MITOCHONDRIA AND OXIDATIVE STRESS IN NEURODEGENERATIVE DISORDERS Mitochondrial DNA Mutations in Disease, Aging, and Neurodegeneration Amy K. Reeve, a Kim J. Krishnan, a,b and Doug Turnbull a,b a Mitochondrial Research Group, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom b Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom Patients with disorders from mutations in the mitochondrial genome have variable phe- notypes, but common to many of these disorders are underlying changes in postmitotic cells, particularly neurons and muscle fibers. The mitochondrial dysfunction caused by these mutations has been shown to be associated with signs of apoptosis and to cause cell loss. Mutations of the mitochondrial genome have also been shown to accumulate with age and in common neurodegenerative diseases, such as Parkinson’s disease. This review presents recent data to show that the information gained from studying patients with mitochondrial disorders can help our understanding of the role of mitochondrial DNA mutations in brain aging and neurodegeneration. Key words: mitochondrial; DNA; mutations Introduction The production of energy, in the form of ATP, is a process which is essential for all cells. The generation of this energy occurs through a number of protein complexes, the electron transport chain, or oxidative phosphorylation (OXPHOS) system. These protein complexes are situated within the inner mitochondrial membrane. The transfer of electrons through the protein complexes to molecular oxygen and the translocation of protons generates a proton gradient across the inner mitochondrial mem- brane. This gradient is then used by the final complex in the chain, ATP synthase, to gener- ate ATP. Mitochondria are dynamic organelles that, via the processes of fission and fusion, are capable of forming networks within individual cells. 1 They have a number of other impor- tant roles in cell function, including mainte- Address for correspondence: Prof. D.M. Turnbull, Mitochondrial Research Group, The Medical School, Newcastle University, New- castle upon Tyne, NE2 4HH, UK. Voice: +44(0)1912228565; fax: +44(0)1912228553. d.m.turnbull@ncl.ac.uk nance and storage of intracellular calcium lev- els and regulation of apoptosis. 2,3 Mitochon- dria are also the main site of reactive oxygen species (ROS) generation within the cell. Such radicals are produced as a natural by-product during OXPHOS. These ROS are capable of causing damage to DNA, proteins, and lipids. It has been previously proposed that this may initiate a vicious cycle whereby ROS damages mitochondrial DNA (mtDNA), which leads to an inefficient OXPHOS system, which in turn leads to a further production of ROS—the pro- posal of a mitochondrial theory of aging. 4,5 Mitochondria are thought to be descended from free-living bacteria that became trapped to form eukaryotic cells. 6 During evolution, mitochondria have transferred the majority of their genetic material to the nucleus, 6 but some DNA remains within the mitochondria. MtDNA is a double-stranded circular genome of approximately 16.5 kb in length, and, with the exception of approximately an 1kb noncod- ing region, the rest of the genome is entirely transcribed. MtDNA can be replicated inde- pendently of the cell cycle and independent Mitochondria and Oxidative Stress in Neurodegenerative Disorders: Ann. N.Y. Acad. Sci. 1147: 21–29 (2008). doi: 10.1196/annals.1427.016 C  2008 New York Academy of Sciences. 21