Supralinear Dependence of the IP Receptor-to-Mitochondria Local Ca Transfer on the Endoplasmic Reticulum Ca Loading
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. Ca 2+ transfer is optimal at the ER-mitochondrial contacts, where inositol 1,4,5-trisphosphate (IP 3 ) rec...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2024-02-01
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| Series: | Contact |
| Online Access: | https://doi.org/10.1177/25152564241229273 |
| _version_ | 1797306707310804992 |
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| author | György Csordás David Weaver Péter Várnai György Hajnóczky |
| author_facet | György Csordás David Weaver Péter Várnai György Hajnóczky |
| author_sort | György Csordás |
| collection | DOAJ |
| description | 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. Ca 2+ transfer is optimal at the ER-mitochondrial contacts, where inositol 1,4,5-trisphosphate (IP 3 ) receptors (IP3R) can locally expose the mitochondrial Ca 2+ uniporter (mtCU) to high [Ca 2+ ] nanodomains. The Ca 2+ loading state of the ER (Ca 2 + ER ) can vary broadly in physiological and pathological scenarios, however, the correlation between Ca 2 + ER and the local Ca 2+ transfer is unclear. Here, we studied IP 3 -induced Ca 2+ transfer to mitochondria at different Ca 2 + ER in intact and permeabilized RBL-2H3 cells via fluorescence measurements of cytoplasmic [Ca 2+ ] ([Ca 2+ ] c ) and mitochondrial matrix [Ca 2+ ] ([Ca 2+ ] m ). Preincubation of intact cells in high versus low extracellular [Ca 2+ ] caused disproportionally greater increase in [Ca 2+ ] m than [Ca 2+ ] c responses to IP 3 -mobilizing agonist. Increasing Ca 2 + ER by small Ca 2+ boluses in suspensions of permeabilized cells supralinearly enhanced the mitochondrial Ca 2+ uptake from IP 3 -induced Ca 2+ release. The IP 3 -induced local [Ca 2+ ] spikes exposing the mitochondrial surface measured using a genetically targeted sensor appeared to linearly correlate with Ca 2 + 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 Ca 2+ uptake. Interestingly, the IP 3 -induced [Ca 2+ ] m signal plateaued at high Ca 2 + ER , indicating activation of a matrix Ca 2+ binding/chelating species. Mitochondria thus seem to maintain a “working [Ca 2+ ] m range” via a low-affinity and high-capacity buffer species, and the ER loading steeply enhances the IP3R-linked [Ca 2+ ] m signals in this working range. |
| first_indexed | 2024-03-08T00:45:44Z |
| format | Article |
| id | doaj.art-06c04454411f40e5b415f1a68288aa74 |
| institution | Directory Open Access Journal |
| issn | 2515-2564 |
| language | English |
| last_indexed | 2024-03-08T00:45:44Z |
| publishDate | 2024-02-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Contact |
| spelling | doaj.art-06c04454411f40e5b415f1a68288aa742024-02-15T10:03:19ZengSAGE PublishingContact2515-25642024-02-01710.1177/25152564241229273Supralinear Dependence of the IP Receptor-to-Mitochondria Local Ca Transfer on the Endoplasmic Reticulum Ca LoadingGyörgy Csordás0David Weaver1Péter Várnai2György Hajnóczky3 MitoCare Center for Mitochondrial Imaging Research and Diagnostics, Department of Pathology, Anatomy and Cell Biology, , Philadelphia, PA, USA MitoCare Center for Mitochondrial Imaging Research and Diagnostics, Department of Pathology, Anatomy and Cell Biology, , Philadelphia, PA, USA Department of Physiology, , Budapest, Hungary MitoCare Center for Mitochondrial Imaging Research and Diagnostics, Department of Pathology, Anatomy and Cell Biology, , Philadelphia, PA, USACalcium signal propagation from endoplasmic reticulum (ER) to mitochondria regulates a multitude of mitochondrial and cell functions, including oxidative ATP production and cell fate decisions. Ca 2+ transfer is optimal at the ER-mitochondrial contacts, where inositol 1,4,5-trisphosphate (IP 3 ) receptors (IP3R) can locally expose the mitochondrial Ca 2+ uniporter (mtCU) to high [Ca 2+ ] nanodomains. The Ca 2+ loading state of the ER (Ca 2 + ER ) can vary broadly in physiological and pathological scenarios, however, the correlation between Ca 2 + ER and the local Ca 2+ transfer is unclear. Here, we studied IP 3 -induced Ca 2+ transfer to mitochondria at different Ca 2 + ER in intact and permeabilized RBL-2H3 cells via fluorescence measurements of cytoplasmic [Ca 2+ ] ([Ca 2+ ] c ) and mitochondrial matrix [Ca 2+ ] ([Ca 2+ ] m ). Preincubation of intact cells in high versus low extracellular [Ca 2+ ] caused disproportionally greater increase in [Ca 2+ ] m than [Ca 2+ ] c responses to IP 3 -mobilizing agonist. Increasing Ca 2 + ER by small Ca 2+ boluses in suspensions of permeabilized cells supralinearly enhanced the mitochondrial Ca 2+ uptake from IP 3 -induced Ca 2+ release. The IP 3 -induced local [Ca 2+ ] spikes exposing the mitochondrial surface measured using a genetically targeted sensor appeared to linearly correlate with Ca 2 + 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 Ca 2+ uptake. Interestingly, the IP 3 -induced [Ca 2+ ] m signal plateaued at high Ca 2 + ER , indicating activation of a matrix Ca 2+ binding/chelating species. Mitochondria thus seem to maintain a “working [Ca 2+ ] m range” via a low-affinity and high-capacity buffer species, and the ER loading steeply enhances the IP3R-linked [Ca 2+ ] m signals in this working range.https://doi.org/10.1177/25152564241229273 |
| spellingShingle | György Csordás David Weaver Péter Várnai György Hajnóczky Supralinear Dependence of the IP Receptor-to-Mitochondria Local Ca Transfer on the Endoplasmic Reticulum Ca Loading Contact |
| title | Supralinear Dependence of the IP Receptor-to-Mitochondria Local Ca Transfer on the Endoplasmic Reticulum Ca Loading |
| title_full | Supralinear Dependence of the IP Receptor-to-Mitochondria Local Ca Transfer on the Endoplasmic Reticulum Ca Loading |
| title_fullStr | Supralinear Dependence of the IP Receptor-to-Mitochondria Local Ca Transfer on the Endoplasmic Reticulum Ca Loading |
| title_full_unstemmed | Supralinear Dependence of the IP Receptor-to-Mitochondria Local Ca Transfer on the Endoplasmic Reticulum Ca Loading |
| title_short | Supralinear Dependence of the IP Receptor-to-Mitochondria Local Ca Transfer on the Endoplasmic Reticulum Ca Loading |
| title_sort | supralinear dependence of the ip receptor to mitochondria local ca transfer on the endoplasmic reticulum ca loading |
| url | https://doi.org/10.1177/25152564241229273 |
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