Bezafibrate induced increase in mitochondrial electron transport chain complex IV activity in human astrocytoma cells: Implications for mitochondrial cytopathies and neurodegenerative diseases

Abstract

Mitochondrial encephalomyopathies resulting from electron transport chain (ETC) dysfunction can present with a wide spectrum of clinical manifestations having significant neuropathology and a progressive nature. Despite advances in diagnosis of ETC disorders, treatment still remains inadequate. A recent study in fibroblasts and myoblasts revealed the ability of fibrate treatment to correct ETC enzyme deficiencies. Therefore, fibrates may represent potential therapeutic agents to correct the neurological ETC impairment responsible for the encephalopathic presentation of these disorders. Consequently, this study assessed the effect of bezafibrate on human astrocytoma (HA) 1321N cell ETC activity and coenzyme Q(10) (CoQ(10) ) status. HA cells were incubated for 72 H with 300 μM or 500 μM bezafibrate and for 7 days with only 500 μM bezafibrate. A significant effect on ETC activity was observed after 7 days incubation with 500 μM bezafibrate yielding a 130% (P < 0.05) increase in complex IV activity, accompanied by a 33% (P < 0.05) increase in cellular ATP level and a 25% (P < 0.001) decrease in extracellular lactate/pyruvate ratio compared to control levels. Following 7 days culture with bezafibrate, the CoQ(10) status of the HA cells appeared to increase although this was not found to be significant. The results of this study have indicated evidence of a bezafibrate induced increase in ETC complex IV activity. Further studies are required to assess the ability of bezafibrate treatment to correct neurological ETC impairment in available animal models of ETC dysfunction before the therapeutic efficacy of this pharmacological agent can be further considered in the treatment of the encephalopathic presentation of ETC disorders.

Mitochondrial Genetic Disorders: Cell Signaling and Pharmacological Therapies

“…Consistent with the presumed mode of action of BZ, positive effects of treatment were only achieved in cell lines that exhibited some level of residual RC function, i.e., when the disease causing mutations did not lead to highly unstable or absent mutant protein [105]. Further studies from other groups confirmed that BZ could upregulate the activities of RC complex I, III, and IV in human skin fibroblasts, and displayed similar effects in a variety of cell lines including HeLa, HEK293, bone marrow-derived cells, and human brain astrocytoma cells [106,107,108]. In a compared study of patients’ fibroblasts harboring mutations in Sco2 or Surf1 gene , it was found that treatment with BZ could correct COX activity in the Sco2-deficient cell line, which exhibited partial COX deficiency, but not in the Surf1 mutant, which was almost devoid of residual enzyme activity [107].…”