Protective role of transient pore openings in calcium handling by cardiac mitochondria.

Journal Article (Journal Article)

Long-lasting mitochondrial permeability transition pore (mPTP) openings damage mitochondria, but transient mPTP openings protect against chronic cardiac stress. To probe the mechanism, we subjected isolated cardiac mitochondria to gradual Ca(2+) loading, which, in the absence of BSA, induced long-lasting mPTP opening, causing matrix depolarization. However, with BSA present to mimic cytoplasmic fatty acid-binding proteins, the mitochondrial population remained polarized and functional, even after matrix Ca(2+) release caused an extramitochondrial free [Ca(2+)] increase to >10 μM, unless mPTP openings were inhibited. These findings could be explained by asynchronous transient mPTP openings allowing individual mitochondria to depolarize long enough to flush accumulated matrix Ca(2+) and then to repolarize rapidly after pore closure. Because subsequent matrix Ca(2+) reuptake via the Ca(2+) uniporter is estimated to be >100-fold slower than matrix Ca(2+) release via mPTP, only a tiny fraction of mitochondria (<1%) are depolarized at any given time. Our results show that transient mPTP openings allow cardiac mitochondria to defend themselves collectively against elevated cytoplasmic Ca(2+) levels as long as respiratory chain activity is able to balance proton influx with proton pumping. We found that transient mPTP openings also stimulated reactive oxygen species production, which may engage reactive oxygen species-dependent cardioprotective signaling.

Full Text

Duke Authors

Cited Authors

  • Korge, P; Yang, L; Yang, J-H; Wang, Y; Qu, Z; Weiss, JN

Published Date

  • October 7, 2011

Published In

Volume / Issue

  • 286 / 40

Start / End Page

  • 34851 - 34857

PubMed ID

  • 21859717

Pubmed Central ID

  • PMC3186421

Electronic International Standard Serial Number (EISSN)

  • 1083-351X

Digital Object Identifier (DOI)

  • 10.1074/jbc.M111.239921

Language

  • eng

Conference Location

  • United States