Mitochondrial dysfunction in focal segmental glomerulosclerosis of puromycin aminonucleoside nephrosis.

Focal segmental glomerular sclerosis (FSGS) is a major renal complication of mitochondrial (mt) cytopathies. The present study was designed to investigate the possibility of mtDNA lesion accumulation in podocytes, which are a primary pathogenic site of FSGS, during the development of glomerulopathy in puromycin aminonucleoside nephrosis (PAN). Two renal pathological phases of PAN, nephrosis phase and FSGS phase were studied. We investigated the expression of mt proteins, the copy number of a 4834 base-pair deletion (del-mtDNA), and total mtDNA content by real-time polymerase chain reaction, as well as the mRNA expression levels of the mt transcription factor A (mtTFA) and the nuclear respiratory factor-1 (NRF-1) in glomeruli. The mtDNA encoded cytochrome c oxidase subunit I (COX I) protein level was identical to control in nephrosis phase, however, a 45% reduction was seen in FSGS phase. Intraglomerular del-mtDNA was 16-21 times higher than controls in both phases, but the proportion of this mutation was <1% of total mtDNA. The copy number of total mtDNA at nephrosis phase increased up to 241%, whereas, it decreased to 34% at FSGS phase in glomeruli. The mRNA expression of both mtTFA and NRF-1 was upregulated at nephrosis phase, but mtTFA was downregulated at FSGS phase. A reduction in mtDNA copy number resulted in reduced levels of COX I in glomeruli at FSGS phase, suggesting that mt dysfunction by mtDNA depletion potentially plays a key role in the pathogenesis of FSGS in PAN.