Valentina Parra
Giovanni Monaco
Giampaolo Morciano
Gaetano Santulli- 1Advanced Center of Chronic Diseases (ACCDiS), Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
- 2Departamento de Bioquímica y Biología Molecular, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile
- 3Center for Innovation and Stimulation of Drug Discovery (CISTIM), Leuven, Belgium
- 4Section of Experimental Medicine, Laboratory for Technologies of Advanced Therapies (LTTA), Department of Medical Sciences, University of Ferrara, Ferrara, Italy
- 5Maria Cecilia Hospital, GVM Care and Research, Cotignola, Italy
- 6Division of Cardiology, Department of Medicine, Albert Einstein College of Medicine, Wilf Family Cardiovascular Research Institute and Einstein Institute for Aging Research, New York, NY, United States
- 7Department of Molecular Pharmacology, Einstein-Sinai Diabetes Research Center (ES-DRC), Fleischer Institute for Diabetes and Metabolism (FIDAM), Montefiore University Hospital, New York, NY, United States
- 8International Translational Research and Medical Education Academic Research Unit (ITME), Department of Advanced Biomedical Sciences, “Federico II” University, Naples, Italy
Editorial on the Research Topic
Mitochondrial remodeling and dynamic inter-organellar contacts in cardiovascular physiopathology-Volume II
Inter-cellular and inter-organellar communications are required to maintain homeostasis in complex organisms (Jain and Zoncu, 2022). Most of subcellular organelles evolved as entities needing connections, rather than separate units with unitary functions. Indeed, besides the anterograde and retrograde communication between the nucleus and organelles which involves gene transcription regulation, there is ample evidence that they come into contact with each other through several physical contact sites (Scorrano et al., 2019). Usually, such sites are represented by dynamic changes of membranes juxtaposition of neighboring organelles with specific purposes: the exchange of biological material and thus, information. Information that is required to coordinate a series of signaling pathways to sustain life.
Over the years, the understanding of inter-organellar communications has been thoroughly investigated and eventually transformed our view of cellular physiology (Quirós et al., 2016; Ghai et al., 2017; Lopez-Crisosto et al., 2017; Shai et al., 2018). Although the vesicular transport (import and export) has been described as the main system for material exchange (Bonifacino and Glick, 2004; Di Mambro et al., 2023), not all biomolecules follow this route (Lev, 2012). Non-vesicular lipid trafficking (Kaplan and Simoni, 1985; Urbani and Simoni, 1990; Heino et al., 2000) and spatio-temporal calcium (Ca2+) transfer (Giorgi et al., 2018) are just a couple of notable examples. These communication systems are mutually coordinated and actively participate to the intracellular signaling and the transcriptional program.
In the cardiovascular setting, mitochondrial signaling acquires considerable importance for countless reasons that can be roughly summarized with the functional role played for ATP production, in the so-called ATP cycling in cardiac contraction, as well as in Ca2+ handling (Gambardella et al., 2018). This second messenger is able to induce cell death and tissue function loss as consequence of the mitochondrial permeability transition pore (PTP) opening (Campo et al., 2017; Morciano et al., 2021a) and the activation of Ca2+-dependent proteases inducing hypercontracture (Neuhof and Neuhof, 2014). Given the critical role of these pathways for cell survival, mitochondrial dysfunctions have been disclosed as key hallmarks of cardiovascular diseases (CVDs). Also, being ATP generators and biosynthetic centers, mitochondria are important for cell metabolism with pathophysiological phenotypic features highly dependent on their morphology (Wai and Langer, 2016; Morciano et al., 2022).
In this Research Topic, Mostafavi et al. investigated the degree of mitochondrial remodeling accompanying the metabolic switch occurring in cardiomyocyte differentiation. In this regard, mitochondria from human pluripotent stem cells (hPSCs) and terminally differentiated cardiomyocytes have been evaluated by assessing differences in their number, morphology, membrane potential and the activity of the respiratory chain. Differentiated cells displayed a greater efficiency in energy production (ATP) and a greater dependence on oxidative phosphorylation (OXPHOS) with a more electronegative membrane potential despite a decrease in the number, DNA levels and mitochondrial biogenesis. These investigations, in concert with examining the impact of mitochondrial remodeling on inter-organellar dynamics, are fundamental in order to gain pathologically relevant insights.
