Seneff Stephanie, Kyriakopoulos Anthony M
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, United States.
Laboratory of Molecular Biology and Immunology, Department of Pharmacy, University of Patras, Rio-Patras, Greece.
Front Mol Biosci. 2025 Jul 22;12:1639327. doi: 10.3389/fmolb.2025.1639327. eCollection 2025.
Deuterium is a natural heavy isotope of hydrogen, containing an extra neutron. Eukaryotic organisms have devised complex metabolic policies that restrict the amount of deuterium reaching the mitochondria, because it damages the ATPase pumps, leading to release of excessive reactive oxygen species and inefficiencies in ATP production. Human metabolism relies heavily on the gut microbiome to assure an abundant supply of deuterium depleted (deupleted) nutrients to the host. Mitochondrial dysfunction is a hallmark of many chronic diseases, and deuterium overload, often due to gut dysbiosis, may be a major factor contributing to this issue. In this paper, we explore the potential role of certain amyloidogenic proteins, including amylin, amyloid beta, the prion protein, huntingtin, and -synuclein, in disease processes that result in the accumulation of deposits of protein fibrils, along with lipid membrane components of damaged mitochondria, which we argue may be a mechanism to sequester deuterium in order to reduce the deuterium burden in the tissues. We show how cardiolipin, an anionic lipid synthesized in mitochondria and localized to the mitochondrial membrane, may play a central role both in trapping deuterium in the mitochondrial membrane and in inducing protein misfolding to facilitate the formation of deuterium-rich deposits. We focus on the potential role of the amino acid histidine and its interaction with the mineral copper, both to catalyze certain essential reactions and to facilitate the misfolding of amyloidogenic proteins triggered by contact with anionic phospholipids, particularly cardiolipin, and especially in the outer mitochondrial membrane of deuterium-damaged mitochondria.
氘是氢的一种天然重同位素，含有一个额外的中子。真核生物已经制定了复杂的代谢策略来限制进入线粒体的氘的量，因为它会损害ATP酶泵，导致过量活性氧的释放以及ATP生成效率低下。人体新陈代谢严重依赖肠道微生物群，以确保向宿主提供充足的低氘（去氘）营养物质。线粒体功能障碍是许多慢性疾病的一个标志，而氘过载（通常由于肠道菌群失调）可能是导致这一问题的一个主要因素。在本文中，我们探讨了某些淀粉样蛋白，包括胰淀素、β淀粉样蛋白、朊病毒蛋白、亨廷顿蛋白和α-突触核蛋白，在导致蛋白质原纤维沉积物积累的疾病过程中的潜在作用，以及受损线粒体的脂质膜成分，我们认为这可能是一种隔离氘以减轻组织中氘负担的机制。我们展示了心磷脂（一种在线粒体中合成并定位于线粒体内膜的阴离子脂质）如何在将氘捕获在线粒体内膜以及诱导蛋白质错误折叠以促进富含氘的沉积物形成方面发挥核心作用。我们关注氨基酸组氨酸的潜在作用及其与矿物质铜的相互作用，这两者既能催化某些关键反应，又能促进由与阴离子磷脂（特别是心磷脂）接触引发的淀粉样蛋白错误折叠，尤其是在氘损伤的线粒体的线粒体外膜中。
