Maternally inherited mitochondrial respiratory disorders are rare, progressive, and multi-systemic diseases that remain intractable, with no effective therapeutic interventions. Patients share a defective oxidative phosphorylation pathway responsible for mitochondrial ATP synthesis, in most cases due to pathogenic mitochondrial variants transmitted from mother to child or to a rare de novo mutation or large-scale deletion of the mitochondrial genome. The clinical diagnosis of these mitochondrial diseases is difficult due to exceptionally high clinical variability, while their genetic diagnosis has improved with the advent of next-generation sequencing. The mechanisms regulating the penetrance of the mitochondrial variants remain unresolved with the patient’s nuclear background, epigenomic regulation, heteroplasmy, mitochondrial haplogroups, and environmental factors thought to act as rheostats. The lack of animal models mimicking the phenotypic manifestations of these disorders has hampered efforts toward curative therapies. Patient-derived cellular paradigms provide alternative models for elucidating the pathogenic mechanisms and screening pharmacological small molecules to enhance mitochondrial function. Recent progress has been made in designing promising approaches to curtail the negative impact of dysfunctional mitochondria and alleviate clinical symptoms: 1) boosting mitochondrial biogenesis; 2) shifting heteroplasmy; 3) reprogramming metabolism; and 4) administering hypoxia-based treatment. Here, we discuss their varying efficacies and limitations and provide an outlook on their therapeutic potential and clinical application.

母系遗传的线粒体呼吸系统疾病是罕见的、进行性的、多系统疾病，仍然难以治疗，没有有效的治疗干预措施。患者共享负责线粒体 ATP 合成的有缺陷的氧化磷酸化途径，在大多数情况下是由于从母婴传播的致病性线粒体变异或罕见的从头传播线粒体基因组的突变或大规模缺失。由于异常高的临床变异性，这些线粒体疾病的临床诊断很困难，而随着下一代测序的出现，它们的基因诊断得到了改善。由于患者的核背景、表观基因组调节、异质性、线粒体单倍群和被认为充当变阻器的环境因素，调节线粒体变体外显率的机制仍未得到解决。缺乏模仿这些疾病表型表现的动物模型阻碍了治愈性治疗的努力。源自患者的细胞范例为阐明致病机制和筛选药理学小分子以增强线粒体功能提供了替代模型。最近在设计有希望的方法来减少线粒体功能障碍的负面影响和减轻临床症状方面取得了进展：1) 促进线粒体生物发生；2) 转移异质性；3) 重编程代谢；4)进行基于缺氧的治疗。在这里，我们讨论了它们不同的功效和局限性，并对它们的治疗潜力和临床应用进行了展望。