Journal
AGING-US
Volume 13, Issue 23, Pages 24963-24988Publisher
IMPACT JOURNALS LLC
Keywords
metallothionein; metabolomic profiling; L-carnitine; N6,N6,N6-trimethyl-L-lysine; tmlhe gene
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Funding
- JSPS KAKENHI [JP19K11732]
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Metallothionein (MT) deficiency in mice led to higher levels of metabolic intermediate TML and lower mRNA levels of TML dioxygenase in the liver and kidney, suggesting reduced capacity for carnitine biosynthesis and potential metabolic disorders in mitochondria, which may contribute to shortened lifespans in MT knockout mice compared to wild-type mice.
Metallothionein (MT) is a family of low molecular weight, cysteine-rich proteins that regulate zinc homeostasis and have potential protective effects against oxidative stress and toxic metals. MT1 and MT2 gene knockout (MTKO) mice show shorter lifespans than wild-type (WT) mice. In this study, we aimed to investigate how MT gene deficiency accelerates aging. We performed comparative metabolomic analyses of plasma between MTKO and WT male mice at middle age (50-week-old) and advanced age (100-week-old) using liquid chromatography with time-of-flight mass spectrometry (LC-TOF-MS). The concentration of N6,N6,N6-trimethyl-L-lysine (TML), which is a metabolic intermediate in carnitine biosynthesis, was consistently higher in the plasma of MTKO mice compared to that of WT mice at middle and advanced age. Quantitative reverse transcription PCR (RT-PCR) analysis revealed remarkably lower mRNA levels of Tmlhe, which encodes TML dioxygenase, in the liver and kidney of male MTKO mice compared to that of WT mice. L-carnitine is essential for beta-oxidation of long-chain fatty acids in mitochondria, the activity of which is closely related to aging. Our results suggest that reduced carnitine biosynthesis capacity in MTKO mice compared to WT mice led to metabolic disorders of fatty acids in mitochondria in MTKO mice, which may have caused shortened lifespans.
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