“The Loss of Golden Touch”: Mitochondria-Organelle Interactions, Metabolism, and Cancer

Mitochondria represent the energy hub of cells and their function is under the constant influence of their tethering with other subcellular organelles. Mitochondria interact with the endoplasmic reticulum, lysosomes, cytoskeleton, peroxisomes, and nucleus in several ways, ranging from signal transduction, vesicle transport, and membrane contact sites, to regulate energy metabolism, biosynthetic processes, apoptosis, and cell turnover. Tumorigenesis is often associated with mitochondrial dysfunction, which could likely be the result of an altered interaction with different cell organelles or structures. The purpose of the present review is to provide an updated overview of the links between inter-organellar communications and interactions and metabolism in cancer cells, with a focus on mitochondria. The very recent publication of several reviews on these aspects testifies the great interest in the area. Here, we aim at (1) summarizing recent evidence supporting that the metabolic rewiring and adaptation observed in tumors deeply affect organelle dynamics and cellular functions and vice versa; (2) discussing insights on the underlying mechanisms, when available; and (3) critically presenting the gaps in the field that need to be filled, for a comprehensive understanding of tumor cells’ biology. Chemo-resistance and druggable vulnerabilities of cancer cells related to the aspects mentioned above is also outlined.

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Mitochondria Endoplasmic Reticulum Contact Sites (MERCs): Proximity Ligation Assay as a Tool to Study Organelle Interaction

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.789959 ◽

2021 ◽

Vol 9 ◽

Author(s):

Sara Benhammouda ◽

Anjali Vishwakarma ◽

Priya Gatti ◽

Marc Germain

Keyword(s):

Endoplasmic Reticulum ◽

Fluorescence Probes ◽

Proximity Ligation Assay ◽

Proximity Ligation ◽

Membrane Contact Sites ◽

Contact Sites ◽

Membrane Contact ◽

Endogenous Proteins ◽

Underlying Mechanisms

Organelles cooperate with each other to regulate vital cellular homoeostatic functions. This occurs through the formation of close connections through membrane contact sites. Mitochondria-Endoplasmic-Reticulum (ER) contact sites (MERCS) are one of such contact sites that regulate numerous biological processes by controlling calcium and metabolic homeostasis. However, the extent to which contact sites shape cellular biology and the underlying mechanisms remain to be fully elucidated. A number of biochemical and imaging approaches have been established to address these questions, resulting in the identification of a number of molecular tethers between mitochondria and the ER. Among these techniques, fluorescence-based imaging is widely used, including analysing signal overlap between two organelles and more selective techniques such as in-situ proximity ligation assay (PLA). While these two techniques allow the detection of endogenous proteins, preventing some problems associated with techniques relying on overexpression (FRET, split fluorescence probes), they come with their own issues. In addition, proper image analysis is required to minimise potential artefacts associated with these methods. In this review, we discuss the protocols and outline the limitations of fluorescence-based approaches used to assess MERCs using endogenous proteins.

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The Vacuole and Mitochondria Patch (vCLAMP) Protein Mcp1 Is Involved in Maintenance of Mitochondrial Function and Mitophagy in Candida albicans

Frontiers in Microbiology ◽

10.3389/fmicb.2021.633380 ◽

2021 ◽

Vol 12 ◽

Author(s):

Xiaolong Mao ◽

Li Yang ◽

Yiming Fan ◽

Jiazhen Wang ◽

Dongkai Cui ◽

...

Keyword(s):

Candida Albicans ◽

Carbon Sources ◽

Cellular Functions ◽

Core Component ◽

Membrane Contact Sites ◽

Contact Sites ◽

Mitochondrial Functions ◽

Abnormal Accumulation ◽

Membrane Contact

The vacuole and mitochondria patches (vCLAMPs) are novel membrane contact sites in yeast. However, their role in autophagy has not been elucidated so far. In this article, the role of Mcp1, one core component of vCLAMP, in mitophagy of Candida albicans was investigated. Deletion of MCP1 led to abnormal accumulation of enlarged mitochondria and attenuated stability of mitochondrial DNA (mtDNA) in C. albicans when cultured in non-fermentable carbon sources. Furthermore, the mcp1Δ/Δ mutant exhibited defective growth and degradation of Csp37-GFP. These results indicate that Mcp1 plays a crucial role in mitophagy and maintenance of mitochondrial functions under the non-fermentable condition. Interestingly, this deletion had no impact on degradation of Atg8 (the macroautophagy reporter) and Lap41 (the cytoplasm-to-vacuole targeting pathway marker) under SD-N medium. Moreover, deletion of MCP1 inhibited filamentous growth and impaired virulence of the pathogen. This study provides an insight to vCLAMPs in cellular functions and pathogenicity in C. albicans.

