Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah-Hebrew University Medical Center, Jerusalem 9112001, Israel.
Faculty of Medicine, Hebrew University of Jerusalem, Ein Kerem, Jerusalem 9112102, Israel.
Biomolecules. 2024 Sep 1;14(9):1096. doi: 10.3390/biom14091096.
Glycogen storage disorders (GSDs) are a group of inherited metabolic disorders characterized by defects in enzymes involved in glycogen metabolism. Deficiencies in enzymes responsible for glycogen breakdown and synthesis can impair mitochondrial function. For instance, in GSD type II (Pompe disease), acid alpha-glucosidase deficiency leads to lysosomal glycogen accumulation, which secondarily impacts mitochondrial function through dysfunctional mitophagy, which disrupts mitochondrial quality control, generating oxidative stress. In GSD type III (Cori disease), the lack of the debranching enzyme causes glycogen accumulation and affects mitochondrial dynamics and biogenesis by disrupting the integrity of muscle fibers. Malfunctional glycogen metabolism can disrupt various cascades, thus causing mitochondrial and cell metabolic dysfunction through various mechanisms. These dysfunctions include altered mitochondrial morphology, impaired oxidative phosphorylation, increased production of reactive oxygen species (ROS), and defective mitophagy. The oxidative burden typical of GSDs compromises mitochondrial integrity and exacerbates the metabolic derangements observed in GSDs. The intertwining of mitochondrial dysfunction and GSDs underscores the complexity of these disorders and has significant clinical implications. GSD patients often present with multisystem manifestations, including hepatomegaly, hypoglycemia, and muscle weakness, which can be exacerbated by mitochondrial impairment. Moreover, mitochondrial dysfunction may contribute to the progression of GSD-related complications, such as cardiomyopathy and neurocognitive deficits. Targeting mitochondrial dysfunction thus represents a promising therapeutic avenue in GSDs. Potential strategies include antioxidants to mitigate oxidative stress, compounds that enhance mitochondrial biogenesis, and gene therapy to correct the underlying mitochondrial enzyme deficiencies. Mitochondrial dysfunction plays a critical role in the pathophysiology of GSDs. Recognizing and addressing this aspect can lead to more comprehensive and effective treatments, improving the quality of life of GSD patients. This review aims to elaborate on the intricate relationship between mitochondrial dysfunction and various types of GSDs. The review presents challenges and treatment options for several GSDs.
糖原贮积病（GSD）是一组遗传性代谢疾病，其特征为参与糖原代谢的酶缺陷。负责糖原分解和合成的酶缺乏会损害线粒体功能。例如，在 GSD II 型（庞贝病）中，酸性α-葡萄糖苷酶缺乏导致溶酶体糖原积累，进而通过功能失调的自噬影响线粒体功能，破坏线粒体质量控制，产生氧化应激。在 GSD III 型（科里病）中，分支酶缺乏导致糖原积累，并通过破坏肌肉纤维的完整性影响线粒体动力学和生物发生，从而影响线粒体动力学和生物发生。糖原代谢功能障碍可破坏各种级联反应，通过多种机制导致线粒体和细胞代谢功能障碍。这些功能障碍包括线粒体形态改变、氧化磷酸化受损、活性氧（ROS）产生增加和自噬缺陷。GSD 特有的氧化应激负担损害线粒体完整性，并加剧 GSD 中观察到的代谢紊乱。线粒体功能障碍与 GSD 的交织突显了这些疾病的复杂性，并具有重要的临床意义。GSD 患者常表现为多系统表现，包括肝肿大、低血糖和肌肉无力，这些表现可因线粒体损伤而加重。此外，线粒体功能障碍可能导致 GSD 相关并发症的进展，如心肌病和神经认知缺陷。因此，靶向线粒体功能障碍是 GSD 的一种有前途的治疗方法。潜在的策略包括抗氧化剂来减轻氧化应激、增强线粒体生物发生的化合物以及纠正潜在线粒体酶缺乏的基因治疗。线粒体功能障碍在 GSD 的病理生理学中起着关键作用。认识和解决这一方面可以导致更全面和有效的治疗方法，提高 GSD 患者的生活质量。本综述旨在详细阐述线粒体功能障碍与各种 GSD 之间的复杂关系。该综述介绍了几种 GSD 的挑战和治疗选择。
