Mitochondrial DNA sequence variation and neurodegeneration

Mitochondrial DNA sequence variation and neurodegeneration Michelangelo Mancuso 0 Massimiliano Filosto 0 Daniele Orsucci 0 Gabriele Siciliano 0 0 Department of Neuroscience, Neurological Clinic, University of Pisa , Via Roma 67, 56126 Pisa , Italy , and Neurological Institute, University of Brescia, Section for Neuromuscular Diseases and Neuropathies, University Hospital Spedali Civili , Piazza Spedali Civili 1, 25100 Bresia , Italy Mitochondria, the powerhouse of the cell, play a critical role in several metabolic processes and apoptotic pathways. Many lines of evidence suggest that mitochondria have a central role in ageing-related neurodegenerative diseases. Moreover, there is a long history of investigations on mitochondria aimed at identifying genetic markers relating to ageing and neurodegenerative diseases. In this review, some of the major neurodegenerative disorders are highlighted and the role of mitochondrial haplogroups in the pathogenetic cascade leading to these diseases is discussed. mitochondria; mtDNA; mtDNA haplogroups; neurodegenerative disorders - Mitochondria and their DNA (mitochondrial DNA [mtDNA]) result from a process of endosymbiosis which occurred about 1.5 billion years ago, when protobacteria populated primordial eukaryotic cells and took permanent residence in the new environment. MtDNA a relic but not a fossil has lost much of its independence but keeps functioning under the overarching control of the nuclear genome (nDNA). Mitochondria are ubiquitous in eukaryotes and are essential for survival. Their primary function is to support aerobic respiration and to provide energy and heat. Mitochondria also play other important roles, including in cell signalling for apoptotic cell death. By convention, the term mitochondrial diseases refers to disorders of the mitochondrial respiratory chain, thus excluding dysfunction in other metabolic pathways located in the mitochondria (ie pyruvate metabolism, Krebs cycle and fatty acid oxidation). The respiratory chain is the only metabolic pathway in the cell that is under the dual control of mtDNA and nDNA. There is a long history of investigations on mitochondria, which have been aimed at identifying genetic markers relating to ageing, neuromuscular and neurodegenerative diseases and, more recently, common diseases such as diabetes and cancer. This paper will include a brief section on mitochondrial biology and genetics, and will then focus on the role of mtDNA haplogroups in selected neurodegenerative disorders. Mitochondrial compartment Mitochondria are highly dynamic and pleomorphic organelles. They are composed of a smooth outer membrane surrounding an inner membrane of significantly larger surface area, which, in turn, surrounds a protein-rich core the matrix.1 Although mitochondria contain their own genome and protein-synthesising machinery, the majority of mitochondrial polypeptides are encoded in the nuclear genome, synthesised in the cytosol and imported into the mitochondria post-transcriptionally. The main mitochondrial role is in the synthesis of ATP formed by oxidative phosphorylation. They are also involved in other metabolic processes, including the biosynthesis of amino acids, vitamin cofactors, fatty acids, iron-sulphur clusters, cell signalling and programmed cell death. ATP molecules are generated via glycolysis or by oxidation of glucose to ethanol or lactic acid. Electrons from oxidative substrates are transferred to oxygen, via a series of redox reactions, to generate water. In the process, protons are pumped from the matrix across the mitochondrial inner membrane via the electron transport chain (ETC), which consists of four multimeric complexes (I to IV) plus two small electron carriers coenzyme Q (also known as ubiquinone) and cytochrome c. This process creates an electrochemical proton gradient. ATP is produced by the influx of these protons back through the complex V, or ATP synthase (the rotary motor).2 Mitochondrial genome and common mtDNA haplogroups Mitochondria contain two to ten molecules of mtDNA. It is a circular molecule of 16.5 kilobases lacking introns, and consisting of a heavy chain (H) and a light chain (L).1,3 MtDNA carries 37 genes encoding 22 transfer RNAs (tRNAs), two ribosomal RNAs (12S and 16S) and 13 polypeptides (mRNAs). The 13 mtDNA-encoded polypeptides are part of the respiratory chain system and are assembled together with nuclear-encoded subunits. Seven of these belong to complex I or reduced nicotinamide adenine dinucleotide (NADH) dehydrogenase NADH, ubiquinone oxidoreductase (ND1, ND2, ND3, ND4, ND4L, ND5, ND6). One belongs to complex III or ubiquinol ferricytochrome c oxidoreductase. Three belong to complex IV or cytochrome c oxidase COX I, COX II and COX III. The final two belong to complex V or ATP synthase ATPase6 and ATPase8. The remaining mitochondrial proteins, including all of the complex II subunits, are encoded by nDNA. In humans, mtDNA is transmitte (...truncated)