Vásquez-Trincado et al. provided further evidence on the pivotal role played by mitochondria and mitochondrial signaling in metabolic disorders linked to CVDs. Indeed, they demonstrated how lipotoxic stress, induced by fatty acid overload, triggered cardiac hypertrophy and insulin desensitization by increasing E3 ubiquitin ligase MUL1 expression, a protein localized at mitochondria. Lipotoxic stress-induced MUL1 activation impaired some mitochondrial features by promoting organelle fragmentation through dynamin-related protein 1 (DRP1) and by decreasing mitofusin 2 (MFN2) expression. MUL1 would be required for this process as its silencing prevents cardiac hypertrophy and metabolic impairment. Further investigations on this process can lead to the identification of a reliable therapeutic target for metabolic diseases.
In the field of organelles communication, mitochondria interact at multiple levels to communicate with other organelles. Noteworthy examples are described by the existence of mitochondria—nucleus contact sites (Desai et al., 2020), mitochondria—associated membranes (MAMs) (Morciano et al., 2018) and mitochondria—plasmalemma contacts (Montes de Oca Balderas, 2021). Additionally, Guajardo-Correa et al. summarized the importance of mitochondria in CVDs by highlighting a key aspect of their connection with the nucleus. In detail, Estrogens modulation of cardiovascular physiology has been revealed as one of the most potent cardioprotective factor in humans. Multiple evidence found estrogen signaling pathways to involve mitochondria, mainly in antioxidant defense mechanisms, by reducing mitochondrial reactive oxygen species (ROS) and increasing mitochondrial antioxidant enzymes (Lynch et al., 2020). Estrogens are also potentially able to improve cellular Ca2+ handling, which is essential for heart contraction and relaxation (Jiao et al., 2020). How these pathways are inter-linked and intracellularly signaling to the nucleus is of growing interest. Although estrogens have pleiotropic effects, most of them are described in the nuclear—mitochondrial anterograde and retrograde communication, such as the estrogen–mediated transcriptional activity of many master regulators of mitochondrial pathways. Among them, PGC-1α, that in turn may affect fatty acid oxidation (FAO), tricarboxylic acid (TCA) cycle, and OXPHOS. PGC-1α related pathways result to be impaired in CVDs and can be finely regulated through estrogen receptors (ERs) localized on the membranes of several organelles. On the other hand, retrograde signaling also exists, and is mainly mediated by mitochondrial energetic deprivation (Hu et al., 2011), ROS stress responses (Tan et al., 2008), Ca2+-dependent signaling (Novotny et al., 2009), and by mitochondrial unfolded protein response (mtUPR) (Germain, 2016).
Finally, the review authored by Pedriali et al. expanded the current view on mitochondrial connections moving the focus on other points of contacts, especially those established with either the SR or the sarcolemma. The architecture of MAMs in physiology is dynamic and aims to optimize Ca2+ transfer (and not only) from SR to mitochondria to support cell bioenergetics. This aspect is so important for cell survival that an impairment in the architecture of MAMs is at the basis of many molecular pathways in cardiac diseases (Dridi et al., 2022; Morgado-Cáceres et al., 2022). A striking example occurs in ischemia/reperfusion (I/R) injury and heart failure, in which many studies supported the hypothesis that mitochondria are subjected to an overload of Ca2+, an event triggering cell death through the PTP opening (Morciano et al., 2021b). At the basis of these phenomena, an impaired interaction between SR and mitochondria occurs; here, a pharmacological or genetic approach in reducing SR-mitochondria tethering would correlate with a decrease in Ca2+ transfer and thus a significant lower amount of myocardial cell death. Also, a close proximity between mitochondria and cardiomyocytes gap junctions have been described (Forbes and Sperelakis, 1982) with a prominent role in I/R (Rodriguez-Sinovas et al., 2004; Fridolfsson et al., 2012).
