Juhaszova 2019 bioRxiv

Juhaszova M, Kobrinsky E, Zorov DB, Nuss HB, Yaniv Y, Fishbein KW, de Cabo R, Montoliu L, Gabelli SB, Aon MA, Cortassa S, Sollott SJ (2019) ATP synthase K+- and H+-flux drive ATP synthesis and enable mitochondrial K+-uniporter function. bioRxiv doi: https://doi.org/10.1101/355776 .

» bioRxiv Open Access

Juhaszova M, Kobrinsky E, Zorov DB, Nuss HB, Yaniv Y, Fishbein KW, de Cabo R, Montoliu L, Gabelli SB, Aon MA, Cortassa S, Sollott SJ (2019) bioRxiv

Abstract: ATP synthase (F₁F_o) synthesizes daily our body’s weight in ATP, whose production-rate can be transiently increased several-fold. Using purified mammalian F₁F_o-reconstituted proteoliposomes and isolated mitochondria, we show that F₁F_o 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. F₁F_o 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 F₁F_o to operate as a primary mitochondrial K⁺-uniporter regulating energy supply-demand matching, and as the recruitable mitochondrial K_ATP-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 F₁F_o 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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