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Ye Q, Xiao Z, Bai C, Yao H, Zhao L, Tan WS. Unveiling the multi-characteristic potential of hyper-productive suspension MDCK cells for advanced influenza A virus propagation. Vaccine 2025; 52:126900. [PMID: 39985968 DOI: 10.1016/j.vaccine.2025.126900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 02/14/2025] [Accepted: 02/14/2025] [Indexed: 02/24/2025]
Abstract
The global population faces persistent threats from influenza viruses, with vaccination remaining the most cost-effective preventive measure against influenza. Mammalian cell-based influenza vaccine production has garnered significant attention due to its enhanced safety profile, process controllability, and ability to circumvent adaptive mutations commonly associated with traditional egg-based vaccines, and the particular promise of suspension cell-based production systems for their convenience, economic viability, and scalability potential. Despite years of development and an increasing number of approved animal substrate-based vaccines, numerous challenges persist, especially the incomplete understanding of influenza virus amplification features in the producing cell lines. In previous research, we developed a high-titer suspension MDCK cell-based influenza virus production process and established a high-generation MDCK cell line (MDCK-HG). This study demonstrated enhanced productive capacity of MDCK-HG cells across diverse operational conditions. The maximum hemagglutination titer achieved 15.02 Log2HAU/100 μL for H9N2 strain and 12.55 Log2HAU/100 μL for H1N1 strain, which evidenced by a 56.95 % and a 189.79 % increase compared to the original suspension MDCK cells. Through kinetics analyses, transcriptomic profiling, and metabolic characterization, we identified the kinetic features of high-generation cell lines for efficient influenza virus production and discovered that the redistribution of cell cycles, enhanced anti-apoptotic capabilities, elevated membrane synthesis rates, and efficient energy metabolism likely contribute to their increased viral production capacity. These findings not only deepen our understanding of the influenza vaccine production process but also provide valuable guidance for future systematic metabolic engineering efforts aimed at establishing more robust vaccine production processes.
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Affiliation(s)
- Qian Ye
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China; Shanghai Collaborative Innovation Center for Biomanufacturing Technology (SCIBT), Shanghai 200237, China
| | - Zhiying Xiao
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China; Shanghai Collaborative Innovation Center for Biomanufacturing Technology (SCIBT), Shanghai 200237, China
| | - Chunli Bai
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China
| | - Hong Yao
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China
| | - Liang Zhao
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China; Shanghai BioEngine Sci-Tech Co., LTD, Shanghai 201203, PR China; Shanghai Collaborative Innovation Center for Biomanufacturing Technology (SCIBT), Shanghai 200237, China.
| | - Wen-Song Tan
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, PR China; Shanghai BioEngine Sci-Tech Co., LTD, Shanghai 201203, PR China; Shanghai Collaborative Innovation Center for Biomanufacturing Technology (SCIBT), Shanghai 200237, China
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Wang R, Wang J, Yu J, Li Z, Zhang M, Chen Y, Liu F, Jiang D, Guo J, Li X, Wu Y. Mfn2 regulates calcium homeostasis and suppresses PASMCs proliferation via interaction with IP3R3 to mitigate pulmonary arterial hypertension. J Transl Med 2025; 23:366. [PMID: 40128893 PMCID: PMC11934582 DOI: 10.1186/s12967-025-06384-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 03/14/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs). Recent studies indicate that Mitochondrial fusion protein 2 (Mfn2) maintains intracellular calcium (Ca2+) homeostasis via the mitochondria-associated endoplasmic reticulum membranes (MAMs) pathway, thereby inhibiting PASMCs proliferation and reducing pulmonary artery pressure. However, the precise mechanisms remain unclear. METHODS This study explored the roles of Mfn2 and IP3R3 in PAH progression by assessing their expression in lung tissues of a monocrotaline (MCT)-induced PAH rat model. Immunoprecipitation assays were performed to confirm the interaction between Mfn2 and IP3R3. PASMCs were treated with either silenced or overexpressed Mfn2 and exposed to TNF-ɑ to observe effects on ER stress, IP3R3 expression, mitochondrial Ca2+ transport, and mitochondrial integrity. We also evaluated the effects of 4-phenylbutyric acid (4-PBA) and cistanche phenylethanol glycosides (CPGs) on the Mfn2-IP3R3 interaction in a TNF-α-induced PAH cell model, focusing on Ca2+ transport and mitochondrial structure. RESULTS Mfn2 expression was significantly down-regulated in the MCT-induced PAH rat model. Inhibition of ER stress upregulated Mfn2 expression, downregulated IP3R3 expression, increased mitochondrial Ca2+ concentration, and reduced autophagy, improving pulmonary hemodynamics and vascular remodeling. Overexpression of Mfn2 reduced ER stress, decreased IP3R3 expression, decreased mitochondrial Ca2+ transport, and restored mitochondrial integrity. Immunoprecipitation assays confirmed the interaction between Mfn2 and IP3R3. Inhibition of IP3R3 elevated Mfn2 levels, yielding similar beneficial effects as Mfn2 overexpression. 4-PBA and CPGs modulated the Mfn2-IP3R3 signaling axis, effectively inhibiting PAH progression. CONCLUSIONS Mfn2 mediates mitochondrial Ca2+ transport via IP3R3, suppressing PASMCs proliferation and pulmonary vascular remodeling, underscoring Mfn2's potential in regulating metabolic processes and vascular remodeling in PAH. These findings provide new insights for developing PAH-targeted therapeutics and establish a theoretical basis for traditional Chinese medicine in PAH prevention and treatment.
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Affiliation(s)
- Rui Wang
- Department of General Medicine, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China
| | - Jie Wang
- Department of Pharmacy, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China
| | - Jing Yu
- College of Pharmacy, Xinjiang Medical University, Urumqi, 830011, China
| | - Zhiqiang Li
- Animal Laboratory Center, Xinjiang Medical University, Urumqi, 830011, China
| | - Minfang Zhang
- Electron Microscope Lab, Xinjiang Medical University, Urumqi, 830011, China
| | - Yuhu Chen
- Department of General Surgery, Lingcheng District People's Hospital, Dezhou, 253500, China
| | - Fen Liu
- A State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Clinical Medical Research Institute, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China
| | - Dongmei Jiang
- Department of General Medicine, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China
| | - Jingfei Guo
- Department of General Medicine, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China
| | - Xiaomei Li
- Department of Cardiology, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China.
| | - Yun Wu
- Department of General Medicine, First Affiliated Hospital of Xinjiang Medical University, Urumqi, 830011, China.
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Cartes-Saavedra B, Ghosh A, Hajnóczky G. The roles of mitochondria in global and local intracellular calcium signalling. Nat Rev Mol Cell Biol 2025:10.1038/s41580-024-00820-1. [PMID: 39870977 DOI: 10.1038/s41580-024-00820-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/11/2024] [Indexed: 01/29/2025]
Abstract
Activation of Ca2+ channels in Ca2+ stores in organelles and the plasma membrane generates cytoplasmic calcium ([Ca2+]c) signals that control almost every aspect of cell function, including metabolism, vesicle fusion and contraction. Mitochondria have a high capacity for Ca2+ uptake and chelation, alongside efficient Ca2+ release mechanisms. Still, mitochondria do not store Ca2+ in a prolonged manner under physiological conditions and lack the capacity to generate global [Ca2+]c signals. However, mitochondria take up Ca2+ at high local [Ca2+]c signals that originate from neighbouring organelles, and also during sustained global elevations of [Ca2+]c. Accumulated Ca2+ in the mitochondria stimulates oxidative metabolism and upon return to the cytoplasm, can produce spatially confined rises in [Ca2+]c to exert control over processes that are sensitive to Ca2+. Thus, the mitochondrial handling of [Ca2+]c is of physiological relevance. Furthermore, dysregulation of mitochondrial Ca2+ handling can contribute to debilitating diseases. We discuss the mechanisms and relevance of mitochondria in local and global calcium signals.
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Affiliation(s)
- Benjamín Cartes-Saavedra
- MitoCare Center, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Arijita Ghosh
- MitoCare Center, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - György Hajnóczky
- MitoCare Center, Department of Pathology and Genomic Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
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Li X, Zhao X, Qin Z, Li J, Sun B, Liu L. Regulation of calcium homeostasis in endoplasmic reticulum-mitochondria crosstalk: implications for skeletal muscle atrophy. Cell Commun Signal 2025; 23:17. [PMID: 39789595 PMCID: PMC11721261 DOI: 10.1186/s12964-024-02014-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 12/23/2024] [Indexed: 01/12/2025] Open
Abstract
This review comprehensively explores the critical role of calcium as an essential small-molecule biomessenger in skeletal muscle function. Calcium is vital for both regulating muscle excitation-contraction coupling and for the development, maintenance, and regeneration of muscle cells. The orchestrated release of calcium from the endoplasmic reticulum (ER) is mediated by receptors such as the ryanodine receptor (RYR) and inositol 1,4,5-trisphosphate receptor (IP3R), which is crucial for skeletal muscle contraction. The sarcoendoplasmic reticulum calcium ATPase (SERCA) pump plays a key role in recapturing calcium, enabling the muscle to return to a relaxed state. A pivotal aspect of calcium homeostasis involves the dynamic interaction between mitochondria and the ER. This interaction includes local calcium signaling facilitated by RYRs and a "quasi-synaptic" mechanism formed by the IP3R-Grp75-VDAC/MCU axis, allowing rapid calcium uptake by mitochondria with minimal interference at the cytoplasmic level. Disruption of calcium transport can lead to mitochondrial calcium overload, triggering the opening of the mitochondrial permeability transition pore and subsequent release of reactive oxygen species and cytochrome C, ultimately resulting in muscle damage and atrophy. This review explores the complex relationship between the ER and mitochondria and how these organelles regulate calcium levels in skeletal muscle, aiming to provide valuable perspectives for future research on the pathogenesis of muscle diseases and the development of prevention strategies.
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Affiliation(s)
- Xuexin Li
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Road, Lu Zhou, Luzhou, Sichuan, 646000, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, China
| | - Xin Zhao
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Road, Lu Zhou, Luzhou, Sichuan, 646000, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, China
| | - Zhengshan Qin
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Road, Lu Zhou, Luzhou, Sichuan, 646000, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, China
| | - Jie Li
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Road, Lu Zhou, Luzhou, Sichuan, 646000, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, China
| | - Bowen Sun
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Road, Lu Zhou, Luzhou, Sichuan, 646000, China
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, China
| | - Li Liu
- Department of Anesthesiology, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Road, Lu Zhou, Luzhou, Sichuan, 646000, China.
- Anesthesiology and Critical Care Medicine Key Laboratory of Luzhou, Southwest Medical University, Luzhou, Sichuan Province, 646000, China.
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5
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Taha M, Cartereau A, Taillebois E, Thany SH. Flupyradifurone activates DUM neuron nicotinic acetylcholine receptors and stimulates an increase in intracellular calcium through the ryanodine receptors. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2024; 205:106147. [PMID: 39477600 DOI: 10.1016/j.pestbp.2024.106147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 09/16/2024] [Accepted: 09/22/2024] [Indexed: 11/07/2024]
Abstract
Insect neuronal nicotinic acetylcholine receptors (nAChRs) are transmembrane receptors that play a key role in the development and synaptic plasticity of both vertebrates and invertebrates, and are considered to be major targets of several insecticides. We used dorsal unpaired median (DUM) neurons, which are insect neurosecretory cells, to explore what type of nAChRs are involved in flupyradifurone's (FLU) mode of action, and to study the role of calcium release from intracellular stores in this process. Using whole-cell patch-clamp and fura-2-AM calcium imaging techniques, we found that inhibition of IP3Rs through application of 2-APB reduced FLU inward currents, but did not affect the intracellular calcium release induced by FLU. In contrast, inhibition of RyRs using ryanodine, led to reduction of intracellular calcium increase following FLU pulse application. These results suggested that FLU inward currents are likely due to a combination of the direct effects of FLU on DUM neuron nAChRs and the subsequent calcium release from RyRs.
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Affiliation(s)
- Maria Taha
- Laboratoire Physiologie, Ecologie et Environnement (P2E), USC-INRAE 1328, Université d'Orléans, 1 rue de Chartres, 45067 Orléans, France
| | - Alison Cartereau
- Laboratoire Physiologie, Ecologie et Environnement (P2E), USC-INRAE 1328, Université d'Orléans, 1 rue de Chartres, 45067 Orléans, France
| | - Emiliane Taillebois
- Laboratoire Physiologie, Ecologie et Environnement (P2E), USC-INRAE 1328, Université d'Orléans, 1 rue de Chartres, 45067 Orléans, France
| | - Steeve H Thany
- Laboratoire Physiologie, Ecologie et Environnement (P2E), USC-INRAE 1328, Université d'Orléans, 1 rue de Chartres, 45067 Orléans, France; Institut Universitaire de France, 1 rue Descartes, 75005 Paris, France.
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6
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Huber T, Horioka-Duplix M, Chen Y, Saca VR, Ceraudo E, Chen Y, Sakmar TP. The role of signaling pathways mediated by the GPCRs CysLTR1/2 in melanocyte proliferation and senescence. Sci Signal 2024; 17:eadp3967. [PMID: 39288219 PMCID: PMC11920964 DOI: 10.1126/scisignal.adp3967] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 08/15/2024] [Indexed: 09/19/2024]
Abstract
In contrast with sun exposure-induced melanoma, rarer melanocytic tumors and neoplasms with low mutational burden present opportunities to study isolated signaling mechanisms. These include uveal melanoma and blue nevi, which are often driven by mutations within the G protein-coupled signaling cascade downstream of cysteinyl leukotriene receptor 2. Here, we review how the same mutations within this pathway drive the growth of melanocytes in one tissue but can inhibit the growth of those in another, exemplifying the role of the tissue environment in the delicate balance between uncontrolled cell growth and senescence.
