Loss of Ptpmt1 limits mitochondrial utilization of carbohydrates and leads to muscle atrophy and heart failure in tissue-specific knockout mice.
Loss of Ptpmt1 limits mitochondrial utilization of carbohydrates and leads to muscle atrophy and heart failure in tissue-specific knockout mice.
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作者：
Zheng H;Li Q;Li S;Li Z;Brotto M;Weiss D;Prosdocimo D;Xu C;Reddy A;Puchowicz M;Zhao X;Weitzmann MN;Jain MK;Qu CK
虽然不同组织中的线粒体对能量来源有不同的偏好，但它们能够根据生理和营养状况灵活利用相互竞争的底物进行代谢。然而，代谢灵活性的调节机制及其重要性尚未完全被理解。在此，我们报道一种基于线粒体的磷酸酶Ptpmt1的缺失会严重改变线粒体的燃料选择——丙酮酸（一种来自葡萄糖（主要的单糖）的关键线粒体底物）的利用受到抑制，而脂肪酸的利用则增强。Ptpmt1基因敲除并不影响骨骼肌或心脏的发育。然而，这种代谢不灵活性最终导致肌肉萎缩、心力衰竭和猝死。机制分析表明，底物从碳水化合物向脂质的长期转变会导致氧化应激和线粒体破坏，进而导致基因敲除的肌肉细胞和心肌细胞中脂质显著积累和严重损伤。有趣的是，肝脏或脂肪组织中Ptpmt1的缺失不会产生任何局部或全身性缺陷。这些发现表明Ptpmt1在维持线粒体灵活性方面起着重要作用，并且尽管这两种组织有不同的首选能量来源，但碳水化合物和脂质的平衡利用对骨骼肌和心脏都是至关重要的。
细胞由线粒体提供能量，线粒体是一组细胞器，以一种叫做三磷酸腺苷（ATP）的分子形式产生化学能。这种能量来自碳水化合物、脂肪和蛋白质的分解。
一个细胞中线粒体的数量以及它们用于产生ATP的能量来源因细胞类型而异。当细胞应对压力或疾病时，线粒体也可以转换它们用于产生能量的分子。
心脏和骨骼肌（用于运动）是两种需要大量能量的组织，但破坏线粒体燃料选择是否会影响这些组织的功能仍不清楚。
为了回答这些问题，郑、李、李等人研究了一种在线粒体中发现的叫做Ptpmt1的酶的作用。在小鼠的心脏和骨骼肌中基因敲除Ptpmt1表明，虽然这些器官的发育没有受到影响，但这些细胞中的线粒体从使用碳水化合物转变为使用脂肪作为能量来源。随着时间的推移，这种转变损害了线粒体和组织，导致小鼠肌肉萎缩、心力衰竭和猝死。这表明碳水化合物和脂肪的平衡使用对肌肉和心脏是至关重要的。
这些发现意味着长期使用改变线粒体所用燃料的药物可能对患者健康有害，并可能导致心脏功能障碍。这对于未来的药物开发以及临床用药决策可能都很重要。
While mitochondria in different tissues have distinct preferences for energy sources, they are flexible in utilizing competing substrates for metabolism according to physiological and nutritional circumstances. However, the regulatory mechanisms and significance of metabolic flexibility are not completely understood. Here, we report that the deletion of Ptpmt1, a mitochondria-based phosphatase, critically alters mitochondrial fuel selection – the utilization of pyruvate, a key mitochondrial substrate derived from glucose (the major simple carbohydrate), is inhibited, whereas the fatty acid utilization is enhanced. Ptpmt1 knockout does not impact the development of the skeletal muscle or heart. However, the metabolic inflexibility ultimately leads to muscular atrophy, heart failure, and sudden death. Mechanistic analyses reveal that the prolonged substrate shift from carbohydrates to lipids causes oxidative stress and mitochondrial destruction, which in turn results in marked accumulation of lipids and profound damage in the knockout muscle cells and cardiomyocytes. Interestingly, Ptpmt1 deletion from the liver or adipose tissue does not generate any local or systemic defects. These findings suggest that Ptpmt1 plays an important role in maintaining mitochondrial flexibility and that their balanced utilization of carbohydrates and lipids is essential for both the skeletal muscle and the heart despite the two tissues having different preferred energy sources. Cells are powered by mitochondria, a group of organelles that produce chemical energy in the form of molecules called ATP. This energy is derived from the breakdown of carbohydrates, fats, and proteins. The number of mitochondria in a cell and the energy source they use to produce ATP varies depending on the type of cell. Mitochondria can also switch the molecules they use to produce energy when the cell is responding to stress or disease. The heart and the skeletal muscles – which allow movement – are two tissues that require large amounts of energy, but it remained unknown whether disrupting mitochondrial fuel selection affects how these tissues work. To answer these questions, Zheng, Li, Li et al. investigated the role of an enzyme found in mitochondria called Ptpmt1. Genetically deleting Ptpmt1 in the heart and skeletal muscle of mice showed that while the development of these organs was not affected, mitochondria in these cells switched from using carbohydrates to using fats as an energy source. Over time, this shift damaged both the mitochondria and the tissues, leading to muscle wasting, heart failure, and sudden death in the mice. This suggests that balanced use of carbohydrates and fats is essential for the muscles and heart. These findings imply that long-term use of medications that alter the fuel that mitochondria use may be detrimental to patients’ health and could cause heart dysfunction. This may be important for future drug development, as well as informing decisions about medication taken in the clinic.