PT  - JOURNAL ARTICLE
AU  - Grażyna Nowak
AU  - Ginger L. Clifton
AU  - Diana Bakajsova
TI  - Succinate Ameliorates Energy Deficits and Prevents Dysfunction of Complex I in Injured Renal Proximal Tubular Cells
AID  - 10.1124/jpet.107.130872
DP  - 2008 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1155--1162
VI  - 324
IP  - 3
4099  - http://jpet.aspetjournals.org/content/324/3/1155.short
4100  - http://jpet.aspetjournals.org/content/324/3/1155.full
SO  - J Pharmacol Exp Ther2008 Mar 01; 324
AB  - We previously reported that mitochondrial function, intracellular ATP levels, and complex I activity are decreased in renal proximal tubular cells (RPTC) after oxidant (tert-butyl hydroperoxide; TBHP)-induced injury. This study examined the hypothesis that succinate supplementation decreases mitochondrial dysfunction, ameliorates energy deficits, and increases viability in TBHP-injured RPTC. Basal and uncoupled respirations in injured RPTC decreased 33 and 35%, respectively, but remained unchanged in injured RPTC supplemented with 10 mM succinate (electron donor to respiratory complex II). State 3 respiration supported by electron donors to complex I decreased 40% in injured RPTC but improved significantly by succinate supplements. The activity of mitochondrial complex I in TBHP-injured RPTC decreased 48%, whereas complex II activity remained unchanged. Succinate supplementation prevented decreases in complex I activity. ATP levels decreased 43% in injured RPTC but were maintained in injured cells supplemented with succinate. Lipid peroxidation increased 19-fold in injured RPTC but only 9-fold in injured cells supplemented with succinate. Exposure of primary cultures of RPTC to TBHP produced 24% cell injury and lysis but no apoptosis. In contrast, no cell lysis was found in RPTC supplemented with succinate. We conclude that mitochondrial dysfunction and energy deficits in oxidant-injured RPTC are ameliorated by succinate, and we propose that succinate supplementation may prove therapeutically valuable. Succinate 1) uses an alternate pathway of mitochondrial energy metabolism, 2) improves activity of complex I and oxidation of substrates through complex I, and 3) decreases oxidative stress and cell lysis in oxidant-injured RPTC. The American Society for Pharmacology and Experimental Therapeutics