Alignment of sarcoplasmic reticulum-mitochondrial junctions with mitochondrial contact points

Propagation of ryanodine receptor (RyR2)-derived Ca(2+) signals to the mitochondrial matrix supports oxidative ATP production or facilitates mitochondrial apoptosis in cardiac muscle. Ca(2+) transfer likely occurs locally at focal associations of the sarcoplasmic reticulum (SR) and mitochondria, whi...

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Published in:American journal of physiology. Heart and circulatory physiology 2011-11, Vol.301 (5), p.H1907-H1915
Main Authors: García-Pérez, Cecília, Schneider, Timothy G, Hajnóczky, György, Csordás, György
Format: Article
Language:English
Subjects:
Animals
Calcium
Calcium Signaling
Cardiovascular system
Cell Communication
Cell Fractionation
Cells
Cells, Cultured
Energetics and Metabolism
GTP Phosphohydrolases - deficiency
GTP Phosphohydrolases - genetics
Male
Membrane Proteins - metabolism
Mice
Mice, Knockout
Microscopy, Electron, Transmission
Microscopy, Fluorescence
Mitochondria, Heart - metabolism
Mitochondria, Heart - ultrastructure
Mitochondrial Membranes - metabolism
Mitochondrial Membranes - ultrastructure
Mitochondrial Proteins - metabolism
Myocardium - metabolism
Myocardium - ultrastructure
NADP - metabolism
Oxidoreductases - metabolism
Physiology
Proteins
Rats
Rats, Sprague-Dawley
Ryanodine Receptor Calcium Release Channel - metabolism
Sarcoplasmic Reticulum - metabolism
Sarcoplasmic Reticulum - ultrastructure
Signal transduction
Time Factors
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Summary:Propagation of ryanodine receptor (RyR2)-derived Ca(2+) signals to the mitochondrial matrix supports oxidative ATP production or facilitates mitochondrial apoptosis in cardiac muscle. Ca(2+) transfer likely occurs locally at focal associations of the sarcoplasmic reticulum (SR) and mitochondria, which are secured by tethers. The outer mitochondrial membrane and inner mitochondrial membrane (OMM and IMM, respectively) also form tight focal contacts (contact points) that are enriched in voltage-dependent anion channels, the gates of OMM for Ca(2+). Contact points could offer the shortest Ca(2+) transfer route to the matrix; however, their alignment with the SR-OMM associations remains unclear. Here, in rat heart we have studied the distribution of mitochondria-associated SR in submitochondrial membrane fractions and evaluated the colocalization of SR-OMM associations with contact points using transmission electron microscopy. In a sucrose gradient designed for OMM purification, biochemical assays revealed lighter fractions enriched in OMM only and heavier fractions containing OMM, IMM, and SR markers. Pure OMM fractions were enriched in mitofusin 2, an ~80 kDa mitochondrial fusion protein and SR-mitochondrial tether candidate, whereas in fractions of OMM + IMM + SR, a lighter (~50 kDa) band detected by antibodies raised against the NH(2) terminus of mitofusin 2 was dominating. Transmission electron microscopy revealed mandatory presence of contact points at the junctional SR-mitochondrial interface versus a random presence along matching SR-free OMM segments. For each SR-mitochondrial junction at least one tether was attached to contact points. These data establish the contact points as anchorage sites for the SR-mitochondrial physical coupling. Close coupling of the SR, OMM, and IMM is likely to provide a favorable spatial arrangement for local ryanodine receptor-mitochondrial Ca(2+) signaling.
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00397.2011