Anaerobic Glycolysis Maintains the Glomerular Filtration Barrier Independent of Mitochondrial Metabolism and Dynamics

摘要

The cellular responses induced by mitochondrialdysfunction remain elusive. Intrigued by the lackof almost any glomerular phenotype in patientswith profound renal ischemia, we comprehensivelyinvestigated the primary sources of energy ofglomerular podocytes. Combining functional measurementsof oxygen consumption rates, glomerularmetabolite analysis, and determination of mitochondrialdensity of podocytes in vivo, we demonstratethat anaerobic glycolysis and fermentation ofglucose to lactate represent the key energy sourceof podocytes. Under physiological conditions, wecould detect neither a developmental nor late-onsetpathological phenotype in podocytes with impairedmitochondrial biogenesis machinery, defectivemitochondrial fusion-fission apparatus, or reducedmtDNA stability and transcription caused by podocyte-specificdeletion of Pgc-1a, Drp1, or Tfam,respectively. Anaerobic glycolysis represents thepredominant metabolic pathway of podocytes.These findings offer a strategy to therapeuticallyinterfere with the enhanced podocyte metabolismin various progressive kidney diseases, such as diabeticnephropathy or focal segmental glomerulosclerosis(FSGS).