Departments of Medicine and Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA; East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA.
Departments of Medicine and Pharmacology and Cancer Biology, Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Duke University, Durham, NC 27701, USA.
Cell Rep. 2018 Sep 25;24(13):3593-3606.e10. doi: 10.1016/j.celrep.2018.08.091.
Chronic metabolic diseases have been linked to molecular signatures of mitochondrial dysfunction. Nonetheless, molecular remodeling of the transcriptome, proteome, and/or metabolome does not necessarily translate to functional consequences that confer physiologic phenotypes. The work here aims to bridge the gap between molecular and functional phenomics by developing and validating a multiplexed assay platform for comprehensive assessment of mitochondrial energy transduction. The diagnostic power of the platform stems from a modified version of the creatine kinase energetic clamp technique, performed in parallel with multiplexed analyses of dehydrogenase activities and ATP synthesis rates. Together, these assays provide diagnostic coverage of the mitochondrial network at a level approaching that gained by molecular "-omics" technologies. Application of the platform to a comparison of skeletal muscle versus heart mitochondria reveals mechanistic insights into tissue-specific distinctions in energy transfer efficiency. This platform opens exciting opportunities to unravel the connection between mitochondrial bioenergetics and human disease.
慢性代谢性疾病与线粒体功能障碍的分子特征有关。然而，转录组、蛋白质组和/或代谢组的分子重构不一定转化为赋予生理表型的功能后果。这里的工作旨在通过开发和验证一种用于全面评估线粒体能量转导的多重分析平台来弥合分子和功能表型之间的差距。该平台的诊断能力源于改良的肌酸激酶能量钳技术版本，与脱氢酶活性和 ATP 合成率的多重分析并行进行。这些检测共同提供了接近分子“组学”技术获得的水平的线粒体网络的诊断覆盖范围。该平台在骨骼肌与心肌线粒体比较中的应用揭示了能量传递效率在组织特异性方面的机制差异。该平台为揭示线粒体生物能量学与人类疾病之间的联系开辟了令人兴奋的机会。