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Affiliation(s)
- Thomas Huber
- Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, NY 10065, USA
| | - Mizuho Horioka-Duplix
- Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, NY 10065, USA
- Tri-Institutional PhD Program in Chemical Biology, New York, NY 10065, USA
| | - Yuanhuang Chen
- Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, NY 10065, USA
- Tri-Institutional PhD Program in Chemical Biology, New York, NY 10065, USA
| | - Victoria R Saca
- Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, NY 10065, USA
- Tri-Institutional PhD Program in Chemical Biology, New York, NY 10065, USA
| | - Emilie Ceraudo
- Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, NY 10065, USA
| | - Yu Chen
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Thomas P Sakmar
- Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, NY 10065, USA
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7
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Sayehmiri F, Motamedi F, Batool Z, Naderi N, Shaerzadeh F, Zoghi A, Rezaei O, Khodagholi F, Pourbadie HG. Mitochondrial plasticity and synaptic plasticity crosstalk; in health and Alzheimer's disease. CNS Neurosci Ther 2024; 30:e14897. [PMID: 39097920 PMCID: PMC11298206 DOI: 10.1111/cns.14897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 06/19/2024] [Accepted: 07/18/2024] [Indexed: 08/06/2024] Open
Abstract
Synaptic plasticity is believed to underlie the cellular and molecular basis of memory formation. Mitochondria are one of the main organelles involved in metabolism and energy maintenance as plastic organelles that change morphologically and functionally in response to cellular needs and regulate synaptic function and plasticity through multiple mechanisms, including ATP generation, calcium homeostasis, and biogenesis. An increased neuronal activity enhances synaptic efficiency, during which mitochondria's spatial distribution and morphology change significantly. These organelles build up in the pre-and postsynaptic zones to produce ATP, which is necessary for several synaptic processes like neurotransmitter release and recycling. Mitochondria also regulate calcium homeostasis by buffering intracellular calcium, which ensures proper synaptic activity. Furthermore, mitochondria in the presynaptic terminal have distinct morphological properties compared to dendritic or postsynaptic mitochondria. This specialization enables precise control of synaptic activity and plasticity. Mitochondrial dysfunction has been linked to synaptic failure in many neurodegenerative disorders, like Alzheimer's disease (AD). In AD, malfunctioning mitochondria cause delays in synaptic vesicle release and recycling, ionic gradient imbalances, and mostly synaptic failure. This review emphasizes mitochondrial plasticity's contribution to synaptic function. It also explores the profound effect of mitochondrial malfunction on neurodegenerative disorders, focusing on AD, and provides an overview of how they sustain cellular health under normal conditions and how their malfunction contributes to neurodegenerative diseases, highlighting their potential as a therapeutic target for such conditions.
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Affiliation(s)
- Fatemeh Sayehmiri
- Neuroscience Research Center, Faculty of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Fereshteh Motamedi
- Neuroscience Research Center, Faculty of MedicineShahid Beheshti University of Medical SciencesTehranIran
- Faculty of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Zehra Batool
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological SciencesUniversity of KarachiKarachiPakistan
| | - Nima Naderi
- Department of Pharmacology and Toxicology, Faculty of PharmacyShahid Beheshti University of Medical SciencesTehranIran
| | | | - Anahita Zoghi
- Department of Neurology, Loghman Hakim HospitalShahid Beheshti University of Medical SciencesTehranIran
| | - Omidvar Rezaei
- Skull Base Research CenterLoghman Hakim Hospital, Shahid Beheshti University of Medical SciencesTehranIran
| | - Fariba Khodagholi
- Neuroscience Research Center, Faculty of MedicineShahid Beheshti University of Medical SciencesTehranIran
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8
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Atakpa-Adaji P, Ivanova A, Kujawa K, Taylor CW. KRAP regulates mitochondrial Ca2+ uptake by licensing IP3 receptor activity and stabilizing ER-mitochondrial junctions. J Cell Sci 2024; 137:jcs261728. [PMID: 38786982 PMCID: PMC11234384 DOI: 10.1242/jcs.261728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 05/20/2024] [Indexed: 05/25/2024] Open
Abstract
Inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are high-conductance channels that allow the regulated redistribution of Ca2+ from the endoplasmic reticulum (ER) to the cytosol and, at specialized membrane contact sites (MCSs), to other organelles. Only a subset of IP3Rs release Ca2+ to the cytosol in response to IP3. These 'licensed' IP3Rs are associated with Kras-induced actin-interacting protein (KRAP, also known as ITPRID2) beneath the plasma membrane. It is unclear whether KRAP regulates IP3Rs at MCSs. We show, using simultaneous measurements of Ca2+ concentration in the cytosol and mitochondrial matrix, that KRAP also licenses IP3Rs to release Ca2+ to mitochondria. Loss of KRAP abolishes cytosolic and mitochondrial Ca2+ signals evoked by stimulation of IP3Rs via endogenous receptors. KRAP is located at ER-mitochondrial membrane contact sites (ERMCSs) populated by IP3R clusters. Using a proximity ligation assay between IP3R and voltage-dependent anion channel 1 (VDAC1), we show that loss of KRAP reduces the number of ERMCSs. We conclude that KRAP regulates Ca2+ transfer from IP3Rs to mitochondria by both licensing IP3R activity and stabilizing ERMCSs.
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Affiliation(s)
- Peace Atakpa-Adaji
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK
| | - Adelina Ivanova
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK
| | - Karolina Kujawa
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK
| | - Colin W. Taylor
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK
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Chen C, Dong X, Zhang W, Chang X, Gao W. Dialogue between mitochondria and endoplasmic reticulum-potential therapeutic targets for age-related cardiovascular diseases. Front Pharmacol 2024; 15:1389202. [PMID: 38939842 PMCID: PMC11208709 DOI: 10.3389/fphar.2024.1389202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 05/30/2024] [Indexed: 06/29/2024] Open
Abstract
Mitochondria-associated endoplasmic reticulum membranes (MAMs) act as physical membrane contact sites facilitating material exchange and signal transmission between mitochondria and endoplasmic reticulum (ER), thereby regulating processes such as Ca2+/lipid transport, mitochondrial dynamics, autophagy, ER stress, inflammation, and apoptosis, among other pathological mechanisms. Emerging evidence underscores the pivotal role of MAMs in cardiovascular diseases (CVDs), particularly in aging-related pathologies. Aging significantly influences the structure and function of the heart and the arterial system, possibly due to the accumulation of reactive oxygen species (ROS) resulting from reduced antioxidant capacity and the age-related decline in organelle function, including mitochondria. Therefore, this paper begins by describing the composition, structure, and function of MAMs, followed by an exploration of the degenerative changes in MAMs and the cardiovascular system during aging. Subsequently, it discusses the regulatory pathways and approaches targeting MAMs in aging-related CVDs, to provide novel treatment strategies for managing CVDs in aging populations.
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Affiliation(s)
- Chen Chen
- First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xueyan Dong
- Department of Hematology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wang Zhang
- Shandong Provincial Mental Health Center, Jinan, China
| | - Xing Chang
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Wulin Gao
- Department of Geriatric Medicine, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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Cauwelier C, de Ridder I, Bultynck G. Recent advances in canonical versus non-canonical Ca 2+-signaling-related anti-apoptotic Bcl-2 functions and prospects for cancer treatment. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119713. [PMID: 38521468 DOI: 10.1016/j.bbamcr.2024.119713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2023] [Revised: 01/11/2024] [Accepted: 03/20/2024] [Indexed: 03/25/2024]
Abstract
Cell fate is tightly controlled by a continuous balance between cell survival and cell death inducing mechanisms. B-cell lymphoma 2 (Bcl-2)-family members, composed of effectors and regulators, not only control apoptosis at the level of the mitochondria but also by impacting the intracellular Ca2+ homeostasis and dynamics. On the one hand, anti-apoptotic protein Bcl-2, prevents mitochondrial outer membrane permeabilization (MOMP) by scaffolding and neutralizing proapoptotic Bcl-2-family members via its hydrophobic cleft (region composed of BH-domain 1-3). On the other hand, Bcl-2 suppress pro-apoptotic Ca2+ signals by binding and inhibiting IP3 receptors via its BH4 domain, which is structurally exiled from the hydrophobic cleft by a flexible loop region (FLR). As such, Bcl-2 prevents excessive Ca2+ transfer from ER to mitochondria. Whereas regulation of both pathways requires different functional regions of Bcl-2, both seem to be connected in cancers that overexpress Bcl-2 in a life-promoting dependent manner. Here we discuss the anti-apoptotic canonical and non-canonical role, via calcium signaling, of Bcl-2 in health and cancer and evolving from this the proposed anti-cancer therapies with their shortcomings. We also argue how some cancers, with the major focus on diffuse large B-cell lymphoma (DLBCL) are difficult to treat, although theoretically prime marked for Bcl-2-targeting therapeutics. Further work is needed to understand the non-canonical functions of Bcl-2 also at organelles beyond the mitochondria, the interaction partners outside the Bcl-2 family as well as their ability to target or exploit these functions as therapeutic strategies in diseases.
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Affiliation(s)
- Claire Cauwelier
- KU Leuven, Lab. Molecular & Cellular Signaling, Dep. Cellular & Molecular Medicine, Campus Gasthuisberg O/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium
| | - Ian de Ridder
- KU Leuven, Lab. Molecular & Cellular Signaling, Dep. Cellular & Molecular Medicine, Campus Gasthuisberg O/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium
| | - Geert Bultynck
- KU Leuven, Lab. Molecular & Cellular Signaling, Dep. Cellular & Molecular Medicine, Campus Gasthuisberg O/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium.
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Makio T, Simmen T. Not So Rare: Diseases Based on Mutant Proteins Controlling Endoplasmic Reticulum-Mitochondria Contact (MERC) Tethering. CONTACT (THOUSAND OAKS (VENTURA COUNTY, CALIF.)) 2024; 7:25152564241261228. [PMID: 39070058 PMCID: PMC11273598 DOI: 10.1177/25152564241261228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 04/12/2024] [Accepted: 05/27/2024] [Indexed: 07/30/2024]
Abstract
Mitochondria-endoplasmic reticulum contacts (MERCs), also called endoplasmic reticulum (ER)-mitochondria contact sites (ERMCS), are the membrane domains, where these two organelles exchange lipids, Ca2+ ions, and reactive oxygen species. This crosstalk is a major determinant of cell metabolism, since it allows the ER to control mitochondrial oxidative phosphorylation and the Krebs cycle, while conversely, it allows the mitochondria to provide sufficient ATP to control ER proteostasis. MERC metabolic signaling is under the control of tethers and a multitude of regulatory proteins. Many of these proteins have recently been discovered to give rise to rare diseases if their genes are mutated. Surprisingly, these diseases share important hallmarks and cause neurological defects, sometimes paired with, or replaced by skeletal muscle deficiency. Typical symptoms include developmental delay, intellectual disability, facial dysmorphism and ophthalmologic defects. Seizures, epilepsy, deafness, ataxia, or peripheral neuropathy can also occur upon mutation of a MERC protein. Given that most MERC tethers and regulatory proteins have secondary functions, some MERC protein-based diseases do not fit into this categorization. Typically, however, the proteins affected in those diseases have dominant functions unrelated to their roles in MERCs tethering or their regulation. We are discussing avenues to pharmacologically target genetic diseases leading to MERC defects, based on our novel insight that MERC defects lead to common characteristics in rare diseases. These shared characteristics of MERCs disorders raise the hope that they may allow for similar treatment options.
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Affiliation(s)
- Tadashi Makio
- Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
| | - Thomas Simmen
- Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada
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12
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Csordás G, Weaver D, Várnai P, Hajnóczky G. Supralinear Dependence of the IP 3 Receptor-to-Mitochondria Local Ca 2+ Transfer on the Endoplasmic Reticulum Ca 2+ Loading. CONTACT (THOUSAND OAKS (VENTURA COUNTY, CALIF.)) 2024; 7:25152564241229273. [PMID: 38362008 PMCID: PMC10868505 DOI: 10.1177/25152564241229273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/04/2022] [Revised: 12/31/2023] [Accepted: 01/12/2024] [Indexed: 02/17/2024]
Abstract
Calcium signal propagation from endoplasmic reticulum (ER) to mitochondria regulates a multitude of mitochondrial and cell functions, including oxidative ATP production and cell fate decisions. Ca2+ transfer is optimal at the ER-mitochondrial contacts, where inositol 1,4,5-trisphosphate (IP3) receptors (IP3R) can locally expose the mitochondrial Ca2+ uniporter (mtCU) to high [Ca2+] nanodomains. The Ca2+ loading state of the ER (Ca2 + ER) can vary broadly in physiological and pathological scenarios, however, the correlation between Ca2 + ER and the local Ca2+ transfer is unclear. Here, we studied IP3-induced Ca2+ transfer to mitochondria at different Ca2 + ER in intact and permeabilized RBL-2H3 cells via fluorescence measurements of cytoplasmic [Ca2+] ([Ca2+]c) and mitochondrial matrix [Ca2+] ([Ca2+]m). Preincubation of intact cells in high versus low extracellular [Ca2+] caused disproportionally greater increase in [Ca2+]m than [Ca2+]c responses to IP3-mobilizing agonist. Increasing Ca2 + ER by small Ca2+ boluses in suspensions of permeabilized cells supralinearly enhanced the mitochondrial Ca2+ uptake from IP3-induced Ca2+ release. The IP3-induced local [Ca2+] spikes exposing the mitochondrial surface measured using a genetically targeted sensor appeared to linearly correlate with Ca2 + ER, indicating that amplification happened in the mitochondria. Indeed, overexpression of an EF-hand deficient mutant of the mtCU gatekeeper MICU1 reduced the cooperativity of mitochondrial Ca2+ uptake. Interestingly, the IP3-induced [Ca2+]m signal plateaued at high Ca2 + ER, indicating activation of a matrix Ca2+ binding/chelating species. Mitochondria thus seem to maintain a "working [Ca2+]m range" via a low-affinity and high-capacity buffer species, and the ER loading steeply enhances the IP3R-linked [Ca2+]m signals in this working range.
