Anaerobic Glycolysis Maintains the Glomerular Filtration Barrier Independent of Mitochondrial Metabolism and Dynamics
Anaerobic Glycolysis Maintains the Glomerular Filtration Barrier Independent of Mitochondrial Metabolism and Dynamics
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DOI：
10.1016/j.celrep.2019.04.012
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发表时间：
2019-04-30
期刊：
影响因子：
8.8
通讯作者：
Huber, Tobias B.
中科院分区：
文献类型：
--
作者：
Brinkkoetter, Paul T.;Bork, Tillmann;Huber, Tobias B.
由线粒体功能障碍诱导的细胞反应仍然难以捉摸。我们对严重肾缺血患者几乎没有任何肾小球表型感兴趣，我们全面研究了肾小球足细胞的主要能量来源。结合功能测量的耗氧率，肾小球代谢产物分析，并在体内的足细胞的线粒体密度的测定，我们表明，无氧糖酵解和葡萄糖发酵成乳酸代表足细胞的关键能源。在生理条件下，我们既不能检测到发育或迟发性病理表型的足细胞与受损的线粒体生物发生机制，有缺陷的线粒体融合-裂变装置，或减少线粒体DNA的稳定性和转录引起的足细胞特异性缺失Pgc-1 α，Drp 1，或Tfam，分别。无氧糖酵解代表足细胞的主要代谢途径。这些发现提供了一种策略，以治疗干预增强足细胞代谢的各种进行性肾脏疾病，如糖尿病肾病或局灶节段性肾小球硬化症（FSGS）。
The cellular responses induced by mitochondrial dysfunction remain elusive. Intrigued by the lack of almost any glomerular phenotype in patients with profound renal ischemia, we comprehensively investigated the primary sources of energy of glomerular podocytes. Combining functional measurements of oxygen consumption rates, glomerular metabolite analysis, and determination of mitochondrial density of podocytes in vivo, we demonstrate that anaerobic glycolysis and fermentation of glucose to lactate represent the key energy source of podocytes. Under physiological conditions, we could detect neither a developmental nor late-onset pathological phenotype in podocytes with impaired mitochondrial biogenesis machinery, defective mitochondrial fusion-fission apparatus, or reduced mtDNA stability and transcription caused by podocyte-specific deletion of Pgc-1 alpha, Drp1, or Tfam, respectively. Anaerobic glycolysis represents the predominant metabolic pathway of podocytes. These findings offer a strategy to therapeutically interfere with the enhanced podocyte metabolism in various progressive kidney diseases, such as diabetic nephropathy or focal segmental glomerulosclerosis (FSGS).