In conclusion, mitochondrial signaling, especially the one established by nuclear-, SR- and sarcolemma-connections is a growing field of research (Kerkhofs et al., 2019) and may actually represent a fertile field for promising therapeutic purposes.
Author contributions
All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Funding
The Santulli’s Lab is currently supported in part by the National Institutes of Health (NIH): National Heart, Lung, and Blood Institute (NHLBI: R01-HL164772, R01-HL159062, R01-HL146691, and T32-HL144456), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK: R01-DK123259, R01-DK033823), National Center for Advancing Translational Sciences (NCATS: UL1-TR002556-06, UM1-TR004400), by the Diabetes Action Research and Education Foundation and by the Monique Weill-Caulier and Irma T. Hirschl Trusts. VP is supported by grants from the Fondo Nacional de Desarrollo Científico y Tecnológico, FONDECYT, Chile (1230195), Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias, FONDAP, Chile (15130011), and SYSTEMICS Ring ACT210004. GM is supported by the Italian Ministry of Health Grants (GR-2018-12367114 and GR-2019-12369862).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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References
Bonifacino, J. S., and Glick, B. S. (2004). The mechanisms of vesicle budding and fusion. Cell. 116, 153–166. doi:10.1016/s0092-8674(03)01079-1
Campo, G., Pavasini, R., Morciano, G., Lincoff, A. M., Gibson, C. M., Kitakaze, M., et al. (2017). Clinical benefit of drugs targeting mitochondrial function as an adjunct to reperfusion in ST-segment elevation myocardial infarction: A meta-analysis of randomized clinical trials. Int. J. Cardiol. 244, 59–66. doi:10.1016/j.ijcard.2017.06.040
Desai, R., East, D. A., Hardy, L., Faccenda, D., Rigon, M., Crosby, J., et al. (2020). Mitochondria form contact sites with the nucleus to couple prosurvival retrograde response. Sci. Adv. 6, eabc9955. doi:10.1126/sciadv.abc9955
Di Mambro, T., Pellielo, G., Agyapong, E. D., Carinci, M., Chianese, D., Giorgi, C., et al. (2023). The tricky connection between extracellular vesicles and mitochondria in inflammatory-related diseases. Int. J. Mol. Sci. 24, 8181. doi:10.3390/ijms24098181
Dridi, H., Santulli, G., Gambardella, J., Jankauskas, S. S., Yuan, Q., Yang, J., et al. (2022). IP3 receptor orchestrates maladaptive vascular responses in heart failure. J. Clin. Investig. 132, e152859. doi:10.1172/JCI152859
Forbes, M. S., and Sperelakis, N. (1982). Association between mitochondria and gap junctions in mammalian myocardial cells. Tissue Cell. 14, 25–37. doi:10.1016/0040-8166(82)90004-0
Fridolfsson, H. N., Kawaraguchi, Y., Ali, S. S., Panneerselvam, M., Niesman, I. R., Finley, J. C., et al. (2012). Mitochondria-localized caveolin in adaptation to cellular stress and injury. FASEB J. 26, 4637–4649. doi:10.1096/fj.12-215798
Gambardella, J., Trimarco, B., Iaccarino, G., and Santulli, G. (2018). New insights in cardiac calcium handling and excitation-contraction coupling. Adv. Exp. Med. Biol. 1067, 373–385. doi:10.1007/5584_2017_106
Germain, D. (2016). Sirtuins and the estrogen receptor as regulators of the mammalian mitochondrial UPR in cancer and aging. Adv. Cancer Res. 130, 211–256. doi:10.1016/bs.acr.2016.01.004