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Affiliation(s)
- György Csordás
- MitoCare Center for Mitochondrial Imaging Research and Diagnostics, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - David Weaver
- MitoCare Center for Mitochondrial Imaging Research and Diagnostics, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Péter Várnai
- Department of Physiology, Semmelweis Medical University, Budapest, Hungary
| | - György Hajnóczky
- MitoCare Center for Mitochondrial Imaging Research and Diagnostics, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
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13
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Wu L, Chen J. Type 3 IP3 receptor: Its structure, functions, and related disease implications. Channels (Austin) 2023; 17:2267416. [PMID: 37818548 PMCID: PMC10569359 DOI: 10.1080/19336950.2023.2267416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 10/02/2023] [Indexed: 10/12/2023] Open
Abstract
Cell-fate decisions depend on the precise and strict regulation of multiple signaling molecules and transcription factors, especially intracellular Ca2+ homeostasis and dynamics. Type 3 inositol 1,4,5-triphosphate receptor (IP3R3) is an a tetrameric channel that can mediate the release of Ca2+ from the endoplasmic reticulum (ER) in response to extracellular stimuli. The gating of IP3R3 is regulated not only by ligands but also by other interacting proteins. To date, extensive research conducted on the basic structure of IP3R3, as well as its regulation by ligands and interacting proteins, has provided novel perspectives on its biological functions and pathogenic mechanisms. This review aims to discuss recent advancements in the study of IP3R3 and provides a comprehensive overview of the relevant literature pertaining to its structure, biological functions, and pathogenic mechanisms.
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Affiliation(s)
- Lvying Wu
- Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
| | - Jin Chen
- Institute of Clinical Medicine, The Second Affiliated Hospital of Hainan Medical University, Haikou, China
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14
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Rönkkö J, Rodriguez Y, Rasila T, Torregrosa-Muñumer R, Pennonen J, Kvist J, Kuuluvainen E, Bosch LVD, Hietakangas V, Bultynck G, Tyynismaa H, Ylikallio E. Human IP 3 receptor triple knockout stem cells remain pluripotent despite altered mitochondrial metabolism. Cell Calcium 2023; 114:102782. [PMID: 37481871 DOI: 10.1016/j.ceca.2023.102782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Revised: 06/14/2023] [Accepted: 07/13/2023] [Indexed: 07/25/2023]
Abstract
Inositol 1,4,5-trisphosphate receptors (IP3Rs) are ER Ca2+-release channels that control a broad set of cellular processes. Animal models lacking IP3Rs in different combinations display severe developmental phenotypes. Given the importance of IP3Rs in human diseases, we investigated their role in human induced pluripotent stem cells (hiPSC) by developing single IP3R and triple IP3R knockouts (TKO). Genome edited TKO-hiPSC lacking all three IP3R isoforms, IP3R1, IP3R2, IP3R3, failed to generate Ca2+ signals in response to agonists activating GPCRs, but retained stemness and pluripotency. Steady state metabolite profiling and flux analysis of TKO-hiPSC indicated distinct alterations in tricarboxylic acid cycle metabolites consistent with a deficiency in their pyruvate utilization via pyruvate dehydrogenase, shifting towards pyruvate carboxylase pathway. These results demonstrate that IP3Rs are not essential for hiPSC identity and pluripotency but regulate mitochondrial metabolism. This set of knockout hiPSC is a valuable resource for investigating IP3Rs in human cell types of interest.
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Affiliation(s)
- Julius Rönkkö
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland
| | - Yago Rodriguez
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland
| | - Tiina Rasila
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland
| | - Rubén Torregrosa-Muñumer
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland
| | - Jana Pennonen
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland
| | - Jouni Kvist
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland
| | - Emilia Kuuluvainen
- Molecular and Integrative Bioscience Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, 00790, Finland; Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, 00790, Finland
| | - Ludo Van Den Bosch
- Department of Neurosciences, Experimental Neurology and Leuven Brain Institute, KU Leuven - University of Leuven, 3000, Leuven, Belgium; VIB Center for Brain & Disease Research, Laboratory of Neurobiology, 3000, Leuven, Belgium
| | - Ville Hietakangas
- Molecular and Integrative Bioscience Research Programme, Faculty of Biological and Environmental Sciences, University of Helsinki, Helsinki, 00790, Finland; Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, 00790, Finland
| | - Geert Bultynck
- KU Leuven, Laboratory of Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, Leuven, 3000, Belgium
| | - Henna Tyynismaa
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland
| | - Emil Ylikallio
- Stem Cells and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, 00290, Finland; Clinical Neurosciences, Neurology, University of Helsinki and Helsinki University Hospital, Helsinki, 00290, Finland.
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15
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Meng M, Jiang Y, Wang Y, Huo R, Ma N, Shen X, Chang G. β-carotene targets IP3R/GRP75/VDAC1-MCU axis to renovate LPS-induced mitochondrial oxidative damage by regulating STIM1. Free Radic Biol Med 2023; 205:25-46. [PMID: 37270031 DOI: 10.1016/j.freeradbiomed.2023.05.021] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 05/03/2023] [Accepted: 05/18/2023] [Indexed: 06/05/2023]
Abstract
Endoplasmic reticulum (ER) and mitochondria are the main sites for the storage and regulation of Ca2+ homeostasis. An imbalance of Ca2+ homeostasis can cause ER stress and mitochondrial dysfunction, thereby inducing apoptosis. The store-operated calcium entry (SOCE) is the main channel for extracellular calcium influx. Mitochondria-associated endoplasmic reticulum (MAM) is an important agent for Ca2+ transfer from the ER to the mitochondria. Therefore, regulation of SOCE and MAMs has potential therapeutic value for disease prevention and treatment. In this study, bovine mammary epithelial cells (BMECs) and mice were used as models to explore the mechanisms of β-carotene to relieve ER stress and mitochondrial dysfunction. BAPTA-AM, EGTA (Ca2+ inhibitor), and BTP2 (SOCE channel inhibitor) alleviated ER stress and mitochondrial oxidative damage induced by increased intracellular Ca2+ levels after lipopolysaccharide (LPS) stimulation. Furthermore, inhibition of ER stress by 4-PBA (ER stress inhibitor), 2-APB (IP3R inhibitor), and ruthenium red (mitochondrial calcium uniporter (MCU) inhibitor) restored mitochondrial function by reducing mitochondrial ROS. Our data also confirm that β-carotene targeted STIM1 and IP3R channels to repair LPS-induced ER stress and mitochondrial disorders. Consistent with the in vitro study, in vito experiments in mice further showed that β-carotene attenuated LPS-induced ER stress and mitochondrial oxidative damage by inhibiting the expression of STIM1 and ORAI1, and reducing the level of Ca2+ in mouse mammary glands. Therefore, ER stress-mitochondrial oxidative damage mediated by the STIM1-ER-IP3R/GRP75/VDAC1-MCU axis plays an vital role in the development of mastitis. Our results provided novel ideas and therapeutic targets for the prevention and treatment of mastitis.
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Affiliation(s)
- Meijuan Meng
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, PR China
| | - Yijin Jiang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, PR China
| | - Yan Wang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, PR China
| | - Ran Huo
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, PR China
| | - Nana Ma
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, PR China
| | - Xiangzhen Shen
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, PR China
| | - Guangjun Chang
- College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, Jiangsu, PR China.
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16
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Yang Y, Shan S, Huang Z, Wang S, Liu Z, Yong H, Liu Z, Zhang C, Song F. Increased IP3R-3 degradation induced by acrylamide promoted Ca 2+-dependent calpain activation and axon damage in rats. Toxicol Lett 2023:S0378-4274(23)00203-5. [PMID: 37353096 DOI: 10.1016/j.toxlet.2023.06.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 04/23/2023] [Accepted: 06/10/2023] [Indexed: 06/25/2023]
Abstract
Occupational and environmental exposure to acrylamide (ACR) can cause selective peripheral and central nerve fiber degeneration. IP3R-3 is an important transmembrane Ca2+ channel on the endoplasmic reticulum (ER), previous studies have found that ACR could induce Ca2+-dependent calpain activation and axon injury, but the exact role of IP3R-3 in ACR neuropathy is still unclear. Here we show that ACR exposure (40mg/kg) markedly increased the ubiquitination of IP3R-3 in rat spinal cords, and promoted the degradation of IP3R-3 through the ubiquitin-proteasome pathway. Furthermore, the normal structure of ER, especially the mitochondrial associated membranes (MAMs) component, was significantly impaired in ACR neuropathy, and the ER stress pathway was activated, which indicated that the aberrant increase of cytoplasmic Ca2+ could be attributed the destruction of IP3R-3. Further investigation demonstrated that the proteasome inhibitor MG-132 effectively rescued the IP3R-3 loss, attenuated the intracellular Ca2+ increase, and reduced the axon loss of Neuron 2a (N2a) cells following ACR exposure. Moreover, the calpain inhibitor ALLN also reduced the loss of IP3R-3 and axon injury in N2a cells, but did not alleviate the Ca2+ increase in cytosol, supporting that the abnormal ubiquitination of IP3R-3 was the upstream of the cellular Ca2+ rise and axon damage in ACR neuropathy. Taken together, our results suggested that the aberrant IP3R-3 degradation played an important role in the disturbance of Ca2+ homeostasis and the downstream axon loss in ACR neuropathy, thus providing a potential therapeutic target for ACR neurotoxicity.
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Affiliation(s)
- Yiyu Yang
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Shulin Shan
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Zhengcheng Huang
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Shuai Wang
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Zhaoxiong Liu
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Hui Yong
- Qingdao Municipal Center for Disease Control and Prevention, Qingdao, Shandong, 266000, China
| | - Zhidan Liu
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Cuiqin Zhang
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China; School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Fuyong Song
- Department of Toxicology and Nutrition, School of Public Health, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
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17
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Groenendyk J, Michalak M. Interplay between calcium and endoplasmic reticulum stress. Cell Calcium 2023; 113:102753. [PMID: 37209448 DOI: 10.1016/j.ceca.2023.102753] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/05/2023] [Accepted: 05/06/2023] [Indexed: 05/22/2023]
Abstract
Cellular homeostasis is crucial for the healthy functioning of the organism. Disruption of cellular homeostasis activates endoplasmic reticulum (ER) stress coping responses including the unfolded protein response (UPR). There are three ER resident stress sensors responsible for UPR activation - IRE1α, PERK and ATF6. Ca2+ signaling plays an important role in stress responses including the UPR and the ER is the main Ca2+ storage organelle and a source of Ca2+ for cell signaling. The ER contains many proteins involved in Ca2+ import/export/ storage, Ca2+ movement between different cellular organelles and ER Ca2+ stores refilling. Here we focus on selected aspects of ER Ca2+ homeostasis and its role in activation of the ER stress coping responses.
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Affiliation(s)
- Jody Groenendyk
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
| | - Marek Michalak
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
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18
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de Ridder I, Kerkhofs M, Lemos FO, Loncke J, Bultynck G, Parys JB. The ER-mitochondria interface, where Ca 2+ and cell death meet. Cell Calcium 2023; 112:102743. [PMID: 37126911 DOI: 10.1016/j.ceca.2023.102743] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 04/20/2023] [Accepted: 04/24/2023] [Indexed: 05/03/2023]
Abstract
Endoplasmic reticulum (ER)-mitochondria contact sites are crucial to allow Ca2+ flux between them and a plethora of proteins participate in tethering both organelles together. Inositol 1,4,5-trisphosphate receptors (IP3Rs) play a pivotal role at such contact sites, participating in both ER-mitochondria tethering and as Ca2+-transport system that delivers Ca2+ from the ER towards mitochondria. At the ER-mitochondria contact sites, the IP3Rs function as a multi-protein complex linked to the voltage-dependent anion channel 1 (VDAC1) in the outer mitochondrial membrane, via the chaperone glucose-regulated protein 75 (GRP75). This IP3R-GRP75-VDAC1 complex supports the efficient transfer of Ca2+ from the ER into the mitochondrial intermembrane space, from which the Ca2+ ions can reach the mitochondrial matrix through the mitochondrial calcium uniporter. Under physiological conditions, basal Ca2+ oscillations deliver Ca2+ to the mitochondrial matrix, thereby stimulating mitochondrial oxidative metabolism. However, when mitochondrial Ca2+ overload occurs, the increase in [Ca2+] will induce the opening of the mitochondrial permeability transition pore, thereby provoking cell death. The IP3R-GRP75-VDAC1 complex forms a hub for several other proteins that stabilize the complex and/or regulate the complex's ability to channel Ca2+ into the mitochondria. These proteins and their mechanisms of action are discussed in the present review with special attention for their role in pathological conditions and potential implication for therapeutic strategies.
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Affiliation(s)
- Ian de Ridder
- KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, Leuven BE-3000, Belgium
| | - Martijn Kerkhofs
- KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, Leuven BE-3000, Belgium
| | - Fernanda O Lemos
- KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, Leuven BE-3000, Belgium
| | - Jens Loncke
- KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, Leuven BE-3000, Belgium
| | - Geert Bultynck
- KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, Leuven BE-3000, Belgium.
| | - Jan B Parys
- KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine & Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, Leuven BE-3000, Belgium.
