ATP synthase K+- and H+-flux drive ATP synthesis and enable mitochondrial K+-uniporter function

Juhaszova, M.; Kobrinsky, E.; Zorov, D. B.; Nuss, B.; Yaniv, Y.; Fishbein, K. W.; de Cabo, R.; Montoliu, L.; Gabelli, S. B.; Aon, M. A.; Cortassa, S.; Sollott, S. J.

doi:10.1101/355776

bioRxiv · 10.1101/355776

ATP synthase K+- and H+-flux drive ATP synthesis and enable mitochondrial K+-uniporter function

Juhaszova, M.·Kobrinsky, E.·Zorov, D. B.·Nuss, B.·Yaniv, Y.·Fishbein, K. W.·de Cabo, R.·Montoliu, L.·Gabelli, S. B.·Aon, M. A.·Cortassa, S.·Sollott, S. J.

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Abstract

ATP synthase (F1Fo) synthesizes daily our bodys weight in ATP, whose production-rate can be transiently increased several-fold. Using purified mammalian F1Fo-reconstituted proteoliposomes and isolated mitochondria, we show that F1Fo utilizes both H+- and K+-transport (because of >106-fold K+ excess vs H+) to drive ATP synthesis with the H+:K+ permeability of ~106:1. F1Fo can be upregulated by endogenous survival-related proteins (Bcl-xL, Mcl-1) and synthetic molecules (diazoxide, pinacidil) to increase its chemo-mechanical efficiency via IF1. Increasing K+- and H+-driven ATP synthesis enables F1Fo to operate as a primary mitochondrial K+-uniporter regulating energy supply-demand matching, and as the recruitable mitochondrial KATP-channel that can limit ischemia-reperfusion injury. Isolated mitochondria in the presence of K+ can sustain ~3.5-fold higher ATP-synthesis-flux (vs K+ absence) driven by a 2.7:1 K+:H+ stoichiometry with unaltered OxPhos coupling. Excellent agreement between F1Fo single-molecule and intact-mitochondria experiments is consistent with K+-transport through ATP synthase driving a major fraction of ATP synthesis.

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Juhaszova, M., Kobrinsky, E., Zorov, D. B., Nuss, B., Yaniv, Y., Fishbein, K. W., de Cabo, R., Montoliu, L., Gabelli, S. B., Aon, M. A., Cortassa, S., Sollott, S. J.. 2018-06-26. ATP synthase K+- and H+-flux drive ATP synthesis and enable mitochondrial K+-uniporter function. https://doi.org/10.1101/355776

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