Trends in Cell Biology
ReviewBalancing ER-Mitochondrial Ca2+ Fluxes in Health and Disease
Section snippets
Interorganellar Ca2+ Dynamics at Membrane Contact Sites as a Critical Process Underlying Cell Function
Organellar function is essential for cellular homeostasis and physiology. Organelles do not function as isolated entities. Instead, their function is impacted by other organelles via membrane contact sites. These junctions enable the formation of microdomains that comprise different cellular functions by hosting signaling complexes and enabling distinct processes, including Ca2+ signaling (see Glossary) [1]. The role of membrane contact sites and their signaling functions in cell biology and
Basic Players and Principles of Ca2+ Signaling at MAMs
The ER, the main intracellular Ca2+ store, forms areas of close contact (10–80 nm) with the outer mitochondrial membrane (OMM), termed ‘MAMs’ (Figure 1, Key Figure), enabling efficient mitochondrial Ca2+ transfer [1]. Various proteins control ER–mitochondrial apposition, including inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) [3], mitofusin 2 (Mfn2) [4,5], and the vesicle-associated membrane protein-associated protein B (VAPB)–protein tyrosine phosphatase interacting protein 51 (PTPIP51)
Effects of ER–Mitochondrial Ca2+ Fluxes on Cell Fate
ER–mitochondrial Ca2+ fluxes determine cell fate. Low-level rhythmic Ca2+ oscillations provide the mitochondria with adequate Ca2+ levels, thereby stimulating mitochondrial ATP production and sustaining survival. The increase in bioenergetic output is driven by the Ca2+ dependence of metabolic enzyme activity such as pyruvate-, isocitrate-, and α-ketoglutarate dehydrogenase [9]. Conversely, insufficient ER–mitochondrial Ca2+ flux by either inhibition or suppression of IP3Rs [19] or by impaired
Cancer
Cancer cells remodel their Ca2+-signaling machinery, thereby contributing to cancer hallmarks [20]. Part of this remodeling is due to loss of tumor suppressor function and increased activity/upregulation of oncogene products [20]. Again, Ca2+ plays a dual role: While ER–mitochondrial Ca2+ fluxes may be dampened in cancer cells to evade cell death, enhanced Ca2+ signaling may promote metabolism and migration [20]. IP3Rs thus can act in both a pro-oncogenic and tumor-suppressive manner. The
Concluding Remarks
Several disease-linked proteins recently emerged to reside and function at the MAMs as controllers of ER–mitochondrial Ca2+ transfer. Numerous studies implicate them in the pathogenesis of various diseases, such as cancer, neurodegenerative diseases, and other MAM-related disorders. Yet, several aspects of ER–mitochondrial Ca2+ fluxes in health and disease, including aging, the importance in sporadic forms of neurodegenerative diseases, and integration of ER–mitochondrial Ca2+ signals with
Acknowledgments
Research in the authors’ laboratories was supported by research grants from the Research Foundation – Flanders (FWO) (G.0A34.16N, G.0901.18N, and G.0818.21N to G.B.; grant G0E7520N to G.B. and I.B.; grant G.0C91.14N to G.B. and J.B.P.; and grant G0A6919N to J.B.P.), the Research Council – KU Leuven (OT14/101and AKUL/19/34 to G.B. and C14/19/101 to G.B. and J.B.P.), the Central European Leuven Strategic Alliance (CELSA/18/040 to G.B. and A.K.), Stichting Alzheimer Onderzoek (SAO IP3 RECEPTOR to
Declaration of Interests
The authors declare no competing interests.
Glossary
- Autophagy
- a general term that refers to the lysosomal process important for the removal of misfolded/aggregated proteins, damaged organelles, and intracellular pathogens. Specific terms are used for specific organelles (e.g., ‘mitophagy’ for removal of damaged mitochondria). Autophagy is a prosurvival process key for cellular homeostasis, though when deregulated, it can also lead to cell death.
- B cell lymphoma 2 (Bcl-2)
- founding member of the Bcl-2-protein family, which controls cell survival by
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