Currently, mtDNA is regarded as a vulnerable plasmid-like DNA molecule, lacking protective histone-like structures and sufficient repair mechanisms. Recent progress however suggests a nucleosome-like organization (nucleoids) with protein-DNA complexes. In previous unpublished work we have obtained circumstantial evidence that manganese superoxide dismutase (MnSOD) is an integral component of mitochondrial nucleoid complexes and that glutathione peroxidase may also be part of a postulated new mtDNA associated antioxidant system. Such challenging results need further verification and a biochemical characterization of the cell specificity of association/dissociation and its regulation. Furthermore it has to be shown that this antioxidant system functions preventively under cellular conditions. This will be tested in different systems like isolated DNA, cells, tissues and MnSOD+/- mice, using a newly developed assay for oxidative DNA modifications. A dysfunction of nucleoid-associated antioxidant system may be related to mitochondrial diseases and even the aging process.