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19
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Bernal AF, Mota N, Pamplona R, Area-Gomez E, Portero-Otin M. Hakuna MAM-Tata: Investigating the role of mitochondrial-associated membranes in ALS. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166716. [PMID: 37044239 DOI: 10.1016/j.bbadis.2023.166716] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 04/03/2023] [Indexed: 04/14/2023]
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease leading to selective and progressive motor neuron (MN) death. Despite significant heterogeneity in pathogenic and clinical terms, MN demise ultimately unifies patients. Across the many disturbances in neuronal biology present in the disease and its models, two common trends are loss of calcium homeostasis and dysregulations in lipid metabolism. Since both mitochondria and endoplasmic reticulum (ER) are essential in these functions, their intertwin through the so-called mitochondrial-associated membranes (MAMs) should be relevant in this disease. In this review, we present a short overview of MAMs functional aspects and how its dysfunction could explain a substantial part of the cellular disarrangements in ALS's natural history. MAMs are hubs for lipid synthesis, integrating glycerophospholipids, sphingolipids, and cholesteryl ester metabolism. These lipids are essential for membrane biology, so there should be a close coupling to cellular energy demands, a role that MAMs may partially fulfill. Not surprisingly, MAMs are also host part of calcium signaling to mitochondria, so their impairment could lead to mitochondrial dysfunction, affecting oxidative phosphorylation and enhancing the vulnerability of MNs. We present data supporting that MAMs' maladaptation could be essential to MNs' vulnerability in ALS.
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Affiliation(s)
- Anna Fernàndez Bernal
- Metabolic Pathophysiology Research Group, Department of Experimental Medicine, University of Lleida-IRBLleida, Edifici Biomedicina I, Avda Rovira Roure 80, E25196 Lleida, Spain.
| | - Natàlia Mota
- Metabolic Pathophysiology Research Group, Department of Experimental Medicine, University of Lleida-IRBLleida, Edifici Biomedicina I, Avda Rovira Roure 80, E25196 Lleida, Spain.
| | - Reinald Pamplona
- Metabolic Pathophysiology Research Group, Department of Experimental Medicine, University of Lleida-IRBLleida, Edifici Biomedicina I, Avda Rovira Roure 80, E25196 Lleida, Spain.
| | - Estela Area-Gomez
- Centro de Investigaciones Biológicas Margarita Salas CSIC, C. Ramiro de Maeztu, 9, 28040 Madrid, Spain.
| | - Manuel Portero-Otin
- Metabolic Pathophysiology Research Group, Department of Experimental Medicine, University of Lleida-IRBLleida, Edifici Biomedicina I, Avda Rovira Roure 80, E25196 Lleida, Spain.
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20
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Ma Y, Du C, Xie X, Zhang Y, Wang C, Xu J, Xia G, Yang Y. To explore the regulatory role of Wnt/P53/Caspase3 signal in mouse ovarian development based on LFQ proteomics. J Proteomics 2023; 272:104772. [PMID: 36414229 DOI: 10.1016/j.jprot.2022.104772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 10/31/2022] [Accepted: 11/08/2022] [Indexed: 11/21/2022]
Abstract
Early ovarian follicular development is regulated by multiple proteins and signaling pathways, including the Wnt gene. To explore the regulatory mechanism of Wnt signaling on early ovarian follicular development, ovaries from 17.5 days post coitum (17.5 dpc) mice were collected and cultured in vitro for four days in the presence of IWP2 as a Wnt activity inhibitor and KN93 as a CaMKII inhibitor. LFQ proteomics technique was then used to analyze the significant differentially abundant (P-SDA) 93 and 262 proteins in the IWP2 and KN93 groups, respectively. Of these, 63 up-regulated proteins and 30 down-regulated proteins were identified for IWP2, along with 3 significant KEGG pathways (P < 0.05). For the KN93 group, 168 up-regulated proteins and 94 down-regulated ones were P-SDA, with 9 significant KEGG pathways also noted (P < 0.05). In both IWP2 and KN93 groups, key pathways (Wnt signaling pathway, Notch signaling pathway, P53 signaling pathway, TGF-β signaling pathway, ovarian steroid production) and metabolic regulation (energy metabolism, metal ion metabolism) were found to be related to early ovarian follicular development. Finally, western blotting demonstrated the regulatory role of Wnt/P53/Caspase3 signaling pathway in mouse ovarian development. These results contribute new knowledge to the understanding of regulatory factors of early ovarian follicular development. SIGNIFICANCE: In this study, label-free quantification (LFQ) was used in combination with liquid chromatography-mass spectrometer (LC-MS/MS) to study potential changes in the proteomic profiles of embryonic mice subjected to Wnt inhibitor IWP2 and CaMKIIinhibitor KN93. In addition, bioinformatics and comparative analyses were performed using publicly available proteomics databases to further explore the underlying mechanisms associated with early mouse ovarian growth and development.
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Affiliation(s)
- Yabo Ma
- Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan, Ningxia 750021, China; School of Life Sciences, Ningxia University, Yinchuan, Ningxia 750021, China
| | - Changzheng Du
- Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan, Ningxia 750021, China; School of Life Sciences, Ningxia University, Yinchuan, Ningxia 750021, China
| | - Xianguo Xie
- Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan, Ningxia 750021, China; School of Life Sciences, Ningxia University, Yinchuan, Ningxia 750021, China
| | - Yan Zhang
- Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan, Ningxia 750021, China; School of Life Sciences, Ningxia University, Yinchuan, Ningxia 750021, China
| | - Chao Wang
- Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan, Ningxia 750021, China; School of Life Sciences, Ningxia University, Yinchuan, Ningxia 750021, China; State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Jinrui Xu
- Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan, Ningxia 750021, China; School of Life Sciences, Ningxia University, Yinchuan, Ningxia 750021, China
| | - Guoliang Xia
- Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan, Ningxia 750021, China; School of Life Sciences, Ningxia University, Yinchuan, Ningxia 750021, China; State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing, China
| | - Yi Yang
- Key Laboratory of Ministry of Education for Conservation and Utilization of Special Biological Resources in the Western, Ningxia University, Yinchuan, Ningxia 750021, China; School of Life Sciences, Ningxia University, Yinchuan, Ningxia 750021, China.
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21
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Bushra, Maha IF, Xie X, Yin F. Integration of transcriptomic and metabolomic profiling of encystation in Cryptocaryon irritans regulated by rapamycin. Vet Parasitol 2023; 314:109868. [PMID: 36603452 DOI: 10.1016/j.vetpar.2022.109868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Revised: 12/20/2022] [Accepted: 12/21/2022] [Indexed: 12/24/2022]
Abstract
Encystation in Cryptocaryon irritans is a fundamental process for environmental resistance and development. Autophagy participates in the encystation of ciliates, and rapamycin can induce autophagy in the cells. A set of genes and metabolites related to autophagy and encystation are highly elaborative. The existence of these genes and metabolites and their role are well characterized. However, little is known about their role in protozoans such as ciliates. The newly produced C. irritans protomonts were exposed to an optimal concentration of rapamycin (1400 nM), and the survival, encystation, microstructure/ultrastructure, transcriptomic and metabolomic profile in treated and control protomonts were investigated. The results showed that exposure of protomonts to rapamycin at 4 h significantly lowered the survival and encystation rates to 91.62 % and 98.44 % compared to the control group (100 %, p ≤ 0.05). Morphological alterations observed in light microscopy and transmission electron microscopy (TEM) demonstrated that the drug significantly changed cell symmetry by causing the formation of various autophagic vacuoles/vesicles. The transcriptome sequencing of rapamycin-treated protomont revealed that 2249 (1837 up-regulated and 977 down-regulated) differentially expressed genes (DEGs) were identified. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that 226 DEGs were successfully annotated in 21 pathways (p˂0.05), including most enriched pathways apoptosis and phagosome with 25 and 24 DEGs, respectively. Most unigenes were assigned to autophagy-related pathways; 24 DEGs were classified into phagosomes, and 15 DEGs were assigned to lysosome pathways. Cytoskeleton and cell progression-associated genes were down-regulated. Besides, cell death-inducing proteins were up-regulated. The metabolomic analysis revealed exposure to rapamycin treatment enhanced protomont metabolites, including L-Cysteine, which is related to autophagy. Rapamycin had influenced the gene and metabolites of protomont; activating autophagy with inhibition of mechanistic target of rapamycin, (mTOR). The process negatively influences protomont morphology, encystation, and survival. Further autophagy-related gene silencing can be investigated via genome sequencing of C. irritans to study encystation.
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Affiliation(s)
- Bushra
- School of Marine Sciences, Ningbo University, 818 Fenghua Road, Ningbo 315211, PR China; State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, 818 Fenghua Road, Ningbo 315211, PR China; Key Laboratory of Applied Marine Biotechnology, Ministry of Education, Ningbo University, 818 Fenghua Road, Ningbo 315211, PR China
| | - Ivon F Maha
- School of Marine Sciences, Ningbo University, 818 Fenghua Road, Ningbo 315211, PR China; State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, 818 Fenghua Road, Ningbo 315211, PR China; Key Laboratory of Applied Marine Biotechnology, Ministry of Education, Ningbo University, 818 Fenghua Road, Ningbo 315211, PR China
| | - Xiao Xie
- School of Marine Sciences, Ningbo University, 818 Fenghua Road, Ningbo 315211, PR China; State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, 818 Fenghua Road, Ningbo 315211, PR China; Key Laboratory of Applied Marine Biotechnology, Ministry of Education, Ningbo University, 818 Fenghua Road, Ningbo 315211, PR China.
| | - Fei Yin
- School of Marine Sciences, Ningbo University, 818 Fenghua Road, Ningbo 315211, PR China; State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, 818 Fenghua Road, Ningbo 315211, PR China; Key Laboratory of Applied Marine Biotechnology, Ministry of Education, Ningbo University, 818 Fenghua Road, Ningbo 315211, PR China.
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22
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Atakpa-Adaji P, Ivanova A. IP 3R at ER-Mitochondrial Contact Sites: Beyond the IP 3R-GRP75-VDAC1 Ca 2+ Funnel. CONTACT (THOUSAND OAKS (VENTURA COUNTY, CALIF.)) 2023; 6:25152564231181020. [PMID: 37426575 PMCID: PMC10328019 DOI: 10.1177/25152564231181020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 05/23/2023] [Indexed: 07/11/2023]
Abstract
Membrane contact sites (MCS) circumvent the topological constraints of functional coupling between different membrane-bound organelles by providing a means of communication and exchange of materials. One of the most characterised contact sites in the cell is that between the endoplasmic reticulum and the mitochondrial (ERMCS) whose function is to couple cellular Ca2+ homeostasis and mitochondrial function. Inositol 1,4,5-trisphosphate receptors (IP3Rs) on the ER, glucose-regulated protein 75 (GRP 75) and voltage-dependent anion channel 1 (VDAC1) on the outer mitochondrial membrane are the canonical component of the Ca2+ transfer unit at ERMCS. These are often reported to form a Ca2+ funnel that fuels the mitochondrial low-affinity Ca2+ uptake system. We assess the available evidence on the IP3R subtype selectivity at the ERMCS and consider if IP3Rs have other roles at the ERMCS beyond providing Ca2+. Growing evidence suggests that all three IP3R subtypes can localise and regulate Ca2+ signalling at ERMCS. Furthermore, IP3Rs may be structurally important for assembly of the ERMCS in addition to their role in providing Ca2+ at these sites. Evidence that various binding partners regulate the assembly and Ca2+ transfer at ERMCS populated by IP3R-GRP75-VDAC1, suggesting that cells have evolved mechanisms that stabilise these junctions forming a Ca2+ microdomain that is required to fuel mitochondrial Ca2+ uptake.
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Affiliation(s)
- Peace Atakpa-Adaji
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK
| | - Adelina Ivanova
- Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1PD, UK
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23
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Katona M, Bartók Á, Nichtova Z, Csordás G, Berezhnaya E, Weaver D, Ghosh A, Várnai P, Yule DI, Hajnóczky G. Capture at the ER-mitochondrial contacts licenses IP 3 receptors to stimulate local Ca 2+ transfer and oxidative metabolism. Nat Commun 2022; 13:6779. [PMID: 36351901 PMCID: PMC9646835 DOI: 10.1038/s41467-022-34365-8] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 10/24/2022] [Indexed: 11/10/2022] Open
Abstract
Endoplasmic reticulum-mitochondria contacts (ERMCs) are restructured in response to changes in cell state. While this restructuring has been implicated as a cause or consequence of pathology in numerous systems, the underlying molecular dynamics are poorly understood. Here, we show means to visualize the capture of motile IP3 receptors (IP3Rs) at ERMCs and document the immediate consequences for calcium signaling and metabolism. IP3Rs are of particular interest because their presence provides a scaffold for ERMCs that mediate local calcium signaling, and their function outside of ERMCs depends on their motility. Unexpectedly, in a cell model with little ERMC Ca2+ coupling, IP3Rs captured at mitochondria promptly mediate Ca2+ transfer, stimulating mitochondrial oxidative metabolism. The Ca2+ transfer does not require linkage with a pore-forming protein in the outer mitochondrial membrane. Thus, motile IP3Rs can traffic in and out of ERMCs, and, when 'parked', mediate calcium signal propagation to the mitochondria, creating a dynamic arrangement that supports local communication.
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Affiliation(s)
- Máté Katona
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Ádám Bartók
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Zuzana Nichtova
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - György Csordás
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Elena Berezhnaya
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - David Weaver
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Arijita Ghosh
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA
| | - Péter Várnai
- Department of Physiology, Semmelweis University, Budapest, Hungary
| | - David I Yule
- Department of Physiology and Pharmacology, University of Rochester, Rochester, NY, USA
| | - György Hajnóczky
- MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
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24
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Means RE, Katz SG. Balancing life and death: BCL-2 family members at diverse ER-mitochondrial contact sites. FEBS J 2022; 289:7075-7112. [PMID: 34668625 DOI: 10.1111/febs.16241] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 10/11/2021] [Accepted: 10/19/2021] [Indexed: 01/13/2023]
Abstract
The outer mitochondrial membrane is a busy place. One essential activity for cellular survival is the regulation of membrane integrity by the BCL-2 family of proteins. Another critical facet of the outer mitochondrial membrane is its close approximation with the endoplasmic reticulum. These mitochondrial-associated membranes (MAMs) occupy a significant fraction of the mitochondrial surface and serve as key signaling hubs for multiple cellular processes. Each of these pathways may be considered as forming their own specialized MAM subtype. Interestingly, like membrane permeabilization, most of these pathways play critical roles in regulating cellular survival and death. Recently, the pro-apoptotic BCL-2 family member BOK has been found within MAMs where it plays important roles in their structure and function. This has led to a greater appreciation that multiple BCL-2 family proteins, which are known to participate in numerous functions throughout the cell, also have roles within MAMs. In this review, we evaluate several MAM subsets, their role in cellular homeostasis, and the contribution of BCL-2 family members to their functions.
