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Alterations of mitochondrial respiration induced by aminoglycoside antibiotics
Abstract:
In vitro gentamicin treatment stimulates State 4 mitochondrial respiration and inhibits State 3 and DNP-uncoupled respiration. These effects are qualitatively similar in both hepatic and renal mitochondria. Threshold gentamicin concentrations for these effects were between 1 and 2 mM for renal mitochondria while hepatic mitochondria were slightly more sensitive. Neomycin, kanamycin, and streptomycin had effects qualitatively similar to those of gentamicin on State 4, State 3, and DNP-uncoupled respiration. The potency of the aminoglycosides in producing these effects strongly correlated with the number of ionizable amino groups present on the aminoglycoside molecule suggesting that cationic charge is an important molecular determinant of aminoglycoside-induced mitochondrial toxicity.
Insights
Gentamicin and similar antibiotics disrupt mitochondrial respiration in liver and kidney cells. This mitochondrial toxicity is linked to the positive charge of these drugs, affecting cellular energy production.
Area of Science:
- Biochemistry
- Pharmacology
- Toxicology
Background:
- Aminoglycoside antibiotics, like gentamicin, are widely used but can cause cellular toxicity.
- Mitochondria are crucial for cellular energy production and are potential targets for drug-induced toxicity.
Purpose of the Study:
- To investigate the in vitro effects of gentamicin on mitochondrial respiration in hepatic and renal cells.
- To compare the mitochondrial effects of gentamicin with other aminoglycoside antibiotics.
- To identify molecular determinants of aminoglycoside-induced mitochondrial toxicity.
Main Methods:
- In vitro treatment of isolated hepatic and renal mitochondria with gentamicin and other aminoglycosides.
- Measurement of mitochondrial respiration states (State 4, State 3, and DNP-uncoupled) using respirometry.
- Correlation analysis between aminoglycoside chemical properties (e.g., cationic charge) and observed mitochondrial effects.
Main Results:
- Gentamicin stimulated State 4 (basal) mitochondrial respiration while inhibiting State 3 (ADP-stimulated) and DNP-uncoupled respiration in both hepatic and renal mitochondria.
- Similar effects were observed with neomycin, kanamycin, and streptomycin, indicating a class effect of aminoglycosides.
- The potency of these effects correlated with the number of ionizable amino groups, suggesting cationic charge is a key factor.
Conclusions:
- Aminoglycosides, including gentamicin, induce mitochondrial dysfunction in vitro.
- Cationic charge is a significant molecular determinant of aminoglycoside-induced mitochondrial toxicity.
- These findings provide insight into the mechanisms underlying aminoglycoside nephrotoxicity and ototoxicity.