Sharma Shashwat, McKenzie Matthew
School of Life and Environmental Sciences, Faculty of Science, Engineering and Built Environment, Deakin University, 75 Pigdons Road, Waurn Ponds, VIC 3216, Australia.
Institute for Physical Activity and Nutrition, Deakin University, 75 Pigdons Road, Waurn Ponds, VIC 3216, Australia.
Biomolecules. 2025 Mar 14;15(3):416. doi: 10.3390/biom15030416.
Living systems require energy to maintain their existence and perform tasks such as cell division. This energy is stored in several molecular forms in nature, specifically lipids, carbohydrates, and amino acids. At a cellular level, energy is extracted from these complex molecules and transferred to adenosine triphosphate (ATP) in the cytoplasm and mitochondria. Within the mitochondria, fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are crucial metabolic processes involved in generating ATP, with defects in these pathways causing mitochondrial disease. Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a fatty acid β-oxidation disorder (FAOD) affecting 1 to 2 individuals per 100,000. Similar to other mitochondrial disorders, there is no cure for VLCADD, with symptomatic treatment comprising dietary management and supplementation with medium-chain fatty acids to bypass the enzyme deficiency. While this addresses the primary defect in VLCADD, there is growing evidence that other aspects of mitochondrial function are also affected in VLCADD, including secondary defects in OXPHOS function. Here, we review our current understanding of VLCADD with a focus on the associated biochemical and molecular defects that can disrupt multiple aspects of mitochondrial function. We describe the interactions between FAO proteins and the OXPHOS complexes and how these interactions are critical for maintaining the activity of both metabolic pathways. In particular, we describe what is now known about the protein-protein interactions between VLCAD and the OXPHOS supercomplex and how their disruption contributes to overall VLCADD pathogenesis.
生命系统需要能量来维持自身存在并执行诸如细胞分裂等任务。这种能量以几种分子形式储存在自然界中，特别是脂质、碳水化合物和氨基酸。在细胞水平上，能量从这些复杂分子中提取出来，并在细胞质和线粒体中转移到三磷酸腺苷（ATP）。在线粒体内，脂肪酸β-氧化（FAO）和氧化磷酸化（OXPHOS）是参与生成ATP的关键代谢过程，这些途径中的缺陷会导致线粒体疾病。极长链酰基辅酶A脱氢酶缺乏症（VLCADD）是一种脂肪酸β-氧化障碍（FAOD），每10万人中有1至2人受影响。与其他线粒体疾病类似，VLCADD无法治愈，对症治疗包括饮食管理和补充中链脂肪酸以绕过酶缺乏。虽然这解决了VLCADD的主要缺陷，但越来越多的证据表明，VLCADD中线粒体功能的其他方面也受到影响，包括氧化磷酸化功能的继发性缺陷。在这里，我们回顾了我们目前对VLCADD的理解，重点关注可能破坏线粒体功能多个方面的相关生化和分子缺陷。我们描述了FAO蛋白与OXPHOS复合物之间的相互作用，以及这些相互作用如何对维持两种代谢途径的活性至关重要。特别是，我们描述了目前已知的VLCAD与OXPHOS超复合物之间的蛋白质-蛋白质相互作用，以及它们的破坏如何导致整体VLCADD发病机制。