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Relevance of Membrane Contact Sites in Cancer Progression

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.622215 ◽

2021 ◽

Vol 8 ◽

Author(s):

Aurora Gil-Hernández ◽

Miguel Arroyo-Campuzano ◽

Arturo Simoni-Nieves ◽

Cecilia Zazueta ◽

Luis Enrique Gomez-Quiroz ◽

...

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Lipid Signaling ◽

Cell Physiology ◽

Vesicular Traffic ◽

Membrane Contact Sites ◽

Contact Sites ◽

Diagnostic Potential ◽

Specific Proteins ◽

Membrane Contact

Membrane contact sites (MCS) are typically defined as areas of proximity between heterologous or homologous membranes characterized by specific proteins. The study of MCS is considered as an emergent field that shows how crucial organelle interactions are in cell physiology. MCS regulate a myriad of physiological processes such as apoptosis, calcium, and lipid signaling, just to name a few. The membranal interactions between the endoplasmic reticulum (ER)–mitochondria, the ER–plasma membrane, and the vesicular traffic have received special attention in recent years, particularly in cancer research, in which it has been proposed that MCS regulate tumor metabolism and fate, contributing to their progression. However, as the therapeutic or diagnostic potential of MCS has not been fully revisited, in this review, we provide recent information on MCS relevance on calcium and lipid signaling in cancer cells and on its role in tumor progression. We also describe some proteins associated with MCS, like CERT, STIM1, VDAC, and Orai, that impact on cancer progression and that could be a possible diagnostic marker. Overall, these information might contribute to the understanding of the complex biology of cancer cells.

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Gold Nanoparticles Impinge on Nucleoli and the Stress Response in MCF7 Breast Cancer Cells

Nanobiomedicine ◽

10.5772/62337 ◽

2016 ◽

Vol 3 ◽

pp. 3 ◽

Cited By ~ 7

Author(s):

Mohamed Kodiha ◽

Hicham Mahboubi ◽

Dusica Maysinger ◽

Ursula Stochaj

Keyword(s):

Gold Nanoparticles ◽

Stress Response ◽

Cancer Cells ◽

Ribosome Biogenesis ◽

Cellular Stress ◽

Cellular Stress Response ◽

Cellular Functions ◽

Gold Nanoflowers ◽

Underlying Mechanisms ◽

And Function

Cancer cells can take up gold nanoparticles of different morphologies. These particles interact with the plasma membrane and often travel to intracellular organelles. Among organelles, the nucleus is especially susceptible to the damage that is inflicted by gold nanoparticles. Located inside the nucleus, nucleoli are specialized compartments that transcribe ribosomal RNA genes, produce ribosomes and function as cellular stress sensors. Nucleoli are particularly prone to gold nanoparticle-induced injury. As such, small spherical gold nanoparticles and gold nanoflowers interfere with the transcription of ribosomal DNA. However, the underlying mechanisms are not fully understood. In this study, we examined the effects of gold nanoparticles on nucleolar proteins that are critical to ribosome biogenesis and other cellular functions. We show that B23/nucleophosmin, a nucleolar protein that is tightly linked to cancer, is significantly affected by gold nanoparticles. Furthermore, gold nanoparticles impinge on the cellular stress response, as they reduce the abundance of the molecular chaperone hsp70 and O-GlcNAc modified proteins in the nucleus and nucleoli. Together, our studies set the stage for the development of nanomedicines that target the nucleolus to eradicate proliferating cancer cells.

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Yeast Vps13 promotes mitochondrial function and is localized at membrane contact sites

Molecular Biology of the Cell ◽

10.1091/mbc.e16-02-0112 ◽

2016 ◽

Vol 27 (15) ◽

pp. 2435-2449 ◽

Cited By ~ 70

Author(s):

Jae-Sook Park ◽

Mary K. Thorsness ◽

Robert Policastro ◽

Luke L. McGoldrick ◽

Nancy M. Hollingsworth ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Mitochondrial Dysfunction ◽

