Metallothionein involvement in mitochondrial function and disease : a metabolomics investigation

Abstract

One of the many recorded adaptive responses in respiratory chain complex I deficient cells is the over-expression of the small metal binding proteins, metallothioneins (MTs). The antioxidant properties of MTs putatively protect the deficient cells against oxidative damage, thus limiting further damage and impairment of enzymes involved in energy production. Moreover, the role of metallothioneins in supplying metal cofactors to enzymes and transcription factors in order to promote energy metabolism was previously proposed, which could accompany their role as antioxidants. This view is supported by the observations that MT knockout mice tend to become moderately obese, implying a lower energy metabolic rate. Hence, the involvement of metallothioneins in mitochondrial function and disease cannot be ignored. However, this association is still very vague due to the diversity of their functions and the complexity of the mitochondrion. The use of systems biology technology and more specifically metabolomics technology was thus employed to clarify this association by investigating the metabolic differences between wild type and MT knockout mice in unchallenged conditions as well as when mitochondrial function (energy metabolism) was challenged with exercise and/or a high-fat diet. The metabolic differences between these mice were also studied when complex I of the respiratory chain was inhibited with rotenone. The metabolome content of different tissues and bio-fluids were examined in an untargeted fashion using three standardized analytical platforms and the data mined using modern metabolomics and related statistical methods. Clear metabolic differences were found between the wild type and MT knockout mice during unchallenged conditions. These metabolic differences were persisted and were often amplified when mitochondrial metabolism was specifically challenged through exercise, high-fat intake or complex I inhibition. The data pointed to an overall reduced metabolic rate in the MT knockout mice and possible insulin resistance after the interventions which imply (and confirm) the involvement of MTs in promoting energy metabolism in the wild type mice.