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Affiliation(s)
- Robert E Means
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Samuel G Katz
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
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25
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Rosa N, Speelman-Rooms F, Parys JB, Bultynck G. Modulation of Ca 2+ signaling by antiapoptotic Bcl-2 versus Bcl-xL: From molecular mechanisms to relevance for cancer cell survival. Biochim Biophys Acta Rev Cancer 2022; 1877:188791. [PMID: 36162541 DOI: 10.1016/j.bbcan.2022.188791] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Revised: 08/29/2022] [Accepted: 08/29/2022] [Indexed: 11/17/2022]
Abstract
Members of the Bcl-2-protein family are key controllers of apoptotic cell death. The family is divided into antiapoptotic (including Bcl-2 itself, Bcl-xL, Mcl-1, etc.) and proapoptotic members (Bax, Bak, Bim, Bim, Puma, Noxa, Bad, etc.). These proteins are well known for their canonical role in the mitochondria, where they control mitochondrial outer membrane permeabilization and subsequent apoptosis. However, several proteins are recognized as modulators of intracellular Ca2+ signals that originate from the endoplasmic reticulum (ER), the major intracellular Ca2+-storage organelle. More than 25 years ago, Bcl-2, the founding member of the family, was reported to control apoptosis through Ca2+ signaling. Further work elucidated that Bcl-2 directly targets and inhibits inositol 1,4,5-trisphosphate receptors (IP3Rs), thereby suppressing proapoptotic Ca2+ signaling. In addition to Bcl-2, Bcl-xL was also shown to impact cell survival by sensitizing IP3R function, thereby promoting prosurvival oscillatory Ca2+ release. However, new work challenges this model and demonstrates that Bcl-2 and Bcl-xL can both function as inhibitors of IP3Rs. This suggests that, depending on the cell context, Bcl-xL could support very distinct Ca2+ patterns. This not only raises several questions but also opens new possibilities for the treatment of Bcl-xL-dependent cancers. In this review, we will discuss the similarities and divergences between Bcl-2 and Bcl-xL regarding Ca2+ homeostasis and IP3R modulation from both a molecular and a functional point of view, with particular emphasis on cancer cell death resistance mechanisms.
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Affiliation(s)
- Nicolas Rosa
- KU Leuven, Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, Campus Gasthuisberg O/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium
| | - Femke Speelman-Rooms
- KU Leuven, Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, Campus Gasthuisberg O/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium
| | - Jan B Parys
- KU Leuven, Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, Campus Gasthuisberg O/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium
| | - Geert Bultynck
- KU Leuven, Laboratory of Molecular & Cellular Signaling, Department of Cellular & Molecular Medicine, Campus Gasthuisberg O/N-I bus 802, Herestraat 49, BE-3000 Leuven, Belgium.
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26
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Sassano ML, Felipe-Abrio B, Agostinis P. ER-mitochondria contact sites; a multifaceted factory for Ca 2+ signaling and lipid transport. Front Cell Dev Biol 2022; 10:988014. [PMID: 36158205 PMCID: PMC9494157 DOI: 10.3389/fcell.2022.988014] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 07/22/2022] [Indexed: 11/13/2022] Open
Abstract
Membrane contact sites (MCS) between organelles of eukaryotic cells provide structural integrity and promote organelle homeostasis by facilitating intracellular signaling, exchange of ions, metabolites and lipids and membrane dynamics. Cataloguing MCS revolutionized our understanding of the structural organization of a eukaryotic cell, but the functional role of MSCs and their role in complex diseases, such as cancer, are only gradually emerging. In particular, the endoplasmic reticulum (ER)-mitochondria contacts (EMCS) are key effectors of non-vesicular lipid trafficking, thereby regulating the lipid composition of cellular membranes and organelles, their physiological functions and lipid-mediated signaling pathways both in physiological and diseased conditions. In this short review, we discuss key aspects of the functional complexity of EMCS in mammalian cells, with particular emphasis on their role as central hubs for lipid transport between these organelles and how perturbations of these pathways may favor key traits of cancer cells.
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Affiliation(s)
- Maria Livia Sassano
- Cell Death Research and Therapy Group, Department of Cellular and Molecular Medicine, Leuven, Belgium
- VIB Center for Cancer Biology, Leuven, Belgium
| | - Blanca Felipe-Abrio
- Cell Death Research and Therapy Group, Department of Cellular and Molecular Medicine, Leuven, Belgium
- VIB Center for Cancer Biology, Leuven, Belgium
| | - Patrizia Agostinis
- Cell Death Research and Therapy Group, Department of Cellular and Molecular Medicine, Leuven, Belgium
- VIB Center for Cancer Biology, Leuven, Belgium
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27
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Li ZC, Wang LL, Zhao YS, Peng DJ, Chen J, Jiang SY, Zhao L, Aschner M, Li SJ, Jiang YM. Sodium para-aminosalicylic acid ameliorates lead-induced hippocampal neuronal apoptosis by suppressing the activation of the IP 3R-Ca 2+-ASK1-p38 signaling pathway. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 241:113829. [PMID: 36068756 PMCID: PMC9452829 DOI: 10.1016/j.ecoenv.2022.113829] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 06/25/2022] [Accepted: 06/27/2022] [Indexed: 05/10/2023]
Abstract
Lead (Pb) is a naturally occurring heavy metal, which can damage the brain and affect learning and memory. Sodium para-aminosalicylic acid (PAS-Na), a non-steroidal anti-inflammatory drug, can readily cross the blood-brain barrier. Our previous studies have found that PAS-Na alleviated Pb-induced hippocampal ultrastructural damage and neurodegeneration, but the mechanism has yet to be defined. Here, we investigated the molecular mechanisms that mediate Pb-induced apoptosis in hippocampal neurons, and the efficacy of PAS-Na in alleviating its effects. This work showed that juvenile developmental Pb exposure impaired rats cognitive ability by inducing apoptotic cell death in hippocampal neurons. Pb-induced neuronal apoptosis was accompanied by increased inositol 1,4,5-trisphosphate receptor (IP3R) expression and enhanced intracellular calcium [Ca2+]i levels, which resulted in increased phosphorylation of neuronal apoptosis signal-regulating kinase 1 (ASK1) and p38. Activation of ASK1 and p38 was blocked by IP3R inhibitor and a Ca2+ chelator. Importantly, PAS-Na treatment improved the Pb-induced effects on cognitive deficits in rats, concomitant with rescued neuronal apoptosis. In addition, PAS-Na reduced the expression of IP3R and the ensuing increase in intracellular Ca2+ and decreased the phosphorylation of ASK1 and p38 in Pb-exposed neurons. Taken together, this study demonstrates that the IP3R-Ca2+-ASK1-p38 signaling pathway mediates Pb-induced apoptosis in hippocampal neurons, and that PAS-Na, at a specific dose-range, ameliorates these changes. Collectively, this study sheds novel light on the cellular mechanisms that mediate PAS-Na efficacy, laying the groundwork for future research to examine the treatment potential of PAS-Na upon Pb poisoning.
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Affiliation(s)
- Zhao-Cong Li
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, China
| | - Lei-Lei Wang
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, China
| | - Yue-Song Zhao
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, China
| | - Dong-Jie Peng
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, China
| | - Jing Chen
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, China
| | - Si-Yang Jiang
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, China
| | - Lin Zhao
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, China
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
| | - Shao-Jun Li
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, China.
| | - Yue-Ming Jiang
- Department of Toxicology, School of Public Health, Guangxi Medical University, Nanning 530021, China; Guangxi Colleges and Universities Key Laboratory of Prevention and Control of Highly Prevalent Diseases, Guangxi Medical University, Nanning, China.
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28
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Paschou M, Papazafiri P, Charalampous C, Zachariadis M, Dedos SG, Doxakis E. Neuronal microRNAs safeguard ER Ca 2+ homeostasis and attenuate the unfolded protein response upon stress. Cell Mol Life Sci 2022; 79:373. [PMID: 35727337 PMCID: PMC11073139 DOI: 10.1007/s00018-022-04398-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 04/23/2022] [Accepted: 05/21/2022] [Indexed: 11/30/2022]
Abstract
Ca2+ is a critical mediator of neurotransmitter release, synaptic plasticity, and gene expression, but also excitotoxicity. Ca2+ signaling and homeostasis are coordinated by an intricate network of channels, pumps, and calcium-binding proteins, which must be rapidly regulated at all expression levels. Τhe role of neuronal miRNAs in regulating ryanodine receptors (RyRs) and inositol 1,4,5-triphosphate receptors (IP3Rs) was investigated to understand the underlying mechanisms that modulate ER Ca2+ release. RyRs and IP3Rs are critical in mounting and propagating cytosolic Ca2+ signals by functionally linking the ER Ca2+ content, while excessive ER Ca2+ release via these receptors is central to the pathophysiology of a wide range of neurological diseases. Herein, two brain-restricted microRNAs, miR-124-3p and miR-153-3p, were found to bind to RyR1-3 and IP3R3 3'UTRs, and suppress their expression at both the mRNA and protein level. Ca2+ imaging studies revealed that overexpression of these miRNAs reduced ER Ca2+ release upon RyR/IP3R activation, but had no effect on [Ca2+]i under resting conditions. Interestingly, treatments that cause excessive ER Ca2+ release decreased expression of these miRNAs and increased expression of their target ER Ca2+ channels, indicating interdependence of miRNAs, RyRs, and IP3Rs in Ca2+ homeostasis. Furthermore, by maintaining the ER Ca2+ content, miR-124 and miR-153 reduced cytosolic Ca2+ overload and preserved protein-folding capacity by attenuating PERK signaling. Overall, this study shows that miR-124-3p and miR-153-3p fine-tune ER Ca2+ homeostasis and alleviate ER stress responses.
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Affiliation(s)
- Maria Paschou
- Center for Basic Research, Biomedical Research Foundation, Academy of Athens (BRFAA), Soranou Efesiou 4, 11527, Athens, Greece
- Department of Biology, National and Kapodistrian University of Athens (NKUA), Panepistimiopolis, 15784, Athens, Greece
| | - Panagiota Papazafiri
- Department of Biology, National and Kapodistrian University of Athens (NKUA), Panepistimiopolis, 15784, Athens, Greece
| | - Chrysanthi Charalampous
- Center for Basic Research, Biomedical Research Foundation, Academy of Athens (BRFAA), Soranou Efesiou 4, 11527, Athens, Greece
| | - Michael Zachariadis
- Department of Biology, National and Kapodistrian University of Athens (NKUA), Panepistimiopolis, 15784, Athens, Greece
- Material and Chemical Characterization Facility (MC2), Faculty of Science, University of Bath, Claverton Down, Bath, BA2 7AY, UK
| | - Skarlatos G Dedos
- Department of Biology, National and Kapodistrian University of Athens (NKUA), Panepistimiopolis, 15784, Athens, Greece.
| | - Epaminondas Doxakis
- Center for Basic Research, Biomedical Research Foundation, Academy of Athens (BRFAA), Soranou Efesiou 4, 11527, Athens, Greece.
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29
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Badr H, Blutrich R, Chan K, Tong J, Taylor P, Zhang W, Kafri R, Röst HL, Tsao MS, Moran MF. Proteomic characterization of a candidate polygenic driver of metabolism in non-small cell lung cancer. J Mol Biol 2022; 434:167636. [PMID: 35595168 DOI: 10.1016/j.jmb.2022.167636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 05/03/2022] [Accepted: 05/08/2022] [Indexed: 11/18/2022]
Abstract
Proteome analysis revealed signatures of co-expressed upregulated metabolism proteins highly conserved between primary and non-small cell lung cancer (NSCLC) patient-derived xenograft tumors (Li et al. 2014, Nat. Communications 5:5469). The C10 signature is encoded by seven genes (ADSS, ATP2A2, CTPS1, IMPDH2, PKM2, PTGES3, SGPL1) and DNA alterations in C10-encoding genes are associated with longer survival in a subset of NSCLC. To explore the C10 signature as an oncogenic driver and address potential mechanisms of action, C10 protein expression and protein-protein interactions were determined. In independent NSCLC cohorts, the coordinated expression of C10 proteins was significant and mutations in C10 genes were associated with better outcome. Affinity purification-mass spectrometry and in vivo proximity-based biotin identification defined a C10 interactome involving 667 proteins including candidate drug targets and clusters associated with glycolysis, calcium homeostasis, and nucleotide and sphingolipid metabolism. DNA alterations in genes encoding C10 interactome components were also found to be associated with better survival. These data support the notion that the coordinated upregulation of the C10 signature impinges metabolic processes that collectively function as an oncogenic driver in NSCLC.
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Affiliation(s)
- Heba Badr
- Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Ron Blutrich
- Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Kaitlin Chan
- Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Jiefei Tong
- Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Paul Taylor
- Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; SPARC BioCentre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Wen Zhang
- Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Ran Kafri
- Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Hannes L Röst
- Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada; Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Ming-Sound Tsao
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Departments of Medical Biophysics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Michael F Moran
- Program in Cell Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E1, Canada; SPARC BioCentre, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada.
