Proulx Jessica, Park In-Woo, Borgmann Kathleen
Department of Microbiology, Immunology and Genetics, University of North Texas Health Science Center (HSC), Fort Worth, TX, United States.
Front Neurosci. 2021 Oct 21;15:715945. doi: 10.3389/fnins.2021.715945. eCollection 2021.
The endoplasmic reticulum (ER) is a multifunctional organelle and serves as the primary site for intracellular calcium storage, lipid biogenesis, protein synthesis, and quality control. Mitochondria are responsible for producing the majority of cellular energy required for cell survival and function and are integral for many metabolic and signaling processes. Mitochondria-associated ER membranes (MAMs) are direct contact sites between the ER and mitochondria that serve as platforms to coordinate fundamental cellular processes such as mitochondrial dynamics and bioenergetics, calcium and lipid homeostasis, autophagy, apoptosis, inflammation, and intracellular stress responses. Given the importance of MAM-mediated mechanisms in regulating cellular fate and function, MAMs are now known as key molecular and cellular hubs underlying disease pathology. Notably, neurons are uniquely susceptible to mitochondrial dysfunction and intracellular stress, which highlights the importance of MAMs as potential targets to manipulate MAM-associated mechanisms. However, whether altered MAM communication and connectivity are causative agents or compensatory mechanisms in disease development and progression remains elusive. Regardless, exploration is warranted to determine if MAMs are therapeutically targetable to combat neurodegeneration. Here, we review key MAM interactions and proteins both and models of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. We further discuss implications of MAMs in HIV-associated neurocognitive disorders (HAND), as MAMs have not yet been explored in this neuropathology. These perspectives specifically focus on mitochondrial dysfunction, calcium dysregulation and ER stress as notable MAM-mediated mechanisms underlying HAND pathology. Finally, we discuss potential targets to manipulate MAM function as a therapeutic intervention against neurodegeneration. Future investigations are warranted to better understand the interplay and therapeutic application of MAMs in glial dysfunction and neurotoxicity.
内质网（ER）是一种多功能细胞器，是细胞内钙储存、脂质生物合成、蛋白质合成及质量控制的主要场所。线粒体负责产生细胞存活和功能所需的大部分细胞能量，并且是许多代谢和信号传导过程所必需的。线粒体相关内质网膜（MAM）是内质网和线粒体之间的直接接触位点，作为协调基本细胞过程的平台，如线粒体动力学和生物能量学、钙和脂质稳态、自噬、细胞凋亡、炎症和细胞内应激反应。鉴于MAM介导的机制在调节细胞命运和功能中的重要性，MAM现在被认为是疾病病理学潜在的关键分子和细胞枢纽。值得注意的是，神经元对线粒体功能障碍和细胞内应激特别敏感，这突出了MAM作为操纵与MAM相关机制的潜在靶点的重要性。然而，MAM通讯和连接性的改变是疾病发生和发展中的致病因素还是补偿机制仍不清楚。无论如何，有必要进行探索以确定MAM是否可作为治疗靶点来对抗神经退行性变。在此，我们综述了阿尔茨海默病、帕金森病和肌萎缩侧索硬化症的关键MAM相互作用和蛋白质以及相关模型。我们还进一步讨论了MAM在与HIV相关的神经认知障碍（HAND）中的意义，因为在这种神经病理学中尚未对MAM进行研究。这些观点特别关注线粒体功能障碍、钙调节异常和内质网应激，它们是HAND病理学中显著的MAM介导机制。最后，我们讨论了操纵MAM功能作为对抗神经退行性变的治疗干预的潜在靶点。未来有必要进行进一步研究，以更好地理解MAM在神经胶质功能障碍和神经毒性中的相互作用及治疗应用。
