Cisplatin Nephrotoxicity Involves Mitochondrial Injury with Impaired Tubular Mitochondrial Enzyme Activity
ABSTRACT Cisplatin is a widely used antineoplastic agent. However, its major limitation is dose-dependent nephrotoxicity whose precise mechanism is poorly understood. Recent studies have suggested that mitochondrial dysfunction in tubular epithelium contributes to cisplatin-induced nephrotoxicity. Here the authors extend those findings by describing the role of an important electron transport chain enzyme, cytochrome c oxidase (COX). Immunohistochemistry for COX 1 protein demonstrated that, in response to cisplatin, expression was mostly maintained in focally damaged tubular epithelium. In contrast, COX enzyme activity in proximal tubules (by light microscopy) was decreased. Ultrastructural analysis of the cortex and outer stripe of the outer medulla showed decreased mitochondrial mass, disruption of cristae, and extensive mitochondrial swelling in proximal tubular epithelium. Functional electron microscopy showed that COX enzyme activity was decreased in the remaining mitochondria in the proximal tubules but maintained in distal tubules. In summary, cisplatin-induced nephrotoxicity is associated with structural and functional damage to the mitochondria. More broadly, using functional electron microscopy to measure mitochondrial enzyme activity may generate mechanistic insights across a spectrum of renal disorders.
Full-textDOI: · Available from: Zsuzsanna Kinga Zsengeller, Sep 27, 2015
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Article: Cisplatin Nephrotoxicity Involves Mitochondrial Injury with Impaired Tubular Mitochondrial Enzyme Activity
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- "EM was performed by the BIDMC Electron Micrograph Core. Functional COX EM was performed as previously described (Zsengeller et al., 2012). OCRs (pmol/min) were assessed with the use of an XF Flux Analyzer (Seahorse Biosciences). "
ABSTRACT: The transcriptional coactivators PGC-1α and PGC-1β are widely thought to be required for mitochondrial biogenesis and fiber typing in skeletal muscle. Here, we show that mice lacking both PGC-1s in myocytes do indeed have profoundly deficient mitochondrial respiration but, surprisingly, have preserved mitochondrial content, isolated muscle contraction capacity, fiber-type composition, in-cage ambulation, and voluntary running capacity. Most of these findings are recapitulated in cell culture and, thus, are cell autonomous. Functional electron microscopy reveals normal cristae density with decreased cytochrome oxidase activity. These data lead to the following surprising conclusions: (1) PGC-1s are in fact dispensable for baseline muscle function, mitochondrial content, and fiber typing, (2) endurance fatigue at low workloads is not limited by muscle mitochondrial capacity, and (3) mitochondrial content and cristae density can be dissociated from respiratory capacity.Cell Reports 05/2013; 3(5). DOI:10.1016/j.celrep.2013.04.023 · 8.36 Impact Factor
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ABSTRACT: Scaini G, Maggi DD, De-Nês BT, Gonçalves CL, Ferreira GK, Teodorak BP, Bez GD, Ferreira GC, Schuck PF, Quevedo J, Streck EL. Activity of mitochondrial respiratory chain is increased by chronic administration of antidepressants.Objective: Depressive disorders, including major depression, are serious and disabling for affected patients. Although the neurobiological understanding of major depressive disorder focuses mainly on the monoamine hypothesis, the exact pathophysiology of depression is not fully understood.Methods: Animals received daily intra-peritoneal injections of paroxetine (10 mg/kg), nortriptyline (15 mg/kg) or venlafaxine (10 mg/kg) in 1.0 ml/kg volume for 15 days. Twelve hours after the last injection, the rats were killed by decapitation, where the brain was removed and homogenised. The activities of mitochondrial respiratory chain complexes in different brain structures were measured.Results: We first verified that chronic administration of paroxetine increased complex I activity in prefrontal cortex, hippocampus, striatum and cerebral cortex. In addition, complex II activity was increased by the same drug in hippocampus, striatum and cerebral cortex and complex IV activity in prefrontal cortex. Furthermore, chronic administration of nortriptyline increased complex II activity in hippocampus and striatum and complex IV activity in prefrontal cortex, striatum and cerebral cortex. Finally, chronic administration of venlafaxine increased complex II activity in hippocampus, striatum and cerebral cortex and complex IV activity in prefrontal cortex.Conclusion: On the basis of the present findings, it is tempting to speculate that an increase in brain energy metabolism by the antidepressant paroxetine, nortriptyline and venlafaxine could play a role in the mechanism of action of these drugs. These data corroborate with other studies suggesting that some antidepressants modulate brain energy metabolism.Acta Neuropsychiatrica 04/2011; 23(3):112 - 118. DOI:10.1111/j.1601-5215.2011.00548.x · 0.80 Impact Factor
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ABSTRACT: The influence of acute renal failure induced by gentamicin administration on the effects of MMA on mitochondrial respiratory chain complexes, citrate synthase, succinate dehydrogenase and creatine kinase activities in cerebral cortex and kidney of young rats were investigated. Animals received one intraperitoneal injection of saline or gentamicin (70mg/kg). One hour after, the animals received three consecutive subcutaneous injections of MMA (1.67μmol/g) or saline (11h interval between injections) and 60min after the last injection the animals were killed. Acute MMA administration decreased creatine kinase activity in both tissues and increased complexes I-III activity in cerebral cortex. Creatine kinase activity was also inhibited by gentamicin administration. Simultaneous administration of MMA and gentamicin increased the activities of citrate synthase in cerebral cortex and kidney and complexes II-III in cerebral cortex. The other enzyme activities in cerebral cortex and kidney of animals receiving MMA plus gentamicin did not significantly differ from those observed in animals receiving only MMA. Our present data is line with the hypothesis that MMA acts as a toxin in brain and kidney of rats and suggest that renal injury potentiates the toxicity of MMA on the Krebs cycle and respiratory chain in brain and peripheral tissues.International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 02/2013; 31(4). DOI:10.1016/j.ijdevneu.2013.02.002 · 2.58 Impact Factor