The effect of 5-aminolevulinic acid on cytochrome c oxidase activity in mouse liver

Abstract

Background5-Aminolevulinic acid (ALA) is a precursor of heme that is fundamentally important in aerobic energy metabolism. Among the enzymes involved in aerobic energy metabolism, cytochrome c oxidase (COX) is crucial. In this study, the effect of ALA on cytochrome c oxidase activity was measured.Findingsc57BL/6N species of mice were administered ALA orally for 15 weeks. After ALA administration, mice were sacrificed and livers were obtained. COX activity in mitochondria from ALA-administered mouse livers was 1.5-fold higher than that in mitochondria from PBS-administered mouse livers (P < 0.05). Furthermore, ATP levels in ALA-administered mouse livers were much higher than those in PBS-administered mouse livers. These data suggest that oral administration of ALA promotes aerobic energy metabolism, especially COX activity.ConclusionsThis is the first report of a drug that functions in aerobic energy metabolism directly. Since COX activity is decreased in various diseases and aging, the pharmacological effects of ALA will be expanding.

The heme precursor 5-aminolevulinic acid disrupts the Warburg effect in tumor cells and induces caspase-dependent apoptosis

“…2), supporting a stimulating effect on oxidative phosphorylation. This result is consistent with the result from our previous study, where COX expression in mouse liver was increased following ALA administration (8). In addition, oxygen consumption was significantly higher following ALA exposure (Fig.…”

“…To our knowledge, this is the first in vitro study showing that ALA causes tumor apoptosis via enhancement of oxidative phosphorylation. In a previous study, we showed that in mouse liver, ALA increases the expression and activity of COX, which is an indicator of oxidative phosphorylation (8). The present study goes further by showing that ALA affects both aspects of the Warburg effect by increasing oxidative phosphorylation and suppressing glycolysis.…”

“…This hemoprotein uses a heme group as an active site to oxidize cytochrome c. In most tumor cells, COX activities are suppressed. We recently reported that 5-aminolevulinic acid (ALA) increases COX activity in mouse liver (8). This compound is widely distributed in plant and animal cells and is a common precursor of tetrapyrroles, such as the active core of hemoglobin.…”

5-Aminolevulinic acid strongly enhances delayed intracellular production of reactive oxygen species (ROS) generated by ionizing irradiation: Quantitative analyses and visualization of intracellular ROS production in glioma cells in vitro

“…The biological effect of administration of the heme precursor 5-ALA is not only high accumulation of PpIX within the mitochondria of tumor cells, but also generation of antitumor immunity via activation of heat-shock protein as well as inhibition of heme-oxygenase-1 with photoactivation and hyperthermia (26). Moreover, recent studies have reported that 5-ALA can improve the function of the mitochondrial respiratory chain (particularly COX activity) and thereby disrupt the warburg effect and induce caspase-dependent apoptosis in tumor cells (27,28). In our previous study, we demonstrated that multi-dose ionizing radiation induced strong aggregation of activated macrophages with phagocytic features within tumors, causing strong inhibition of tumor growth in glioma cells in vivo (19).…”

“…This delayed ROS production is induced primarily in the mitochondria of tumor cells (24,25). Meanwhile, the heme precursor 5-ALA presents not only a high accumulation of PpIX in the mitochondria of tumor cells, but also improves dysfunction of the mitochondrial respiratory chain in tumor cells (26)(27)(28). Thus, we hypothesized that 5-ALA-induced PpIX may operate upon mitochondria, and cause changes in delayed production of ROS after ionizing irradiation in tumor cells.…”