Control Mechanisms for Matching ATP Supply and Demand in Heart Mitochondria

不能提供与身体需求相匹配的能量限制了功能储备能力，在某些时期的压力下，如缺血，可能导致不可逆的细胞和组织损伤。这种匹配在代谢率高且波动迅速的组织（如心脏）中是至关重要的。线粒体是满足细胞需要的主要ATP供给者。线粒体使用的燃料通过线粒体内膜被输送到基质中，并产生电子源，这些电子源的氧化还原势能反过来又被电子传递链利用。电子的通量反映在氧气的消耗上。电子流释放的能量被用来将质子从基质中运输出来，穿过线粒体内膜，形成一个梯度，其质子动力驱动ATP合成酶制造ATP。这种“上游”监管被称为“推动”机制。对ATP合酶的控制机制尚缺乏完整的描述。在高水平的能量需求下，问题出现了，是否平行于“推动”机制的信号作用于ATP合酶也可以促进电子传递链的氧化还原通量，提高ATP生产的效率。这种效应模拟了上游通量上明显的额外“拉力”，这导致了呼吸的特定比例增加。迄今为止，这种“拉动”机制及其目标的证据尚未得到证明。

Failure to supply energy to match the body's demands limits the functional reserve capacity, and under certain periods of stress, such as ischemia, can lead to irreversible cell and tissue damage. This matching is critical in tissues with high and rapidly fluctuating metabolic rates such as the heart. Mitochondria are the main ATP suppliers to meet cellular demands. The fuel used by mitochondria is transported across the inner mitochondrial membrane to the matrix and produces a source of electrons whose redox-potential energy is, in turn, harnessed by the electron transport chain. The flux of electrons is reflected in oxygen consumption. The energy released from this electron flow is used to transport protons out of the matrix across the inner mitochondrial membrane forming a gradient whose proton-motive force drives ATP synthase to make ATP. This "upstream" regulation is known as the "push" mechanism. A complete description of the ATP synthase control mechanisms is still lacking. At high levels of energy demand the question arises whether parallel to the "push" mechanism signals acting on ATP synthase could also facilitate the electron transport chain redox flux, enhancing the efficiency of ATP production. This effect simulates an apparent additional "pull" on the upstream flux, which causes as a specific proportionate increase in respiration. Proof of such a "pull" mechanism and its target has not been demonstrated to-date. We found that the mechanisms that control ATP supply from the heart's mitochondria consist of both "push" and "pull" mechanisms and that the "pull" mechanism directly targets ATP synthase. We identified that the "push" and "pull" mechanisms are controlled by mitochondrial volume and Ca2+. At low cardiac workloads, a regulatory mitochondrial volume increase was found to facilitate mitochondrial Ca2+ entry responsible for pushing respiration (and in turn facilitating energy production), whereas at higher workloads, mitochondrial Ca2+ entry did not require such facilitation, and in turn was sufficient to drive both a push and pull effects on respiration. Identification of the matching mechanisms between ATP demand and supply could allow development of agents with better specificity that could potentially lead to the discovery of effective treatments, for example, for pathologies involving a failure of energy supply/demand matching, such as occurs in heart failure which afflicts millions of persons worldwide.