Pretorius 2015 Abstract MiPschool Cape Town 2015

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Metallothioneins are involved in mitochondrial function and disease.

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Pretorius M, Lindeque JZ, Steenkamp A, Dreyer W, Bothma K, Crous A, Pretorius PJ, Louw R, van der Westhuizen FH (2015)

Event: MiPschool Cape Town 2015

The adaptive responses observed when mitochondrial oxidative phosphorylation is deficient are highly varied, but are often accompanied by the induction of genes involved in defense mechanisms against oxidative stress [1]. Among these responses, metallothioneins (MTs) have been identified to be responsive to mitochondrial dysfunction. MTs are small, non-enzymatic proteins, involved in cellular detoxification and metal homeostasis because of their high cysteine content. MTs play a protective role in cells under numerous diseased and stressed states. Because of the three primary functions ascribed to MTs, which are metal homeostasis, heavy metal detoxification and free radical scavenging [2], it is believed that MTs promote the survival of mitochondrial dysfunctional cells mainly by acting as highly efficient reducing agents against the damaging properties of reactive oxygen species (ROS). However, since their main biological role involves metal homeostasis and detoxification, it is also hypothesised that MTs play an important role in the regulation of energy metabolism during normal and dysfunctional oxidative phosphorylation [3,4]. A complex I inhibited, MT-1 and MT-2 knockout (MT1+2KO) mouse model was used to comprehensively investigate the involvement of MTs in specific mitochondrial functions such as the electron transport chain, anti-oxidative stress enzymes, mitochondrial metabolism and ROS production. Large areas of the metabolism of wild type (WT) and MT1+2KO mice were screened using an untargeted metabolomics approach, to investigate the possible implications of MTs on the metabolism. Furthermore, the differences in metabolism and mitochondrial function in these mice were also investigated when complex I of the electron transport chain was inhibited with rotenone. The results indicated that although few significant differences at protein level could be detected, the metabolism of WT and MT1+2KO mice differed markedly during normal mitochondrial function as well as during rotenone-induced complex I deficiency. Clear signs in the metabolic fingerprints indicated that the effect of rotenone-induced complex I inhibition on the metabolism of MT1+2KO mice was more severe than on that of WT mice.


Labels: MiParea: Respiration 

Stress:Oxidative stress;RONS  Organism: Mouse 


Enzyme: Complex I 

Coupling state: OXPHOS 



Affiliations

Centre Human Metabonomics, North-West Univ, South Africa. - 20196946@nwu.ac.za

References

  1. Reinecke F, Levanets O, Olivier Y, Louw R, Semete B, Grobler A, Hidalgo J, Smeitink J, Olckers A, Van Der Westhuizen FH (2006) Metallothionein isoform 2A expression is inducible and protects against ROS-mediated cell death in rotenone-treated HeLa cells. Biochem J 395:405-15.
  2. Cai L, Wang Y, Zhou G, Chen T, Song Y, Li X, Kang YJ (2006) Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy. J Am Coll Cardiol 48:1688-97.
  3. Ogra Y, Aoyama M, Suzuki KT (2006) Protective role of metallothionein against copper depletion. Arch Biochem Biophys 451:112-8.
  4. Lindeque JZ, Levanets O, Louw R, van Der Westhuizen FH (2010) The involvement of metallothioneins in mitochondrial function and disease. Curr Protein Pept Sci 11:292-309.