Makio Tadashi, Simmen Thomas
Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Contact (Thousand Oaks). 2024 Jul 25;7:25152564241261228. doi: 10.1177/25152564241261228. eCollection 2024 Jan-Dec.
Mitochondria-endoplasmic reticulum contacts (MERCs), also called endoplasmic reticulum (ER)-mitochondria contact sites (ERMCS), are the membrane domains, where these two organelles exchange lipids, Ca ions, and reactive oxygen species. This crosstalk is a major determinant of cell metabolism, since it allows the ER to control mitochondrial oxidative phosphorylation and the Krebs cycle, while conversely, it allows the mitochondria to provide sufficient ATP to control ER proteostasis. MERC metabolic signaling is under the control of tethers and a multitude of regulatory proteins. Many of these proteins have recently been discovered to give rise to rare diseases if their genes are mutated. Surprisingly, these diseases share important hallmarks and cause neurological defects, sometimes paired with, or replaced by skeletal muscle deficiency. Typical symptoms include developmental delay, intellectual disability, facial dysmorphism and ophthalmologic defects. Seizures, epilepsy, deafness, ataxia, or peripheral neuropathy can also occur upon mutation of a MERC protein. Given that most MERC tethers and regulatory proteins have secondary functions, some MERC protein-based diseases do not fit into this categorization. Typically, however, the proteins affected in those diseases have dominant functions unrelated to their roles in MERCs tethering or their regulation. We are discussing avenues to pharmacologically target genetic diseases leading to MERC defects, based on our novel insight that MERC defects lead to common characteristics in rare diseases. These shared characteristics of MERCs disorders raise the hope that they may allow for similar treatment options.
线粒体-内质网接触位点（MERC），也称为内质网（ER）-线粒体接触位点（ERMCS），是这两种细胞器交换脂质、钙离子和活性氧的膜结构域。这种相互作用是细胞代谢的主要决定因素，因为它使内质网能够控制线粒体氧化磷酸化和三羧酸循环，反之，它使线粒体能够提供足够的ATP来控制内质网蛋白质稳态。MERC代谢信号受连接蛋白和多种调节蛋白的控制。最近发现，如果这些蛋白质的基因发生突变，许多会引发罕见疾病。令人惊讶的是，这些疾病具有重要的共同特征，并导致神经缺陷，有时伴有骨骼肌缺陷或被其取代。典型症状包括发育迟缓、智力残疾、面部畸形和眼科缺陷。MERC蛋白发生突变时，也可能出现癫痫发作、耳聋、共济失调或周围神经病变。鉴于大多数MERC连接蛋白和调节蛋白具有次要功能，一些基于MERC蛋白产生的疾病并不符合这种分类。然而，通常情况下，那些疾病中受影响的蛋白质具有与其在MERC连接或调节中的作用无关的主要功能。基于我们的新见解，即MERC缺陷导致罕见疾病中的共同特征，我们正在探讨针对导致MERC缺陷的遗传疾病的药物靶点途径。MERC疾病的这些共同特征带来了希望，即它们可能有相似的治疗选择。