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30
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Huang DX, Yu X, Yu WJ, Zhang XM, Liu C, Liu HP, Sun Y, Jiang ZP. Calcium Signaling Regulated by Cellular Membrane Systems and Calcium Homeostasis Perturbed in Alzheimer’s Disease. Front Cell Dev Biol 2022; 10:834962. [PMID: 35281104 PMCID: PMC8913592 DOI: 10.3389/fcell.2022.834962] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/31/2022] [Indexed: 12/12/2022] Open
Abstract
Although anything that changes spatiotemporally could be a signal, cells, particularly neurons, precisely manipulate calcium ion (Ca2+) to transmit information. Ca2+ homeostasis is indispensable for neuronal functions and survival. The cytosolic Ca2+ concentration ([Ca2+]CYT) is regulated by channels, pumps, and exchangers on cellular membrane systems. Under physiological conditions, both endoplasmic reticulum (ER) and mitochondria function as intracellular Ca2+ buffers. Furthermore, efficient and effective Ca2+ flux is observed at the ER-mitochondria membrane contact site (ERMCS), an intracellular membrane juxtaposition, where Ca2+ is released from the ER followed by mitochondrial Ca2+ uptake in sequence. Hence, the ER intraluminal Ca2+ concentration ([Ca2+]ER), the mitochondrial matrix Ca2+ concentration ([Ca2+]MT), and the [Ca2+]CYT are related to each other. Ca2+ signaling dysregulation and Ca2+ dyshomeostasis are associated with Alzheimer’s disease (AD), an irreversible neurodegenerative disease. The present review summarizes the cellular and molecular mechanism underlying Ca2+ signaling regulation and Ca2+ homeostasis maintenance at ER and mitochondria levels, focusing on AD. Integrating the amyloid hypothesis and the calcium hypothesis of AD may further our understanding of pathogenesis in neurodegeneration, provide therapeutic targets for chronic neurodegenerative disease in the central nervous system.
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Affiliation(s)
- Dong-Xu Huang
- Department of Hand and Foot Surgery, The First Hospital of Jilin University, Changchun, China
| | - Xin Yu
- Department of Hand and Foot Surgery, The First Hospital of Jilin University, Changchun, China
| | - Wen-Jun Yu
- Department of Hand and Foot Surgery, The First Hospital of Jilin University, Changchun, China
| | - Xin-Min Zhang
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, China
| | - Chang Liu
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Hong-Ping Liu
- Department of Neurology, The First Hospital of Jilin University, Changchun, China
| | - Yue Sun
- Deparment of The First Operating Room, The First Hospital of Jilin University, Changchun, China
| | - Zi-Ping Jiang
- Department of Hand and Foot Surgery, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Zi-Ping Jiang,
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Wang Q, Chen W, Zhang B, Gao Z, Zhang Q, Deng H, Han L, Shen XL. Perfluorooctanoic acid induces hepatocellular endoplasmic reticulum stress and mitochondrial-mediated apoptosis in vitro via endoplasmic reticulum-mitochondria communication. Chem Biol Interact 2022; 354:109844. [PMID: 35123991 DOI: 10.1016/j.cbi.2022.109844] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 01/24/2022] [Accepted: 01/31/2022] [Indexed: 11/25/2022]
Abstract
Perfluorooctanoic acid (PFOA) is a persistent organic pollutant that is widely distributed in the natural environment. Cohort study showed that PFOA-producing workers displayed a significant increase for mortality of liver cancer and liver cirrhosis. However, the underlying mechanism of PFOA-induced hepatotoxicity is far from clear. In this research, cell viability, apoptosis rate, reactive oxygen species, mitochondrial membrane potential (ΔΨm), calcium ion levels, and protein expressions of human liver L02 cells in response to PFOA were determined. Results indicated that a 24 h-treatment with 64 and 256 μM PFOA could remarkably induce mitochondrial-mediated apoptosis via initiating the vicious cycle between endoplasmic reticulum stress and oxidative stress, thereby increasing the level of calcium ion and decreasing the level of ΔΨm, simultaneously elevating the protein expressions of Cyclophilin D (CYPD), Bcl-2 homologous antagonist/killer (Bak), Bcl-2-associated X protein (Bax), Bcl-2-like protein 11 (Bim), cytochrome C (Cyt-C), 78 kDa glucose-regulated protein (GRP78), CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), and thioredoxin-interacting protein (TXNIP), while inhibiting the protein expression of tumor necrosis factor receptor-associated protein 1 (TRAP1), Lon protease 1 (Lonp1), Pro-caspase-9, B-cell lymphoma-2 (Bcl-2), and Sigma 1-type opioid receptor (Sig-1R) (p < 0.05). To sum up, PFOA-induced hepatocellular endoplasmic reticulum stress and mitochondrial-mediated apoptosis in vitro was regulated by endoplasmic reticulum (ER)-mitochondria communication via mitochondria-associated ER membranes (MAMs).
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Affiliation(s)
- Qian Wang
- School of Public Health, Zunyi Medical University, Zunyi, 563000, Guizhou, PR China.
| | - Wenying Chen
- School of Public Health, Zunyi Medical University, Zunyi, 563000, Guizhou, PR China.
| | - Boyang Zhang
- Key Laboratory of Precision Nutrition and Food Quality, Department of Nutrition and Health, China Agricultural University, Beijing, 100083, PR China.
| | - Zilu Gao
- School of Public Health, Zunyi Medical University, Zunyi, 563000, Guizhou, PR China.
| | - Qipeng Zhang
- School of Public Health, Zunyi Medical University, Zunyi, 563000, Guizhou, PR China.
| | - Huiqiong Deng
- School of Public Health, Zunyi Medical University, Zunyi, 563000, Guizhou, PR China.
| | - Lingyun Han
- School of Public Health, Zunyi Medical University, Zunyi, 563000, Guizhou, PR China.
| | - Xiao Li Shen
- School of Public Health, Zunyi Medical University, Zunyi, 563000, Guizhou, PR China.
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32
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Sun M, Xie Z, Zhang J, Leng Y. Mechanistic insight into sevoflurane-associated developmental neurotoxicity. Cell Biol Toxicol 2022; 38:927-943. [PMID: 34766256 PMCID: PMC9750936 DOI: 10.1007/s10565-021-09677-y] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 10/21/2021] [Indexed: 02/06/2023]
Abstract
With the development of technology, more infants receive general anesthesia for surgery, other interventions, or clinical examination at an early stage after birth. However, whether general anesthetics can affect the function and structure of the developing infant brain remains an important, complex, and controversial issue. Sevoflurane is the most-used anesthetic in infants, but this drug is potentially neurotoxic. Short or single exposure to sevoflurane has a weak effect on cognitive function, while long or repeated exposure to general anesthetics may cause cognitive dysfunction. This review focuses on the mechanisms by which sevoflurane exposure during development may induce long-lasting undesirable effects on the brain. We review neural cell death, neural cell damage, impaired assembly and plasticity of neural circuits, tau phosphorylation, and neuroendocrine effects as important mechanisms for sevoflurane-induced developmental neurotoxicity. More advanced technologies and methods should be applied to determine the underlying mechanism(s) and guide prevention and treatment of sevoflurane-induced neurotoxicity. 1. We discuss the mechanisms underlying sevoflurane-induced developmental neurotoxicity from five perspectives: neural cell death, neural cell damage, assembly and plasticity of neural circuits, tau phosphorylation, and neuroendocrine effects.
2. Tau phosphorylation, IL-6, and mitochondrial dysfunction could interact with each other to cause a nerve damage loop.
3. miRNAs and lncRNAs are associated with sevoflurane-induced neurotoxicity.
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Affiliation(s)
- Mingyang Sun
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, Gansu People’s Republic of China 730000 ,Department of Anesthesiology and Perioperative Medicine, Center for Clinical Single Cell Biomedicine, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, Henan People’s Republic of China 450003
| | - Zhongcong Xie
- Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA USA
| | - Jiaqiang Zhang
- Department of Anesthesiology and Perioperative Medicine, Center for Clinical Single Cell Biomedicine, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, Zhengzhou, Henan People’s Republic of China 450003
| | - Yufang Leng
- Day Surgery Center, The First Hospital of Lanzhou University, Lanzhou, Gansu People’s Republic of China 730000
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Erustes AG, Guarache GC, Guedes EDC, Leão AHFF, Pereira GJDS, Smaili SS. α-Synuclein Interactions in Mitochondria-ER Contacts: A Possible Role in Parkinson's Disease. CONTACT (THOUSAND OAKS (VENTURA COUNTY, CALIF.)) 2022; 5:25152564221119347. [PMID: 37366506 PMCID: PMC10243560 DOI: 10.1177/25152564221119347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 06/28/2023]
Abstract
Endoplasmic reticulum-mitochondria contact sites regulate various biological processes, such as mitochondrial dynamics, calcium homeostasis, autophagy and lipid metabolism. Notably, dysfunctions in these contact sites are closely related to neurodegenerative diseases, including Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis. However, details about the role of endoplasmic reticulum-mitochondria contact sites in neurodegenerative diseases remain unknown. In Parkinson's disease, interactions between α-synuclein in the contact sites and components of tether complexes that connect organelles can lead to various dysfunctions, especially with regards to calcium homeostasis. This review will summarize the main tether complexes present in endoplasmic reticulum-mitochondria contact sites, and their roles in calcium homeostasis and trafficking. We will discuss the impact of α-synuclein accumulation, its interaction with tethering complex components and the implications in Parkinson's disease pathology.
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Affiliation(s)
- Adolfo Garcia Erustes
- Department of Pharmacology, Escola Paulista
de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Gabriel Cicolin Guarache
- Department of Pharmacology, Escola Paulista
de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Erika da Cruz Guedes
- Department of Pharmacology, Escola Paulista
de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | | | | | - Soraya Soubhi Smaili
- Department of Pharmacology, Escola Paulista
de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
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Dalwadi DA, Kim S, Schetz J, Schreihofer DA, Kim S. Brain-derived neurotrophic factor for high-throughput evaluation of selective Sigma-1 receptor ligands. J Pharmacol Toxicol Methods 2022; 113:107129. [PMID: 34678430 PMCID: PMC9358981 DOI: 10.1016/j.vascn.2021.107129] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 10/13/2021] [Accepted: 10/13/2021] [Indexed: 01/03/2023]
Abstract
The Sigma-1 receptor (S1R) is an endoplasmic reticulum (ER) chaperone protein that has been implicated in attenuating inflammatory stress-mediated brain injuries. Selective S1R agonists represent a new class of therapeutic agent for treating neuropsychiatric and neurodegenerative disorders, however, to date, no S1R ligand has been approved for therapeutic purposes. We used three potential methods on known and potential S1R ligands to develop an unambiguous high-throughput cell screen for S1R activity. We screened known and potential S1R ligands using radioligand binding and previously reported markers of S1R activity including BDNF release, modulation of IP3 mediated calcium release, and modulation of NGF-induced neurite sprouting. Here, we present results several prototypical S1R compounds and some compounds with the potential for drug repurposing. Using an in-situ ELISA approach we demonstrated that these compounds could stimulate S1R-mediated BDNF release, which is a valuable therapeutic property since BDNF plays a critical role in neuronal support. These compounds were classified as S1R agonists because the BDNF response was comparable to the prototypical agonist 4-PPBP and because it could be reversed by a S1R selective concentration of the antagonist BD1063. When modulation of IP3 mediated calcium response and NGF-induced neurite sprouting were used as a measure of S1R activation, we were unable to reproduce the published results and determined that they are not reliable measures for evaluating functional properties of S1R ligands.
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Affiliation(s)
- Dhwanil A Dalwadi
- Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; Department of Medicine, Division of Gastroenterology, Oregon Health Sciences University, Portland, OR 97239, USA
| | - Stephanie Kim
- Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; University of Texas Medical Branch at Galveston, School of Medicine, Galveston, TX 77555, USA
| | - John Schetz
- Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Derek A Schreihofer
- Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Seongcheol Kim
- Department of Pharmacology & Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA; Department of Cellular and Molecular Physiology, Loyola University Chicago Stritch School of Medicine, Maywood, IL 60153, USA.
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35
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Yu S, Gao L, Zhang C, Wang Y, Lan H, Chu Q, Li S, Zheng X. Glycine Ameliorates Endoplasmic Reticulum Stress Induced by Thapsigargin in Porcine Oocytes. Front Cell Dev Biol 2021; 9:733860. [PMID: 34917610 PMCID: PMC8670231 DOI: 10.3389/fcell.2021.733860] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 11/08/2021] [Indexed: 02/05/2023] Open
Abstract
The endoplasmic reticulum (ER) is a multifunctional organelle in the cytoplasm that plays important roles in female mammalian reproduction. The endoplasmic reticulum and mitochondria interact to maintain the normal function of cells by maintaining intracellular calcium homeostasis. As proven by previous research, glycine (Gly) can regulate the intracellular free calcium concentration ([Ca2+]i) and enhance mitochondrial function to improve oocyte maturation in vitro. The effect of Gly on ER function during oocyte in vitro maturation (IVM) is not clear. In this study, we induced an ER stress model with thapsigargin (TG) to explore whether Gly can reverse the ER stress induced by TG treatment and whether it is associated with calcium regulation. The results showed that the addition of Gly could improve the decrease in the average cumulus diameter, the first polar body excretion rate caused by TG-induced ER stress, the cleavage rate and the blastocyst rate. Gly supplementation could reduce the ER stress induced by TG by significantly improving the ER levels and significantly downregulating the expression of genes related to ER stress (Xbp1, ATF4, and ATF6). Moreover, Gly also significantly alleviated the increase in reactive oxygen species (ROS) levels and the decrease in mitochondrial membrane potential (ΔΨ m) to improve mitochondrial function in porcine oocytes exposed to TG. Furthermore, Gly reduced the [Ca2+]i and mitochondrial Ca2+ ([Ca2+]m) levels and restored the ER Ca2+ ([Ca2+]ER) levels in TG-exposed porcine oocytes. Moreover, we found that the increase in [Ca2+]i may be caused by changes in the distribution and expression of inositol 1,4,5-triphosphate receptor (IP3R1) and voltage-dependent anion channel 1 (VDAC1), while Gly can restore the distribution and expression of IP3R1 and VDAC1 to normal levels. Apoptosis-related indexes (Caspase 3 activity and Annexin-V) and gene expression Bax, Cyto C, and Caspase 3) were significantly increased in the TG group, but they could be restored by adding Gly. Our results suggest that Gly can ameliorate ER stress and apoptosis in TG-exposed porcine oocytes and can further enhance the developmental potential of porcine oocytes in vitro.
