Control Mechanisms for Matching ATP Supply and Demand in Heart Mitochondria

不能提供能量以满足身体的需求限制了功能储备能力，并且在某些压力时期，如缺血，可能导致不可逆的细胞和组织损伤。 这种匹配在具有高且快速波动的代谢率的组织（如心脏）中至关重要。线粒体是满足细胞需求的主要ATP供应者。线粒体使用的燃料通过线粒体内膜运输到基质，并产生电子源，电子源的氧化还原势能反过来又被电子运输链利用。 电子的通量反映在氧的消耗上。从该电子流释放的能量用于将质子运输出基质穿过线粒体内膜，形成梯度，其质子动力驱动ATP合酶产生ATP。这种“上游”调控被称为“推动”机制。ATP合成酶的控制机制的完整描述仍然缺乏。在高水平的能源需求的问题是否平行的“推”机制信号作用于ATP合酶也可以促进电子传递链氧化还原通量，提高ATP生产的效率。这种效应模拟了对上游通量的明显的额外“拉动”，其导致呼吸的特定比例增加。这种“拉动”机制及其目标的证据迄今尚未得到证实。 我们发现，控制心脏线粒体ATP供应的机制包括“推”和“拉”机制，而“拉”机制直接靶向ATP合酶。我们发现，“推”和“拉”机制是由线粒体体积和Ca 2+控制。 在低心脏工作负荷下，发现调节性线粒体体积增加促进线粒体Ca 2+进入，负责推动呼吸（进而促进能量产生），而在较高工作负荷下，线粒体Ca 2+进入不需要这种促进，进而足以驱动呼吸的推拉效应。 ATP需求和供应之间的匹配机制的鉴定可以允许开发具有更好特异性的试剂，其可以潜在地导致发现有效的治疗，例如，用于涉及能量供应/需求匹配失败的病理学，例如发生在困扰全世界数百万人的心力衰竭中。

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.