title: Modelling biochemical features of mitochondrial neuropathology.
abstract: BACKGROUND
  The neuropathology of mitochondrial disease is well characterised. However, pathophysiological mechanisms at the level of biochemistry and cell biology are less clear. Progress in this area has been hampered by the limited accessibility of neurologically relevant material for analysis.
  
  
  METHODS
  Here we discuss the recent development of a variety of model systems that have greatly extended our capacity to understand the biochemical features associated with mitochondrial neuropathology. These include animal and cell based models, with mutations in both nuclear and mitochondrial DNA encoded genes, which aim to recapitulate the neuropathology and cellular biochemistry of mitochondrial diseases.
  
  
  CONCLUSIONS
  Analysis of neurological tissue and cells from these models suggests that although there is no unifying mode of pathogenesis, dysfunction of the oxidative phosphorylation (OXPHOS) system is often central. This can be associated with altered reactive oxygen species (ROS) generation, disruption of the mitochondrial membrane potential (ΔΨm) and inadequate ATP synthesis. Thus, other cellular processes such as calcium (Ca(2+)) homeostasis, cellular signaling and mitochondrial morphology could be altered, ultimately compromising viability of neuronal cells.
  
  
  CONCLUSIONS
  Mechanisms of neuronal dysfunction in mitochondrial disease are only just beginning to be characterised, are system dependent and complex, and not merely driven by energy deficiency. The diversity of pathogenic mechanisms emphasises the need for characterisation in a wide range of models, as different therapeutic strategies are likely to be needed for different diseases. This article is part of a Special Issue entitled Frontiers of Mitochondrial Research.
authors.affiliation: The Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bird
authors.affiliation: The Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, Australia; Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Thorburn
authors.affiliation: The Murdoch Childrens Research Institute, The Royal Children's Hospital, Melbourne, Australia; Department of Paediatrics, The University of Melbourne, Melbourne, Australia. Electronic address: ann.frazier@mcri.edu.au.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Frazier
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001928:Brain Diseases, Metabolic / Q000378:metabolism*; D004272:DNA, Mitochondrial / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D008928:Mitochondria / Q000473:pathology; D028361:Mitochondrial Diseases / Q000378:metabolism*; D008959:Models, Neurological; D053140:Organelle Shape / Q000502:physiology; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress / Q000502:physiology
chemical_list: D015415:Biomarkers; D004272:DNA, Mitochondrial
keywords: Cells; Mitochondrial disease; Mouse; Neuropathology