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Affiliation(s)
- Sicong Yu
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Lepeng Gao
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Chang Zhang
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Yumeng Wang
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Hainan Lan
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Qianran Chu
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Suo Li
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
| | - Xin Zheng
- College of Animal Science and Technology, Jilin Agricultural University, Changchun, China
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36
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Martens MD, Karch J, Gordon JW. The molecular mosaic of regulated cell death in the cardiovascular system. Biochim Biophys Acta Mol Basis Dis 2021; 1868:166297. [PMID: 34718119 DOI: 10.1016/j.bbadis.2021.166297] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 10/07/2021] [Accepted: 10/22/2021] [Indexed: 12/11/2022]
Abstract
Cell death is now understood to be a highly regulated process that contributes to normal development and tissue homeostasis, alongside its role in the etiology of various pathological conditions. Through detailed molecular analysis, we have come to know that all cells do not always die in the same way, and that there are at least 7 processes involved, including: apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, and autophagy-mediated cell death. These processes act as pieces in the mosaic of cardiomyocyte cell death, which come together depending on context and stimulus. This review details each individual process, as well as highlights how they come together to produce various cardiac pathologies. By knowing how the pieces go together we can aim towards the development of efficacious therapeutics, which will enable us to prevent cardiomyocyte loss in the face of stress, both reducing mortality and improving quality of life.
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Affiliation(s)
- Matthew D Martens
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Manitoba, Canada; The Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme of the Children's Hospital Research Institute of Manitoba, Canada
| | - Jason Karch
- Department of Molecular Physiology and Biophysics, Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, United States
| | - Joseph W Gordon
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Manitoba, Canada; College of Nursing, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Manitoba, Canada; The Diabetes Research Envisioned and Accomplished in Manitoba (DREAM) Theme of the Children's Hospital Research Institute of Manitoba, Canada.
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37
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Loncke J, Vervliet T, Parys JB, Kaasik A, Bultynck G. Uniting the divergent Wolfram syndrome-linked proteins WFS1 and CISD2 as modulators of Ca 2+ signaling. Sci Signal 2021; 14:eabc6165. [PMID: 34582248 DOI: 10.1126/scisignal.abc6165] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Jens Loncke
- KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, BE-3000 Leuven, Belgium
| | - Tim Vervliet
- KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, BE-3000 Leuven, Belgium
| | - Jan B Parys
- KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, BE-3000 Leuven, Belgium
| | - Allen Kaasik
- University of Tartu, Institute of Biomedicine and Translational Medicine, Department of Pharmacology, Tartu, Estonia
| | - Geert Bultynck
- KU Leuven, Laboratory for Molecular and Cellular Signaling, Department of Cellular and Molecular Medicine, Leuven Kanker Instituut, Campus Gasthuisberg O/N-1 B-802, Herestraat 49, BE-3000 Leuven, Belgium
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Xue Y, Morris JL, Yang K, Fu Z, Zhu X, Johnson F, Meehan B, Witkowski L, Yasmeen A, Golenar T, Coatham M, Morin G, Monast A, Pilon V, Fiset PO, Jung S, Gonzalez AV, Camilleri-Broet S, Fu L, Postovit LM, Spicer J, Gotlieb WH, Guiot MC, Rak J, Park M, Lockwood W, Foulkes WD, Prudent J, Huang S. SMARCA4/2 loss inhibits chemotherapy-induced apoptosis by restricting IP3R3-mediated Ca 2+ flux to mitochondria. Nat Commun 2021; 12:5404. [PMID: 34518526 PMCID: PMC8438089 DOI: 10.1038/s41467-021-25260-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 07/27/2021] [Indexed: 12/25/2022] Open
Abstract
Inactivating mutations in SMARCA4 and concurrent epigenetic silencing of SMARCA2 characterize subsets of ovarian and lung cancers. Concomitant loss of these key subunits of SWI/SNF chromatin remodeling complexes in both cancers is associated with chemotherapy resistance and poor prognosis. Here, we discover that SMARCA4/2 loss inhibits chemotherapy-induced apoptosis through disrupting intracellular organelle calcium ion (Ca2+) release in these cancers. By restricting chromatin accessibility to ITPR3, encoding Ca2+ channel IP3R3, SMARCA4/2 deficiency causes reduced IP3R3 expression leading to impaired Ca2+ transfer from the endoplasmic reticulum to mitochondria required for apoptosis induction. Reactivation of SMARCA2 by a histone deacetylase inhibitor rescues IP3R3 expression and enhances cisplatin response in SMARCA4/2-deficient cancer cells both in vitro and in vivo. Our findings elucidate the contribution of SMARCA4/2 to Ca2+-dependent apoptosis induction, which may be exploited to enhance chemotherapy response in SMARCA4/2-deficient cancers.
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Affiliation(s)
- Yibo Xue
- Department of Biochemistry, McGill University, Montreal, QC, Canada
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- Division of Medical Genetics, McGill University Health Centre, and Cancer Research Program, Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada
| | - Jordan L Morris
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK
| | - Kangning Yang
- Department of Biochemistry, McGill University, Montreal, QC, Canada
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
| | - Zheng Fu
- Department of Biochemistry, McGill University, Montreal, QC, Canada
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
| | - Xianbing Zhu
- Department of Biochemistry, McGill University, Montreal, QC, Canada
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
| | - Fraser Johnson
- Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada
- Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Brian Meehan
- Department of Pediatrics, Research Institute of the McGill University Health Centre, Montreal Children's Hospital, McGill University, Montreal, QC, Canada
| | - Leora Witkowski
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- Department of Specialized Medicine, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Amber Yasmeen
- Division of Gynecologic Oncology, Segal Cancer Center, Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Tunde Golenar
- Department of Biochemistry, McGill University, Montreal, QC, Canada
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
| | - Mackenzie Coatham
- Department of Oncology, Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, Canada
| | - Geneviève Morin
- Department of Biochemistry, McGill University, Montreal, QC, Canada
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
| | - Anie Monast
- Department of Biochemistry, McGill University, Montreal, QC, Canada
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
| | - Virginie Pilon
- Department of Biochemistry, McGill University, Montreal, QC, Canada
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
| | | | - Sungmi Jung
- Department of Pathology, McGill University Health Centre, Montreal, QC, Canada
| | - Anne V Gonzalez
- Department of Medicine, Division of Respiratory Medicine, McGill University Health Centre, Montreal Chest Institute, Montreal, QC, Canada
| | | | - Lili Fu
- Department of Pathology, McGill University Health Centre, Montreal, QC, Canada
| | - Lynne-Marie Postovit
- Department of Oncology, Department of Obstetrics and Gynecology, University of Alberta, Edmonton, AB, Canada
- Department of Biomedical and Molecular Sciences, Queen's University, Kingston, ON, Canada
| | - Jonathan Spicer
- Department of Surgery, McGill University Health Center, Montreal, QC, Canada
| | - Walter H Gotlieb
- Division of Gynecologic Oncology, Segal Cancer Center, Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Marie-Christine Guiot
- Department of Pathology, Montreal Neurological Hospital/Institute, McGill University Health Centre, Montreal, QC, Canada
| | - Janusz Rak
- Department of Pediatrics, Research Institute of the McGill University Health Centre, Montreal Children's Hospital, McGill University, Montreal, QC, Canada
| | - Morag Park
- Department of Biochemistry, McGill University, Montreal, QC, Canada
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada
| | - William Lockwood
- Department of Integrative Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada
- Interdisciplinary Oncology Program, University of British Columbia, Vancouver, BC, Canada
- Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada
| | - William D Foulkes
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- Division of Medical Genetics, McGill University Health Centre, and Cancer Research Program, Research Institute of the McGill University Health Centre, McGill University, Montreal, QC, Canada
- Department of Specialized Medicine, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada
| | - Julien Prudent
- Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK.
| | - Sidong Huang
- Department of Biochemistry, McGill University, Montreal, QC, Canada.
- Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, QC, Canada.
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Ca 2+ handling at the mitochondria-ER contact sites in neurodegeneration. Cell Calcium 2021; 98:102453. [PMID: 34399235 DOI: 10.1016/j.ceca.2021.102453] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/03/2021] [Accepted: 08/03/2021] [Indexed: 12/12/2022]
Abstract
Mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) are morpho-functional units, formed at the loci of close apposition of the ER-forming endomembrane and outer mitochondrial membrane (OMM). These sites contribute to fundamental cellular processes including lipid biosynthesis, autophagy, apoptosis, ER-stress and calcium (Ca2+) signalling. At MERCS, Ca2+ ions are transferred from the ER directly to mitochondria through a core protein complex composed of inositol-1,4,5 trisphosphate receptor (InsP3R), voltage-gated anion channel 1 (VDAC1), mitochondrial calcium uniporter (MCU) and adaptor protein glucose-regulated protein 75 (Grp75); this complex is regulated by several associated proteins. Deregulation of ER-mitochondria Ca2+ transfer contributes to pathogenesis of neurodegenerative and other diseases. The efficacy of Ca2+ transfer between ER and mitochondria depends on the protein composition of MERCS, which controls ER-mitochondria interaction regulating, for example, the transversal distance between ER membrane and OMM and the extension of the longitudinal interface between ER and mitochondria. These parameters are altered in neurodegeneration. Here we overview the ER and mitochondrial Ca2+ homeostasis, the composition of ER-mitochondrial Ca2+ transfer machinery and alterations of the ER-mitochondria Ca2+ transfer in three major neurodegenerative diseases: motor neurone diseases, Parkinson disease and Alzheimer's disease.
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Danese A, Leo S, Rimessi A, Wieckowski MR, Fiorica F, Giorgi C, Pinton P. Cell death as a result of calcium signaling modulation: A cancer-centric prospective. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1868:119061. [PMID: 33991539 DOI: 10.1016/j.bbamcr.2021.119061] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 04/19/2021] [Accepted: 04/26/2021] [Indexed: 12/14/2022]
Abstract
Calcium ions (Ca2+) and the complex regulatory system governed by Ca2+ signaling have been described to be of crucial importance in numerous aspects related to cell life and death decisions, especially in recent years. The growing attention given to this second messenger is justified by the pleiotropic nature of Ca2+-binding proteins and transporters and their consequent involvement in cell fate decisions. A growing number of works highlight that deregulation of Ca2+ signaling and homoeostasis is often deleterious and drives pathological conditions; in particular, a disruption of the main Ca2+-mediated death mechanisms may lead to uncontrolled cell growth that results in cancer. In this work, we review the latest useful evidence to better understand the complex network of pathways by which Ca2+ regulates cell life and death decisions.
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Affiliation(s)
- Alberto Danese
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies, University of Ferrara, 44121 Ferrara, Italy
| | - Sara Leo
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies, University of Ferrara, 44121 Ferrara, Italy
| | - Alessandro Rimessi
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies, University of Ferrara, 44121 Ferrara, Italy
| | - Mariusz R Wieckowski
- Laboratory of Mitochondrial Biology and Metabolism, Nencki Institute of Experimental Biology, Pasteur 3 Str., 02-093 Warsaw, Poland
| | | | - Carlotta Giorgi
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies, University of Ferrara, 44121 Ferrara, Italy.
| | - Paolo Pinton
- Department of Medical Sciences, Laboratory for Technologies of Advanced Therapies, University of Ferrara, 44121 Ferrara, Italy.
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41
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The Parkinson's disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release. Proc Natl Acad Sci U S A 2021; 118:2006476118. [PMID: 33443159 PMCID: PMC7817155 DOI: 10.1073/pnas.2006476118] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease of aging, affecting approximately 10 million patients worldwide with no approved therapies to modify progression of disease. Further understanding of the cellular mechanisms contributing to the development of PD is necessary to discover therapies. Here, we characterize the role of a recently identified GWAS hit for sporadic PD, ITPKB, in the aggregation of α-synuclein, the primary pathological feature of disease. These results identify inhibition of inositol-1,4,5,-triphosphate (IP3)-mediated ER-to-mitochondria calcium release as a potential therapeutic approach for reducing neuropathology in PD. Inositol-1,4,5-triphosphate (IP3) kinase B (ITPKB) is a ubiquitously expressed lipid kinase that inactivates IP3, a secondary messenger that stimulates calcium release from the endoplasmic reticulum (ER). Genome-wide association studies have identified common variants in the ITPKB gene locus associated with reduced risk of sporadic Parkinson’s disease (PD). Here, we investigate whether ITPKB activity or expression level impacts PD phenotypes in cellular and animal models. In primary neurons, knockdown or pharmacological inhibition of ITPKB increased levels of phosphorylated, insoluble α-synuclein pathology following treatment with α-synuclein preformed fibrils (PFFs). Conversely, ITPKB overexpression reduced PFF-induced α-synuclein aggregation. We also demonstrate that ITPKB inhibition or knockdown increases intracellular calcium levels in neurons, leading to an accumulation of calcium in mitochondria that increases respiration and inhibits the initiation of autophagy, suggesting that ITPKB regulates α-synuclein pathology by inhibiting ER-to-mitochondria calcium transport. Furthermore, the effects of ITPKB on mitochondrial calcium and respiration were prevented by pretreatment with pharmacological inhibitors of the mitochondrial calcium uniporter complex, which was also sufficient to reduce α-synuclein pathology in PFF-treated neurons. Taken together, these results identify ITPKB as a negative regulator of α-synuclein aggregation and highlight modulation of ER-to-mitochondria calcium flux as a therapeutic strategy for the treatment of sporadic PD.
