.J. Lindqvist E. Indira Chandran V. Kjellén L. Welinder C. Bengzon J. et al.Metastasis stimulation by hypoxia and acidosis-induced extracellular lipid uptake is mediated by proteoglycan-dependent endocytosis.Cancer Res. 2016; 76: 4828-4840Crossref PubMed Scopus (63) Google Scholar). The autophagic turnover of these LDs (e.g., lipophagy) provides additional fatty acids for membrane synthesis and growth, thus promoting cancer cell survival. However, elevated fatty acid turnover correlates with higher ROS production, which can induce cell senescence in prostate cancer (Panda et al., 2020Panda P.K. Patra S. Naik P.P. Praharaj P.P. Mukhopadhyay S. Meher B.R. Gupta P.K. Verma R.S. Maiti T.K. Bhutia S.K. Deacetylation of LAMP1 drives lipophagy-dependent generation of free fatty acids by Abrus agglutinin to promote senescence in prostate cancer.J. Cell. Physiol. 2020; 235: 2776-2791Crossref PubMed Scopus (17) Google Scholar). Thus, LDs are often associated with aggressive cancer cell types, but the role of LDs as mediators of cancer cell survival may be context dependent. In conclusion, numerous quality-control systems have evolved to enable organelle homeostasis and can isolate and/or degrade functionally defective proteins or organelles. These pathways often overlap with each other, and they exist across different length scales of biological complexity, providing fail-safes and ensuring cell health. Recent studies begin to highlight the importance of inter-organelle crosstalk in this homeostasis ballet. A major focus of future research should be how specific quality-control systems of different organelles communicate with one another, and how this crosstalk fine-tunes or synchronizes their activities to enable cell homeostasis. Such crosstalk may be coordinated at sites of inter-organelle contact and enable functional division of labor between organelle systems. Finally, it is clear that cancers have developed mechanisms to hijack or alter the functions of organelles or homeostasis pathways, particularly autophagy, making anti-cancer therapies challenging. A better understanding of the mechanisms underlying organelle homeostasis will teach us not only more about cell physiology but also how to develop better therapies to treat cancers, aging, and metabolic diseases. W.M.H. is supported by funds from the Welch Foundation ( I-1873 ), NIH NIGMS ( R35GM119768 ), NIH NIDDK ( 1R01DK126887 ), the Ara Parseghian Medical Research Fund , and the UT Southwestern Endowed Scholars Program . The author declares no competing interests. Subcellular coordination of plant cell wall synthesisHoffmann et al.Developmental CellMarch 23, 2021In BriefOrganelles of the plant cell cooperate to synthesize and secrete a strong yet flexible cell wall. Hoffmann et al. describe the subcellular locations at which cell wall synthesis occurs and review the mechanisms underlying biosynthesis. They also examine how synthesis is regulated in response to different perturbations to maintain cell wall homeostasis. Full-Text PDF Quality control of the mitochondrionNg et al.Developmental CellMarch 3, 2021In BriefMitochondria are essential organelles that execute and coordinate various metabolic processes in the cell. In this review, Ng et al. discuss current understanding of different mitochondrial quality control mechanisms and their relevance for mitochondrial and cellular health. Full-Text PDF Maintaining the structural and functional homeostasis of the plant endoplasmic reticulumFederica BrandizziDevelopmental CellMarch 3, 2021In BriefThe endoplasmic reticulum (ER) is a highly dynamic organelle that is continuously remodeled through interactions with the cytoskeleton and the action of specialized ER shapers. In this review, Brandizzi discusses mechanisms underlying plant ER structural and functional homeostasis, focusing on the regulation of ER network architecture and ER degradation. Full-Text PDF Autophagy and organelle homeostasis in cancerMiller et al.Developmental CellMarch 8, 2021In BriefAutophagy can both promote and inhibit cancer growth and progression. Miller and Thorburn review the pro- and antitumor effects of organelle-targeted autophagy and their relationship with cancer hallmarks, such as evading cell death, genomic instability, and altered metabolism. These insights may help improve therapeutic targeting of autophagy in cancer. Full-Text PDF ER-phagy responses in yeast, plants, and mammalian cells and their crosstalk with UPR and ERADMaurizio MolinariDevelopmental CellMarch 24, 2021In BriefER-phagy, literally endoplasmic reticulum (ER)-eating, defines the constitutive or regulated clearance of ER portions within eukaryotic cells. In this review, Molinari examines how ER-phagy responses (ERPRs) collaborate with unfolded protein responses (UPRs) to regulate the lysosomal clearance of ER portions and thereby determine ER size and function. Full-Text PDF" @default.
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• W3152257382 title "Organelle homeostasis principles: How organelle quality control and inter-organelle crosstalk promote cell survival" @default.
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