Cardiolipins and mitochondrial proton-selective leakage

The proton-selective leak (State 4 respiratory rate) but not delta psi, in mitochondria from thyroid-sensitive tissues, responds to in vivo stimuli in unique correlation with changes in cardiolipins, saturated and mono-unsaturated (extended) fatty acyl contents, cardiolipins/phospholipids ratios, and/or membrane outer-sidedness. Liver mitochondrial State 4 respiration, basal in fasted rats, contributes little to resting metabolic rate in fed rats, where State 3 depresses delta psi. In a proposed model, an essential inner-membrane outer-surface proton antenna collects protons and donates them, via a water-shuttle, to transmembrane porters: transient water-molecule-chains between extended phospholipid acyls; protonophores, and uncoupling proteins. Only cardiolipin microdomains can donate, from an anomalously-dissociating phosphate group in each headgroup; unadapted cardiolipins have few conducting water chains. Thyroid states regulate each cardiolipin property, and are permissive, via the proton antenna, for proton leaks, including those through adapted and possibly constitutive BAT and ectopic uncoupling proteins. Slow leakage in liposomes may reflect insufficient cardiolipin proton antennas.