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Giamogante F, Poggio E, Barazzuol L, Covallero A, Calì T. Apoptotic signals at the endoplasmic reticulum-mitochondria interface. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2021; 126:307-343. [PMID: 34090618 DOI: 10.1016/bs.apcsb.2021.02.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The maintenance of cellular homeostasis involves the participation of multiple organelles, such as the endoplasmic reticulum (ER) and mitochondria. Specifically, ER plays a key role in calcium (Ca2+) storage, lipid synthesis, protein folding, and assembly, while mitochondria are the "energy factories" and provide energy to drive intracellular processes. Hence, alteration in ER or mitochondrial homeostasis has detrimental effects on cell survival, being linked to the triggering of apoptosis, a programmed form of cell death. Besides, ER stress conditions affect mitochondria functionality and vice-versa, as ER and mitochondria communicate via mitochondria-associated ER membranes (MAMs) to carry out a number of fundamental cellular functions. It is not surprising, thus, that also MAMs perturbations are involved in the regulation of apoptosis. This chapter intends to accurately discuss the involvement of MAMs in apoptosis, highlighting their crucial role in controlling this delicate cellular process.
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Affiliation(s)
- Flavia Giamogante
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Elena Poggio
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Lucia Barazzuol
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Alberto Covallero
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Tito Calì
- Department of Biomedical Sciences, University of Padova, Padova, Italy.
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43
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Involvement of Bcl-xL in Neuronal Function and Development. Int J Mol Sci 2021; 22:ijms22063202. [PMID: 33801158 PMCID: PMC8004157 DOI: 10.3390/ijms22063202] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 03/16/2021] [Accepted: 03/17/2021] [Indexed: 12/23/2022] Open
Abstract
The B-cell lymphoma (Bcl-2) family of proteins are mainly known for their role in the regulation of apoptosis by preventing pore formation at the mitochondrial outer membrane and subsequent caspase activation. However, Bcl-2 proteins also have non-canonical functions, independent of apoptosis. Indeed, the cell death machinery, including Bcl-2 homologs, was reported to be essential for the central nervous system (CNS), notably with respect to synaptic transmission and axon pruning. Here we focused on Bcl-xL, a close Bcl-2 homolog, which plays a major role in neuronal development, as bclx knock out mice prematurely die at embryonic day 13.5, showing massive apoptosis in the CNS. In addition, we present evidence that Bcl-xL fosters ATP generation by the mitochondria to fuel high energy needs by neurons, and its contribution to synaptic transmission. We discuss how Bcl-xL might control local and transient activation of caspases in neurons without causing cell death. Consistently, Bcl-xL may contribute to morphological changes, such as sprouting and retractation of axon branches, in the context of CNS plasticity. Regarding degenerative diseases and aging, a better understanding of the numerous roles of the cell death machinery in neurons may have future clinical implications.
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Carpio MA, Means RE, Brill AL, Sainz A, Ehrlich BE, Katz SG. BOK controls apoptosis by Ca 2+ transfer through ER-mitochondrial contact sites. Cell Rep 2021; 34:108827. [PMID: 33691099 PMCID: PMC7995216 DOI: 10.1016/j.celrep.2021.108827] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Revised: 11/20/2020] [Accepted: 02/16/2021] [Indexed: 12/11/2022] Open
Abstract
Calcium transfer from the endoplasmic reticulum (ER) to mitochondria is a critical contributor to apoptosis. B cell lymphoma 2 (BCL-2) ovarian killer (BOK) localizes to the ER and binds the inositol 1,4,5-trisphosophate receptor (IP3R). Here, we show that BOK is necessary for baseline mitochondrial calcium levels and stimulus-induced calcium transfer from the ER to the mitochondria. Murine embryonic fibroblasts deficient for BOK have decreased proximity of the ER to the mitochondria and altered protein composition of mitochondria-associated membranes (MAMs), which form essential calcium microdomains. Rescue of the ER-mitochondrial juxtaposition with drug-inducible interorganelle linkers reveals a kinetic disruption, which when overcome in Bok−/− cells is still insufficient to rescue thapsigargin-induced calcium transfer and apoptosis. Likewise, a BOK mutant unable to interact with IP3R restores ER-mitochondrial proximity, but not ER-mitochondrial calcium transfer, MAM protein composition, or apoptosis. This work identifies the dynamic coordination of ER-mitochondrial contact by BOK as an important control point for apoptosis. Carpio et al. demonstrate that the proapoptotic BCL-2 family member BOK is present in mitochondrial associated membranes (MAMs). The interaction of BOK with the IP3Rs is critical for its regulation of Ca2+ transfer to the mitochondria, ER-mitochondrial contact sites, and apoptosis.
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Affiliation(s)
- Marcos A Carpio
- Department of Pathology, Yale School of Medicine, New Haven, CT 06525, USA
| | - Robert E Means
- Department of Pathology, Yale School of Medicine, New Haven, CT 06525, USA
| | - Allison L Brill
- Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06525, USA
| | - Alva Sainz
- Department of Pathology, Yale School of Medicine, New Haven, CT 06525, USA
| | - Barbara E Ehrlich
- Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT 06525, USA; Department of Pharmacology, Yale School of Medicine, New Haven, CT 06525, USA
| | - Samuel G Katz
- Department of Pathology, Yale School of Medicine, New Haven, CT 06525, USA.
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Wang K, Zhang W. Mitochondria-associated endoplasmic reticulum membranes: At the crossroad between familiar and sporadic Alzheimer's disease. Synapse 2021; 75:e22196. [PMID: 33559220 DOI: 10.1002/syn.22196] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 01/25/2021] [Indexed: 12/11/2022]
Abstract
Alzheimer's disease (AD) is the leading cause of dementia and is incurable. The widely accepted amyloid hypothesis failed to produce efficient clinical therapies. In contrast, there is increasing evidence suggesting that the disruption of mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) is a critical upstream event of AD pathogenesis. Here, we review MAM's role in some AD symptoms such as plaque formation, tau hyperphosphorylation, synaptic loss, aberrant lipid synthesis, disturbed calcium homeostasis, and abnormal autophagy. At last, we proposed that MAM plays a central role in familial AD (FAD) and sporadic AD (SAD).
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Affiliation(s)
- Kangrun Wang
- Xiangya Hospital, Central South University, Changsha, P.R. China
| | - Wenling Zhang
- The Third Xiangya Hospital, Central South University, Changsha, P.R. China
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Leal NS, Martins LM. Mind the Gap: Mitochondria and the Endoplasmic Reticulum in Neurodegenerative Diseases. Biomedicines 2021; 9:biomedicines9020227. [PMID: 33672391 PMCID: PMC7926795 DOI: 10.3390/biomedicines9020227] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 02/17/2021] [Accepted: 02/18/2021] [Indexed: 12/16/2022] Open
Abstract
The way organelles are viewed by cell biologists is quickly changing. For many years, these cellular entities were thought to be unique and singular structures that performed specific roles. However, in recent decades, researchers have discovered that organelles are dynamic and form physical contacts. In addition, organelle interactions modulate several vital biological functions, and the dysregulation of these contacts is involved in cell dysfunction and different pathologies, including neurodegenerative diseases. Mitochondria–ER contact sites (MERCS) are among the most extensively studied and understood juxtapositioned interorganelle structures. In this review, we summarise the major biological and ultrastructural dysfunctions of MERCS in neurodegeneration, with a particular focus on Alzheimer’s disease as well as Parkinson’s disease, amyotrophic lateral sclerosis and frontotemporal dementia. We also propose an updated version of the MERCS hypothesis in Alzheimer’s disease based on new findings. Finally, we discuss the possibility of MERCS being used as possible drug targets to halt cell death and neurodegeneration.
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Cancer cell death strategies by targeting Bcl-2's BH4 domain. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2021; 1868:118983. [PMID: 33549704 DOI: 10.1016/j.bbamcr.2021.118983] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/19/2021] [Accepted: 01/20/2021] [Indexed: 12/15/2022]
Abstract
The Bcl-2-family proteins have long been known for their role as key regulators of apoptosis. Overexpression of various members of the family is associated with oncogenesis. Its founding member, anti-apoptotic Bcl-2 regulates cell death at different levels, whereby Bcl-2 emerged as a major drug target to eradicate cancers through cell death. This resulted in the development of venetoclax, a Bcl-2 antagonist that acts as a BH3 mimetic. Venetoclax already entered the clinic to treat relapse chronic lymphocytic leukemia patients. Here, we discuss the role of Bcl-2 as a decision-maker in cell death with focus on the recent advances in anti-cancer therapeutics that target the BH4 domain of Bcl-2, thereby interfering with non-canonical functions of Bcl-2 in Ca2+-signaling modulation. In particular, we critically discuss previously developed tools, including the peptide BIRD-2 (Bcl-2/IP3R-disrupter-2) and the small molecule BDA-366. In addition, we present a preliminary analysis of two recently identified molecules that emerged from a molecular modeling approach to target Bcl-2's BH4 domain, which however failed to induce cell death in two Bcl-2-dependent diffuse large B-cell lymphoma cell models. Overall, antagonizing the non-canonical functions of Bcl-2 by interfering with its BH4-domain biology holds promise to elicit cell death in cancer, though improved tools and on-target antagonizing small molecules remain necessary and ought to be designed.
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48
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Kretzschmar T, Wu JMF, Schulze PC. Mitochondrial Homeostasis Mediates Lipotoxicity in the Failing Myocardium. Int J Mol Sci 2021; 22:1498. [PMID: 33540894 PMCID: PMC7867320 DOI: 10.3390/ijms22031498] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 01/27/2021] [Accepted: 01/28/2021] [Indexed: 01/17/2023] Open
Abstract
Heart failure remains the most common cause of death in the industrialized world. In spite of new therapeutic interventions that are constantly being developed, it is still not possible to completely protect against heart failure development and progression. This shows how much more research is necessary to understand the underlying mechanisms of this process. In this review, we give a detailed overview of the contribution of impaired mitochondrial dynamics and energy homeostasis during heart failure progression. In particular, we focus on the regulation of fatty acid metabolism and the effects of fatty acid accumulation on mitochondrial structural and functional homeostasis.
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Affiliation(s)
| | | | - P. Christian Schulze
- Department of Internal Medicine I, University Hospital Jena, 07747 Jena, Thüringen, Germany; (T.K.); (J.M.F.W.)
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49
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Yu H, Sun C, Gong Q, Feng D. Mitochondria-Associated Endoplasmic Reticulum Membranes in Breast Cancer. Front Cell Dev Biol 2021; 9:629669. [PMID: 33634130 PMCID: PMC7902067 DOI: 10.3389/fcell.2021.629669] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 01/08/2021] [Indexed: 11/23/2022] Open
Abstract
Mitochondria-associated ER membranes (MAMs) represent a crucial intracellular signaling hub, that regulates various cellular events including Ca2+ homeostasis, lipid metabolism, mitochondrial function, and cellular survival and death. All of these MAM-mediated cellular events contribute to carcinogenesis. Indeed, altered functions of MAMs in several types of cancers have been documented, in particular for breast cancer. Over the past years, altered expression of many MAM-resident proteins have been reported in breast cancer. These MAM-resident proteins play an important role in regulation of breast cancer initiation and progression. In the current review, we discuss our current knowledge about the functions of MAMs, and address the underlying mechanisms through which MAM-resident proteins regulate breast cancer. A fuller understanding of the pathways through which MAMs regulate breast cancer, and identification of breast cancer-specific MAM-resident proteins may help to develop novel therapeutic strategies for breast cancer.
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Affiliation(s)
- Hongjiao Yu
- Department of Biochemistry and Molecular Biology, Guangzhou Medical University-Guangzhou Institutes of Biomedicine and Health (GMU-GIBH) Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China
| | - Chaonan Sun
- Department of Biochemistry and Molecular Biology, Guangzhou Medical University-Guangzhou Institutes of Biomedicine and Health (GMU-GIBH) Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China
| | - Qing Gong
- Department of Biochemistry and Molecular Biology, Guangzhou Medical University-Guangzhou Institutes of Biomedicine and Health (GMU-GIBH) Joint School of Life Sciences, Guangzhou Medical University, Guangzhou, China
| | - Du Feng
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation, State Key Laboratory of Respiratory Disease, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, China
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50
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Smith JA. STING, the Endoplasmic Reticulum, and Mitochondria: Is Three a Crowd or a Conversation? Front Immunol 2021; 11:611347. [PMID: 33552072 PMCID: PMC7858662 DOI: 10.3389/fimmu.2020.611347] [Citation(s) in RCA: 53] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Accepted: 12/04/2020] [Indexed: 12/20/2022] Open
Abstract
The anti-viral pattern recognition receptor STING and its partnering cytosolic DNA sensor cGAS have been increasingly recognized to respond to self DNA in multiple pathologic settings including cancer and autoimmune disease. Endogenous DNA sources that trigger STING include damaged nuclear DNA in micronuclei and mitochondrial DNA (mtDNA). STING resides in the endoplasmic reticulum (ER), and particularly in the ER-mitochondria associated membranes. This unique location renders STING well poised to respond to intracellular organelle stress. Whereas the pathways linking mtDNA and STING have been addressed recently, the mechanisms governing ER stress and STING interaction remain more opaque. The ER and mitochondria share a close anatomic and functional relationship, with mutual production of, and inter-organelle communication via calcium and reactive oxygen species (ROS). This interdependent relationship has potential to both generate the essential ligands for STING activation and to regulate its activity. Herein, we review the interactions between STING and mitochondria, STING and ER, ER and mitochondria (vis-à-vis calcium and ROS), and the evidence for 3-way communication.
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Affiliation(s)
- Judith A Smith
- Department of Pediatrics and Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, United States
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