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Acutely administered melatonin restores hepatic mitochondrial physiology in old mice
Yuji Okatani1, Akihiko Wakatsuki, Russel J Reiter
1Department of Clinical Nursing Science, Kochi Medical School, Oko, Nankoku, Kochi 783-8505, Japan. okataniy@med.kochi-ms.ac.jp
Abstract:
Damage to mitochondria as a result of the intrinsic generation of free radicals is theoretically involved in the processes of cellular aging. Herein, we investigated whether acutely administered melatonin, due to its free radical scavenging activity, would influence mitochondrial metabolism. Mitochondrial respiratory activity and respiratory chain complex I and IV activities in liver mitochondria from a strain of senescence-accelerated-prone mice (SAMP8) and a strain of senescence-accelerated-resistant mice (SAMR1) were measured when the animals were 12 months of age. Respiratory control index (RCI), ADP/O ratio, State 3 respiration and dinitrophenol (DNP)-dependent uncoupled respiration were significantly lower in SAMP8 than in SAMR1. In contrast, State 4 respiration was significantly higher in SAMP8 than in SAMR1. Activities of complexes I and IV in SAMP8 were significantly lower than in SAMR1. Melatonin administration (10mg/kg body weight, intraperitoneally) 1h prior to sacrifice significantly increased RCI, ADP/O ratio, State 3 respiration and DNP-induced uncoupled respiration in SAMP8 while also significantly reducing State 4 respiration in SAMP8. The injection of melatonin also significantly increased complex I activity in both mouse strains and complex IV activity in the liver of SAMP8 mice. These results document an age-related decrease in hepatic mitochondrial function in SAM which can be modified by an acute pharmacological injection of melatonin; the indole stimulated mitochondrial respiratory chain activity which would likely reduce deteriorative oxidative changes in mitochondria that normally occur in advanced age.
Insights
Melatonin administration improved mitochondrial function in aging mice. This study shows that melatonin can enhance cellular respiration and reduce oxidative damage, potentially slowing the aging process.
Area of Science:
- Mitochondrial biology
- Aging research
- Pharmacology
Background:
- Mitochondrial free radical damage is implicated in cellular aging.
- Melatonin's antioxidant properties suggest a role in mitigating age-related mitochondrial dysfunction.
Purpose of the Study:
- To investigate the effect of acute melatonin administration on mitochondrial metabolism in aging mice.
- To assess melatonin's impact on hepatic mitochondrial respiratory chain complex activities.
Main Methods:
- Mice (SAMP8 and SAMR1 strains) aged 12 months were used.
- Mitochondrial respiratory activity and respiratory chain complex I and IV activities were measured.
- Melatonin (10mg/kg) was administered intraperitoneally 1 hour before sacrifice.
Main Results:
- Aging mice (SAMP8) exhibited lower mitochondrial respiratory control index (RCI), ADP/O ratio, State 3, and complex I/IV activities compared to resistant mice (SAMR1).
- Melatonin significantly increased RCI, ADP/O ratio, State 3 respiration, and complex I/IV activities in SAMP8 mice.
- Melatonin reduced State 4 respiration in SAMP8 mice and increased complex I activity in both strains.
Conclusions:
- Hepatic mitochondrial function declines with age in senescence-accelerated mice.
- Acute melatonin administration can enhance mitochondrial respiratory chain activity.
- Melatonin may reduce age-related mitochondrial oxidative damage.