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First published online 25 September 2007
doi: 10.1242/jcs.03486

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Reversible interactions between smooth domains of the endoplasmic reticulum and mitochondria are regulated by physiological cytosolic Ca²⁺ levels

Jacky G. Goetz^1,2,*, Hélène Genty^2,*, Pascal St-Pierre^1,*, Thao Dang^1,2, Bharat Joshi¹, Rémy Sauvé³, Wayne Vogl¹ and Ivan R. Nabi^1,

¹ Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver V6T 1Z3, Canada
² Department of Pathology and Cell Biology, Université de Montréal, Montreal H3C 3J7, Canada
³ Department of Physiology, Université de Montréal, Montreal H3C 3J7, Canada

Author for correspondence (e-mail: irnabi{at}interchange.ubc.ca)

Accepted 31 July 2007

The 3F3A monoclonal antibody to autocrine motility factor receptor (AMFR) labels mitochondria-associated smooth endoplasmic reticulum (ER) tubules. siRNA down-regulation of AMFR expression reduces mitochondria-associated 3F3A labelling. The 3F3A-labelled ER domain does not overlap with reticulon-labelled ER tubules, the nuclear membrane or perinuclear ER markers and only partially overlaps with the translocon component Sec61. Upon overexpression of FLAG-tagged AMFR, 3F3A labelling is mitochondria associated, excluded from the perinuclear ER and co-distributes with reticulon. 3F3A labelling therefore defines a distinct mitochondria-associated ER domain. Elevation of free cytosolic Ca²⁺ levels with ionomycin promotes dissociation of 3F3A-labelled tubules from mitochondria and, judged by electron microscopy, disrupts close contacts (<50 nm) between smooth ER tubules and mitochondria. The ER tubule-mitochondria association is similarly disrupted upon thapsigargin-induced release of ER Ca²⁺ stores or purinergic receptor stimulation by ATP. The inositol (1,4,5)-trisphosphate [Ins(1,4,5)P₃] receptor (IP3R) colocalises to 3F3A-labelled mitochondria-associated ER tubules, and conditions that induce ER tubule-mitochondria dissociation disrupt continuity between 3F3A- and IP3R-labelled ER domains. RAS-transformed NIH-3T3 cells have increased basal cytosolic Ca²⁺ levels and show dissociation of the 3F3A-labelled, but not IP3R-labelled, ER from mitochondria. Our data indicate that regulation of the ER-mitochondria association by free cytosolic Ca²⁺ is a characteristic of smooth ER domains and that multiple mechanisms regulate the interaction between these organelles.

Key words: Endoplasmic reticulum domains, Mitochondria, Free cytosolic calcium, AMFR, IP3R

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