Role of respiratory uncoupling in drug-induced mitochondrial permeability transition

Lipopolysaccharide (LPS), a component of the outer membrane of gram-negative bacteria, induces various biological reactions in vivo. Our previous study suggested that LPS administration disrupts respiratory chain complex activities, enhances reactive oxygen species production, especially in the liver mitochondria, and sensitizes mitochondrial permeability transition (MPT) pore opening in rats. However, it is unknown whether LPS-induced MPT pore opening in rats is similarly observed in mice and whether the mechanism is the same. LPS administration to mice increased not only cyclosporin A-sensitive swelling (MPT pore opening) susceptibility, but also induced cyclosporin A-insensitive basal swelling, unlike in rats. In addition, respiratory activity observed after adding ADP was significantly decreased. Based on these results, we further investigated the role of adenine nucleotide translocase (ANT). Carboxyatractyloside (CATR; an ANT inhibitor) treatment decreased respiratory activity after ADP was added in vehicle-treated mitochondria similarly to LPS administration. Additionally, CATR treatment increased MPT pore opening susceptibility in LPS-treated mitochondria compared to that of vehicle-treated mitochondria. Our study shows that ANT maintained a c-state conformation upon LPS administration, which increased MPT pore opening susceptibility in mice. These results suggest that LPS enhances MPT pore opening susceptibility across species, but the mechanism may differ between rat and mouse.

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“…After 2 hr, the liver was isolated. Liver mitochondria were isolated as previously described (Sato et al, 2021;Arakawa et al, 2019).…”

Section: Preparation Of Mouse Liver Mitochondriamentioning

confidence: 99%

“…Mitochondrial membrane potential was evaluated using a previously described method (Sato et al, 2021).…”

Section: Measurement Of Mitochondrial Membrane Potentialmentioning

confidence: 99%

Lipopolysaccharide administration increases the susceptibility of mitochondrial permeability transition pore opening via altering adenine nucleotide translocase conformation in the mouse liver

et al. 2023

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New in vitro screening system to detect drug-induced liver injury using a culture plate with low drug sorption and high oxygen permeability

Takemura

Ishii

Ikeyama

et al. 2023

Drug Metabolism and Pharmacokinetics

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Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability Transition

et al. 2021

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Pioglitazone (PIO) is an insulin-sensitizing antidiabetic drug, which normalizes glucose and lipid metabolism but may provoke heart and liver failure and chronic kidney diseases. Both therapeutic and adverse effects of PIO can be accomplished through mitochondrial targets. Here, we explored the capability of PIO to modulate the mitochondrial membrane potential (ΔΨm) and the permeability transition pore (mPTP) opening in different models in vitro. ΔΨm was measured using tetraphenylphosphonium and the fluorescent dye rhodamine 123. The coupling of oxidative phosphorylation was estimated polarographically. The transport of ions and solutes across membranes was registered by potentiometric and spectral techniques. We found that PIO decreased ΔΨm in isolated mitochondria and intact thymocytes and the efficiency of ADP phosphorylation, particularly after the addition of Ca2+. The presence of the cytosolic fraction mitigated mitochondrial depolarization but made it sustained. Carboxyatractyloside diminished the PIO-dependent depolarization. PIO activated proton transport in deenergized mitochondria but not in artificial phospholipid vesicles. PIO had no effect on K+ and Ca2+ inward transport but drastically decreased the mitochondrial Ca2+-retention capacity and protective effects of adenine nucleotides against mPTP opening. Thus, PIO is a mild, partly ATP/ADP-translocase-dependent, uncoupler and a modulator of ATP production and mPTP sensitivity to Ca2+ and adenine nucleotides. These properties contribute to both therapeutic and adverse effects of PIO.

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Role of respiratory uncoupling in drug-induced mitochondrial permeability transition

Cited by 3 publications

References 37 publications

Lipopolysaccharide administration increases the susceptibility of mitochondrial permeability transition pore opening via altering adenine nucleotide translocase conformation in the mouse liver

Lipopolysaccharide administration increases the susceptibility of mitochondrial permeability transition pore opening via altering adenine nucleotide translocase conformation in the mouse liver

New in vitro screening system to detect drug-induced liver injury using a culture plate with low drug sorption and high oxygen permeability

Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability Transition

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