Ghai, R., Du, X., Wang, H., Dong, J., Ferguson, C., Brown, A. J., et al. (2017). ORP5 and ORP8 bind phosphatidylinositol-4, 5-biphosphate (PtdIns(4,5)P 2) and regulate its level at the plasma membrane. Nat. Commun. 8, 757. doi:10.1038/s41467-017-00861-5
Giorgi, C., Danese, A., Missiroli, S., Patergnani, S., and Pinton, P. (2018). Calcium dynamics as a machine for decoding signals. Trends Cell. Biol. 28, 258–273. doi:10.1016/j.tcb.2018.01.002
Heino, S., Lusa, S., Somerharju, P., Ehnholm, C., Olkkonen, V. M., and Ikonen, E. (2000). Dissecting the role of the golgi complex and lipid rafts in biosynthetic transport of cholesterol to the cell surface. Proc. Natl. Acad. Sci. U. S. A. 97, 8375–8380. doi:10.1073/pnas.140218797
Hu, X., Xu, X., Lu, Z., Zhang, P., Fassett, J., Zhang, Y., et al. (2011). AMP activated protein kinase-α2 regulates expression of estrogen-related receptor-α, a metabolic transcription factor related to heart failure development. Hypertension 58, 696–703. doi:10.1161/HYPERTENSIONAHA.111.174128
Jain, A., and Zoncu, R. (2022). Organelle transporters and inter-organelle communication as drivers of metabolic regulation and cellular homeostasis. Mol. Metab. 60, 101481. doi:10.1016/j.molmet.2022.101481
Jiao, L., Machuki, J. O., Wu, Q., Shi, M., Fu, L., Adekunle, A. O., et al. (2020). Estrogen and calcium handling proteins: New discoveries and mechanisms in cardiovascular diseases. Am. J. Physiol. Heart Circ. Physiol. 318, H820–H829. doi:10.1152/ajpheart.00734.2019
Kaplan, M. R., and Simoni, R. D. (1985). Transport of cholesterol from the endoplasmic reticulum to the plasma membrane. J. Cell. Biol. 101, 446–453. doi:10.1083/jcb.101.2.446
Kerkhofs, M., Bultynck, G., Vervliet, T., and Monaco, G. (2019). Therapeutic implications of novel peptides targeting ER-mitochondria Ca2+-flux systems. Drug Discov. Today 24, 1092–1103. doi:10.1016/j.drudis.2019.03.020
Lev, S. (2012). Nonvesicular lipid transfer from the endoplasmic reticulum. Cold Spring Harb. Perspect. Biol. 4, a013300. doi:10.1101/cshperspect.a013300
Lopez-Crisosto, C., Pennanen, C., Vasquez-Trincado, C., Morales, P. E., Bravo-Sagua, R., Quest, A. F. G., et al. (2017). Sarcoplasmic reticulum-mitochondria communication in cardiovascular pathophysiology. Nat. Rev. Cardiol. 14, 342–360. doi:10.1038/nrcardio.2017.23
Lynch, S., Boyett, J. E., Smith, M. R., and Giordano-Mooga, S. (2020). Sex hormone regulation of proteins modulating mitochondrial metabolism, dynamics and inter-organellar cross talk in cardiovascular disease. Front. Cell. Dev. Biol. 8, 610516. doi:10.3389/fcell.2020.610516
Montes de Oca Balderas, P. (2021). Mitochondria-plasma membrane interactions and communication. J. Biol. Chem. 297, 101164. doi:10.1016/j.jbc.2021.101164
Morciano, G., Marchi, S., Morganti, C., Sbano, L., Bittremieux, M., Kerkhofs, M., et al. (2018). Role of mitochondria-associated ER membranes in calcium regulation in cancer-specific settings. Neoplasia 20, 510–523. doi:10.1016/j.neo.2018.03.005
Morciano, G., Naumova, N., Koprowski, P., Valente, S., Sardão, V. A., Potes, Y., et al. (2021a). The mitochondrial permeability transition pore: An evolving concept critical for cell life and death. Biol. Rev. Camb Philos. Soc. 96, 2489–2521. doi:10.1111/brv.12764
