Subplasmalemmal mitochondria modulate the activity of plasma membrane Ca2+-ATPases.
Mitochondria are dynamic organelles that modulate cellular Ca2+ signals by interacting with Ca2+ transporters on the plasma membrane or the endoplasmic reticulum (ER). To study how mitochondria dynamics affects cell Ca2+ homeostasis, we overexpressed two mitochondrial fission proteins, hFis1 and Drp1, and measured Ca2+ changes within the cytosol and the ER in HeLa cells. Both proteins fragmented mitochondria, decreased their total volume by 25-40%, and reduced the fraction of subplasmalemmal mitochondria by 4-fold. The cytosolic Ca2+ signals elicited by histamine were unaltered in cells lacking subplasmalemmal mitochondria as long as Ca2+ was present in the medium, but the signals were significantly blunted when Ca2+ was removed. Upon Ca2+ withdrawal, the free ER Ca2+ concentration decreased rapidly, and hFis1 cells were unable to respond to repetitive histamine stimulations. The loss of stored Ca2+ was due to an increased activity of plasma membrane Ca2+-ATPase (PMCA) pumps and was associated with an increased influx of Ca2+ and Mn2+ across store-operated Ca2+ channels. The increased Ca2+ influx compensated for the loss of stored Ca2+, and brief Ca2+ additions between successive agonist stimulations fully corrected subsequent histamine responses. We propose that the lack of subplasmalemmal mitochondria disrupts the transfer of Ca2+ from plasma membrane channels to the ER and that the resulting increase in subplasmalemmal [Ca2+] up-regulates the activity of PMCA. The increased Ca2+ extrusion promotes ER depletion and the subsequent activation of store-operated Ca2+ channels. Cells thus adapt to the lack of subplasmalemmal mitochondria by relying on external rather than on internal Ca2+ for signaling.
Frieden
Maud
M
Department of Cell Physiology and Metabolism, University of Geneva Medical School, 1 Michel-Servet, CH-1211 Geneva 4, Switzerland.
Arnaudeau
Serge
S
Castelbou
Cyril
C
Demaurex
Nicolas
N
D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000502:physiology*; D027682:Cation Transport Proteins / Q000502:physiology*; D002462:Cell Membrane / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006367:HeLa Cells; D006632:Histamine / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D008345:Manganese / Q000378:metabolism; D008565:Membrane Proteins; D008856:Microscopy, Fluorescence; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000502:physiology*; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D053499:Plasma Membrane Calcium-Transporting ATPases; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D000098855:Collapsin Response Mediator Protein 1
D002118:Calcium; D000252:Calcium-Transporting ATPases; D027682:Cation Transport Proteins; D018076:DNA, Complementary; D006632:Histamine; D008345:Manganese; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D009419:Nerve Tissue Proteins; D053499:Plasma Membrane Calcium-Transporting ATPases; C102924:CRMP1 protein, human; D000098855:Collapsin Response Mediator Protein 1; C476525:FIS1 protein, human