Introduction

Many alterations of the human mitochondrial genome accumulate exponentially with age in well-differentiated tissues such as muscle and nerve, and are also present in almost every other human cell. These mutations may be the result of mitochondrial oxidative stress, which increases with advancing age of the individual as well as in correlation with specific diseases (1-3).

Accumulation of alterations of the mitochondrial DNA (mtDNA) would be expected to impair the bioenergetic function of mitochondria in the affected host cells significantly. Since all the proteins encoded by the mtDNA are essential for the execution of normal oxidative phosphorylation (OXPHOS), disintegration of the mitochondrial genome would cause severe problems with respect to cellular functions and viability. Many of these changes have been associated with several specific diseases and the process of aging (4,5). Mitochondria have more functions than just supplying ATP; they are required for biosynthesis of heme, cholesterol, and phospholipids (6), iron hemostasis and programmed cell death (7).

The increase of mtDNA mutagenesis depends on the capability of repair of damage to mtDNA in the mitochondrium. The early findings of the absence of repair of UV-induced pyrimidine dimers in mtDNA led to the general notion that there were no DNA repair mechanisms in mitochondria. In view of the high copy number, the mitochon-drial genome came to be regarded as disposable: the damage removal in mitochondria seemed to be due to mtDNA replication of intact molecules or to cell detachment and death. Several authors confirmed this opinion in the past years. Since then, however, new reports have documented repair of some types of mtDNA damage (8) including alkylation base damage induced by various agents, cisplatin interstrand cross-links (ICLs), uvrABC excinuclease-sensitive sites induced by the carcinogen 4-nitroquinoline-1-oxide(4NQO), bleomycin-induced strand breaks, and oxidative lesions induced by hydrogen peroxide (9,10).

The analysis of human mtDNA is also becoming increasingly important in forensic sciences. Especially for the identification of poorly preserved skeletons or other human remains, sequence analysis of the human D-loop region is widely employed (11,12). Meanwhile, also other alterations become increasingly relevant for implementation in

Oxidative Stress and Neurodegenerative Disorders Edited by G. Ali Qureshi and S. Hassan Parvez

© 2007 Elsevier B.V. All rights reserved.

forensic and pathological research, e.g. detection of specific mitochondrial deletions to visualize hypoxic brain injuries for determining the cause (and matter) of death, and for reconstructing the time-dependent process.

This chapter summarizes the recent results and investigations in mitochondrial genetics and maintenance, and their application possibilities for pathological and forensic medicine with special regard to mitochondrial mutagenesis in the brain. The first part will deal with findings on mtDNA repair to facilitate the understanding of possible disease-related mechanisms, and causally determined relations between specific diseases and mitochondrial functions. The second part summarizes the basic findings on mitochondrial mutagenesis and maintenance in general, while the third part concentrates on mitochondrial mutagen-esis especially in the brain with special regard to its importance for forensic routine and research.

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