Morciano, G., Patergnani, S., Pedriali, G., Cimaglia, P., Mikus, E., Calvi, S., et al. (2022). Impairment of mitophagy and autophagy accompanies calcific aortic valve stenosis favouring cell death and the severity of disease. Cardiovasc Res. 118, 2548–2559. doi:10.1093/cvr/cvab267
Morciano, G., Pedriali, G., Bonora, M., Pavasini, R., Mikus, E., Calvi, S., et al. (2021b). A naturally occurring mutation in ATP synthase subunit c is associated with increased damage following hypoxia/reoxygenation in STEMI patients. Cell. Rep. 35, 108983. doi:10.1016/j.celrep.2021.108983
Morgado-Cáceres, P., Liabeuf, G., Calle, X., Briones, L., Riquelme, J. A., Bravo-Sagua, R., et al. (2022). The aging of ER-mitochondria communication: A journey from undifferentiated to aged cells. Front. Cell. Dev. Biol. 10, 946678. doi:10.3389/fcell.2022.946678
Neuhof, C., and Neuhof, H. (2014). Calpain system and its involvement in myocardial ischemia and reperfusion injury. World J. Cardiol. 6, 638–652. doi:10.4330/wjc.v6.i7.638
Novotny, J. L., Simpson, A. M., Tomicek, N. J., Lancaster, T. S., and Korzick, D. H. (2009). Rapid estrogen receptor-alpha activation improves ischemic tolerance in aged female rats through a novel protein kinase C epsilon-dependent mechanism. Endocrinology 150, 889–896. doi:10.1210/en.2008-0708
Quirós, P. M., Mottis, A., and Auwerx, J. (2016). Mitonuclear communication in homeostasis and stress. Nat. Rev. Mol. Cell. Biol. 17, 213–226. doi:10.1038/nrm.2016.23
Rodriguez-Sinovas, A., García-Dorado, D., Ruiz-Meana, M., and Soler-Soler, J. (2004). Enhanced effect of gap junction uncouplers on macroscopic electrical properties of reperfused myocardium. J. Physiol. 559, 245–257. doi:10.1113/jphysiol.2004.065144
Scorrano, L., De Matteis, M. A., Emr, S., Giordano, F., Hajnóczky, G., Kornmann, B., et al. (2019). Coming together to define membrane contact sites. Nat. Commun. 10, 1287. doi:10.1038/s41467-019-09253-3
Shai, N., Yifrach, E., van Roermund, C. W. T., Cohen, N., Bibi, C., Ijlst, L., et al. (2018). Systematic mapping of contact sites reveals tethers and a function for the peroxisome-mitochondria contact. Nat. Commun. 9, 1761. doi:10.1038/s41467-018-03957-8
Tan, W.-Q., Wang, K., Lv, D.-Y., and Li, P.-F. (2008). Foxo3a inhibits cardiomyocyte hypertrophy through transactivating catalase. J. Biol. Chem. 283, 29730–29739. doi:10.1074/jbc.M805514200
Urbani, L., and Simoni, R. D. (1990). Cholesterol and vesicular stomatitis virus G protein take separate routes from the endoplasmic reticulum to the plasma membrane. J. Biol. Chem. 265, 1919–1923. doi:10.1016/s0021-9258(19)39918-1
Keywords: mitochondria, intracellular signaling, cell death, cardiovascular disease, calcium
Citation: Parra V, Monaco G, Morciano G and Santulli G (2023) Editorial: Mitochondrial remodeling and dynamic inter-organellar contacts in cardiovascular physiopathology-Volume II. Front. Cell Dev. Biol. 11:1240207. doi: 10.3389/fcell.2023.1240207
Received: 14 June 2023; Accepted: 16 June 2023;
Published: 22 June 2023.
Edited and reviewed by:
Graça Soveral, University of Lisbon, PortugalCopyright © 2023 Parra, Monaco, Morciano and Santulli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Giampaolo Morciano, bXJjZ3BsQHVuaWZlLml0