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. / Thesis (Ph.D. (Biochemistry))--North-West University, Potchefstroom Campus, 2012
| Identifer | oai:union.ndltd.org:NWUBOLOKA1/oai:dspace.nwu.ac.za:10394/8434 |
| Date | January 2011 |
| Creators | Lindeque, Jeremie Zander |
| Publisher | North-West University |
| Source Sets | North-West University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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