Guntur Vamsi P, Nemkov Travis, de Boer Esther, Mohning Michael P, Baraghoshi David, Cendali Francesca I, San-Millán Inigo, Petrache Irina, D'Alessandro Angelo
Division of Pulmonary and Critical Care and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, CO 80206, USA.
Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Metabolites. 2022 Oct 26;12(11):1026. doi: 10.3390/metabo12111026.
Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or "long-COVID"). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests to volitional exertion, suggesting altered metabolism and mitochondrial dysfunction. It remains unclear whether the profound disturbances in metabolism that have been identified in plasma from patients suffering from acute coronavirus disease 2019 (COVID-19) are also present in PASC. To bridge this gap, individuals with a history of previous acute COVID-19 infection that did not require hospitalization were enrolled at National Jewish Health (Denver, CO, USA) and were grouped into those that developed PASC (n = 29) and those that fully recovered (n = 16). Plasma samples from the two groups were analyzed via mass spectrometry-based untargeted metabolomics and compared against plasma metabolic profiles of healthy control individuals (n = 30). Observational demographic and clinical data were retrospectively abstracted from the medical record. Compared to plasma of healthy controls or individuals who recovered from COVID-19, PASC plasma exhibited significantly higher free- and carnitine-conjugated mono-, poly-, and highly unsaturated fatty acids, accompanied by markedly lower levels of mono-, di- and tricarboxylates (pyruvate, lactate, citrate, succinate, and malate), polyamines (spermine) and taurine. Plasma from individuals who fully recovered from COVID-19 exhibited an intermediary metabolic phenotype, with milder disturbances in fatty acid metabolism and higher levels of spermine and taurine. Of note, depletion of tryptophan-a hallmark of disease severity in COVID-19-is not normalized in PASC patients, despite normalization of kynurenine levels-a tryptophan metabolite that predicts mortality in hospitalized COVID-19 patients. In conclusion, PASC plasma metabolites are indicative of altered fatty acid metabolism and dysfunctional mitochondria-dependent lipid catabolism. These metabolic profiles obtained at rest are consistent with previously reported mitochondrial dysfunction during exercise, and may pave the way for therapeutic intervention focused on restoring mitochondrial fat-burning capacity.
运动不耐受是严重急性呼吸综合征冠状病毒感染后急性后遗症（PASC，即“长新冠”）的主要表现。在分级运动试验至力竭时，PASC中的运动不耐受与较高的动脉血乳酸积累和较低的脂肪酸氧化率相关，提示代谢改变和线粒体功能障碍。目前尚不清楚在2019年冠状病毒病（COVID-19）急性期患者血浆中发现的代谢深度紊乱在PASC中是否也存在。为填补这一空白，在美国科罗拉多州丹佛市的国家犹太医学中心招募了有既往急性COVID-19感染史但无需住院治疗的个体，并将其分为发生PASC的个体（n = 29）和完全康复的个体（n = 16）。通过基于质谱的非靶向代谢组学分析两组的血浆样本，并与健康对照个体（n = 30）的血浆代谢谱进行比较。观察性人口统计学和临床数据从病历中进行回顾性提取。与健康对照或从COVID-19中康复的个体的血浆相比，PASC血浆中游离的和肉碱共轭的单不饱和、多不饱和和高度不饱和脂肪酸显著更高，同时单羧酸盐、二羧酸盐和三羧酸盐（丙酮酸、乳酸、柠檬酸、琥珀酸和苹果酸）、多胺（精胺）和牛磺酸的水平明显更低。从COVID-19中完全康复的个体的血浆表现出中间代谢表型，脂肪酸代谢紊乱较轻，精胺和牛磺酸水平较高。值得注意的是，尽管犬尿氨酸水平恢复正常（犬尿氨酸是一种预测住院COVID-19患者死亡率的色氨酸代谢产物），但PASC患者色氨酸的消耗（COVID-19疾病严重程度的一个标志）并未恢复正常。总之，PASC血浆代谢物表明脂肪酸代谢改变和线粒体依赖性脂质分解代谢功能障碍。这些静息状态下获得的代谢谱与先前报道的运动期间线粒体功能障碍一致，并可能为专注于恢复线粒体脂肪燃烧能力的治疗干预铺平道路。
