Dynamics of matrix-free Ca2+ in cardiac mitochondria: Two components of Ca2+ uptake and role of phosphate buffering

An Chi Wei, Ting Liu, Raimond L. Winslow, Brian O'Rourke

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


Mitochondrial Ca2+ uptake is thought to provide an important signal to increase energy production to meet demand but, in excess, can also trigger cell death. The mechanisms defining the relationship between total Ca2+ uptake, changes in mitochondrial matrix free Ca2+, and the activation of the mitochondrial permeability transition pore (PTP) are not well understood. We quantitatively measure changes in [Ca2+]out and [Ca2+]mito during Ca2+ uptake in isolated cardiac mitochondria and identify two components of Ca2+ influx. [Ca2+]mito recordings revealed that the first, MCUmode1, required at least 1 μM Ru360 to be completely inhibited, and responded to small Ca2+ additions in the range of 0.1 to 2 μM with rapid and large changes in [Ca2+]mito. The second component, MCUmode2, was blocked by 100 nM Ru360 and was responsible for the bulk of total Ca2+ uptake for large Ca2+ additions in the range of 2 to 10 μM; however, it had little effect on steady-state [Ca2+]mito. MCUmode1 mediates changes in [Ca2+]mito of 10s of μM, even in the presence of 100 nM Ru360, indicating that there is a finite degree of Ca2+ buffering in the matrix associated with this pathway. In contrast, the much higher Ca2+ loads evoked by MCUmode2 activate a secondary dynamic Ca2+ buffering system consistent with calcium-phosphate complex formation. Increasing Pi potentiated [Ca2+]mito increases via MCUmode1 but suppressed [Ca2+]mito changes via MCUmode2. The results suggest that the role of MCUmode1 might be to modulate oxidative phosphorylation in response to intracellular Ca2+ signaling, whereas MCUmode2 and the dynamic high-capacity Ca2+ buffering system constitute a Ca2+ sink function. Interestingly, the trigger for PTP activation is unlikely to be [Ca2+]mito itself but rather a downstream byproduct of total mitochondrial Ca2+ loading.

Original languageEnglish (US)
Pages (from-to)465-478
Number of pages14
JournalJournal of General Physiology
Issue number6
StatePublished - Jun 2012

ASJC Scopus subject areas

  • Physiology


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