Mitochondrial Function ◽

Protein Sorting ◽

Growth Conditions ◽

Eukaryotic Cells ◽

Cellular Functions ◽

Membrane Contact Sites ◽

Contact Sites ◽

Membrane Contact

The Vps13 protein family is highly conserved in eukaryotic cells. Mutations in human VPS13 genes result in a variety of diseases, such as chorea acanthocytosis (ChAc), but the cellular functions of Vps13 proteins are not well defined. In yeast, there is a single VPS13 orthologue, which is required for at least two different processes: protein sorting to the vacuole and sporulation. This study demonstrates that VPS13 is also important for mitochondrial integrity. In addition to preventing transfer of DNA from the mitochondrion to the nucleus, VPS13 suppresses mitophagy and functions in parallel with the endoplasmic reticulum–mitochondrion encounter structure (ERMES). In different growth conditions, Vps13 localizes to endosome–mitochondrion contacts and to the nuclear–vacuole junctions, indicating that Vps13 may function at membrane contact sites. The ability of VPS13 to compensate for the absence of ERMES correlates with its intracellular distribution. We propose that Vps13 is present at multiple membrane contact sites and that separation-of-function mutants are due to loss of Vps13 at specific junctions. Introduction of VPS13A mutations identified in ChAc patients at cognate sites in yeast VPS13 are specifically defective in compensating for the lack of ERMES, suggesting that mitochondrial dysfunction might be the basis for ChAc.

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ORP5 and ORP8: Sterol Sensors and Phospholipid Transfer Proteins at Membrane Contact Sites?

Biomolecules ◽

10.3390/biom10060928 ◽

2020 ◽

Vol 10 (6) ◽

pp. 928

Author(s):

Nina Criado Santos ◽

Vladimir Girik ◽

Paula Nunes-Hasler

Keyword(s):

Structural Similarity ◽

Lipid Transfer ◽

Cellular Functions ◽

Oxysterol Binding Protein ◽

Membrane Contact Sites ◽

Contact Sites ◽

Phospholipid Transfer ◽

Membrane Contact ◽

And Migration ◽

Phosphatidylinositol 4

Oxysterol binding related proteins 5 and 8 (ORP5 and ORP8) are two close homologs of the larger oxysterol binding protein (OSBP) family of sterol sensors and lipid transfer proteins (LTP). Early studies indicated these transmembrane proteins, anchored to the endoplasmic reticulum (ER), bound and sensed cholesterol and oxysterols. They were identified as important for diverse cellular functions including sterol homeostasis, vesicular trafficking, proliferation and migration. In addition, they were implicated in lipid-related diseases such as atherosclerosis and diabetes, but also cancer, although their mechanisms of action remained poorly understood. Then, alongside the increasing recognition that membrane contact sites (MCS) serve as hubs for non-vesicular lipid transfer, added to their structural similarity to other LTPs, came discoveries showing that ORP5 and 8 were in fact phospholipid transfer proteins that rather sense and exchange phosphatidylserine (PS) for phosphoinositides, including phosphatidylinositol-4-phosphate (PI(4)P) and potentially phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P2). Evidence now points to their action at MCS between the ER and various organelles including the plasma membrane, lysosomes, mitochondria, and lipid droplets. Dissecting exactly how this unexpected phospholipid transfer function connects with sterol regulation in health or disease remains a challenge for future studies.

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Functions of Oxysterol-Binding Proteins at Membrane Contact Sites and Their Control by Phosphoinositide Metabolism

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.664788 ◽

2021 ◽

Vol 9 ◽

Author(s):

Fubito Nakatsu ◽

Asami Kawasaki

Keyword(s):

Lipid Transport ◽

Phosphoinositide Metabolism ◽

Lipid Transfer ◽

Cellular Functions ◽

Characteristic Functional ◽

Membrane Contact Sites ◽

Contact Sites ◽

Tightly Coupled ◽

Membrane Contact ◽

The Right

Lipids must be correctly transported within the cell to the right place at the right time in order to be fully functional. Non-vesicular lipid transport is mediated by so-called lipid transfer proteins (LTPs), which contain a hydrophobic cavity that sequesters lipid molecules. Oxysterol-binding protein (OSBP)-related proteins (ORPs) are a family of LTPs known to harbor lipid ligands, such as cholesterol and phospholipids. ORPs act as a sensor or transporter of those lipid ligands at membrane contact sites (MCSs) where two different cellular membranes are closely apposed. In particular, a characteristic functional property of ORPs is their role as a lipid exchanger. ORPs mediate counter-directional transport of two different lipid ligands at MCSs. Several, but not all, ORPs transport their lipid ligand from the endoplasmic reticulum (ER) in exchange for phosphatidylinositol 4-phosphate (PI4P), the other ligand, on apposed membranes. This ORP-mediated lipid “countertransport” is driven by the concentration gradient of PI4P between membranes, which is generated by its kinases and phosphatases. In this review, we will discuss how ORP function is tightly coupled to metabolism of phosphoinositides such as PI4P. Recent progress on the role of ORP-mediated lipid transport/countertransport at multiple MCSs in cellular functions will be also discussed.

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