Department of Anesthesiology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53792, USA.
Laboratory of Genetics, School of Medicine and Public Health and College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Exp Biol Med (Maywood). 2023 Apr;248(7):545-552. doi: 10.1177/15353702231165025. Epub 2023 May 19.
One of the unsolved mysteries of medicine is how do volatile anesthetics (VAs) cause a patient to reversibly lose consciousness. In addition, identifying mechanisms for the collateral effects of VAs, including anesthetic-induced neurotoxicity (AiN) and anesthetic preconditioning (AP), has proven challenging. Multiple classes of molecules (lipids, proteins, and water) have been considered as potential VA targets, but recently proteins have received the most attention. Studies targeting neuronal receptors or ion channels had limited success in identifying the critical targets of VAs mediating either the phenotype of "anesthesia" or their collateral effects. Recent studies in both nematodes and fruit flies may provide a paradigm shift by suggesting that mitochondria may harbor the upstream molecular switch activating both primary and collateral effects. The disruption of a specific step of electron transfer within the mitochondrion causes hypersensitivity to VAs, from nematodes to and to humans, while also modulating the sensitivity to collateral effects. The downstream effects from mitochondrial inhibition are potentially legion, but inhibition of presynaptic neurotransmitter cycling appears to be specifically sensitive to the mitochondrial effects. These findings are perhaps of even broader interest since two recent reports indicate that mitochondrial damage may well underlie neurotoxic and neuroprotective effects of VAs in the central nervous system (CNS). It is, therefore, important to understand how anesthetics interact with mitochondria to affect CNS function, not just for the desired facets of general anesthesia but also for significant collateral effects, both harmful and beneficial. A tantalizing possibility exists that both the primary (anesthesia) and secondary (AiN, AP) mechanisms may at least partially overlap in the mitochondrial electron transport chain (ETC).
医学中的一个未解之谜是挥发性麻醉剂（VA）如何使患者可逆性地失去意识。此外，确定 VA 的副作用机制，包括麻醉诱导的神经毒性（AiN）和麻醉预处理（AP），一直具有挑战性。已经有多种分子类别（脂质、蛋白质和水）被认为是潜在的 VA 靶标，但最近蛋白质受到了最多的关注。针对神经元受体或离子通道的研究在确定介导“麻醉”表型或其副作用的 VA 的关键靶标方面取得的成功有限。线虫和果蝇的最近研究可能通过暗示线粒体可能拥有激活主要和副作用的上游分子开关来提供范式转变。在线粒体中破坏电子传递的特定步骤会导致对 VA 的超敏反应，从线虫到人类，同时也调节对副作用的敏感性。线粒体抑制的下游效应可能很多，但抑制突触前神经递质循环似乎对线粒体效应特别敏感。这些发现可能更具广泛的意义，因为最近的两项报告表明，线粒体损伤可能是 VA 在中枢神经系统（CNS）中产生神经毒性和神经保护作用的基础。因此，了解麻醉剂如何与线粒体相互作用以影响 CNS 功能非常重要，这不仅是为了全身麻醉的理想方面，而且还为有害和有益的重要副作用。一个诱人的可能性是，主要（麻醉）和次要（AiN、AP）机制至少在部分上可能重叠在线粒体电子传递链（ETC）中。
