title: Immortalized Parkinson's disease lymphocytes have enhanced mitochondrial respiratory activity.
abstract: In combination with studies of post-mortem Parkinson's disease (PD) brains, pharmacological and genetic models of PD have suggested that two fundamental interacting cellular processes are impaired - proteostasis and mitochondrial respiration. We have re-examined the role of mitochondrial dysfunction in lymphoblasts isolated from individuals with idiopathic PD and an age-matched control group. As previously reported for various PD cell types, the production of reactive oxygen species (ROS) by PD lymphoblasts was significantly elevated. However, this was not due to an impairment of mitochondrial respiration, as is often assumed. Instead, basal mitochondrial respiration and ATP synthesis are dramatically elevated in PD lymphoblasts. The mitochondrial mass, genome copy number and membrane potential were unaltered, but the expression of indicative respiratory complex proteins was also elevated. This explains the increased oxygen consumption rates by each of the respiratory complexes in experimentally uncoupled mitochondria of iPD cells. However, it was not attributable to increased activity of the stress- and energy-sensing protein kinase AMPK, a regulator of mitochondrial biogenesis and activity. The respiratory differences between iPD and control cells were sufficiently dramatic as to provide a potentially sensitive and reliable biomarker of the disease state, unaffected by disease duration (time since diagnosis) or clinical severity. Lymphoblasts from control and PD individuals thus occupy two distinct, quasi-stable steady states; a 'normal' and a 'hyperactive' state characterized by two different metabolic rates. The apparent stability of the 'hyperactive' state in patient-derived lymphoblasts in the face of patient ageing, ongoing disease and mounting disease severity suggests an early, permanent switch to an alternative metabolic steady state. With its associated, elevated ROS production, the 'hyperactive' state might not cause pathology to cells that are rapidly turned over, but brain cells might accumulate long-term damage leading ultimately to neurodegeneration and the loss of mitochondrial function observed post-mortem. Whether the 'hyperactive' state in lymphoblasts is a biomarker specifically of PD or more generally of neurodegenerative disease remains to be determined.
authors.affiliation: Discipline of Microbiology, Department of Physiology Anatomy and Microbiology, School of Life Sciences, College of Science Health and Engineering, La Trobe University, Melbourne, Victoria 3086, Australia.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Annesley
authors.affiliation: Discipline of Microbiology, Department of Physiology Anatomy and Microbiology, School of Life Sciences, College of Science Health and Engineering, La Trobe University, Melbourne, Victoria 3086, Australia.
authors.forename: Sui T
authors.initials: ST
authors.lastname: Lay
authors.affiliation: Discipline of Microbiology, Department of Physiology Anatomy and Microbiology, School of Life Sciences, College of Science Health and Engineering, La Trobe University, Melbourne, Victoria 3086, Australia.
authors.forename: Shawn W
authors.initials: SW
authors.lastname: De Piazza
authors.affiliation: Discipline of Microbiology, Department of Physiology Anatomy and Microbiology, School of Life Sciences, College of Science Health and Engineering, La Trobe University, Melbourne, Victoria 3086, Australia.
authors.forename: Oana
authors.initials: O
authors.lastname: Sanislav
authors.affiliation: Department of Psychology and Counselling, School of Psychology and Public Health, College of Science Health and Engineering, La Trobe University, Melbourne, Victoria 3986, Australia.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Hammersley
authors.affiliation: Discipline of Microbiology, Department of Physiology Anatomy and Microbiology, School of Life Sciences, College of Science Health and Engineering, La Trobe University, Melbourne, Victoria 3086, Australia.
authors.forename: Claire Y
authors.initials: CY
authors.lastname: Allan
authors.affiliation: Discipline of Microbiology, Department of Physiology Anatomy and Microbiology, School of Life Sciences, College of Science Health and Engineering, La Trobe University, Melbourne, Victoria 3086, Australia.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Francione
authors.affiliation: Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria 3010, Australia.
authors.forename: Minh Q
authors.initials: MQ
authors.lastname: Bui
authors.affiliation: Department of Medicine, University of Melbourne St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
authors.forename: Zhi-Ping
authors.initials: ZP
authors.lastname: Chen
authors.affiliation: Department of Medicine, University of Melbourne St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
authors.forename: Kevin R W
authors.initials: KR
authors.lastname: Ngoei
authors.affiliation: UC Davis MIND Institute, Sacramento, CA 95817, USA.
authors.forename: Flora
authors.initials: F
authors.lastname: Tassone
authors.affiliation: Department of Medicine, University of Melbourne St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Kemp
authors.affiliation: Department of Medicine (Neuroscience), Monash University, (Alfred Hospital Campus), Commercial Road, Melbourne, Victoria 3004, Australia.
authors.forename: Elsdon
authors.initials: E
authors.lastname: Storey
authors.affiliation: Department of Neurology, Royal Melbourne Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Evans
authors.affiliation: Department of Psychology and Counselling, School of Psychology and Public Health, College of Science Health and Engineering, La Trobe University, Melbourne, Victoria 3986, Australia.
authors.forename: Danuta Z
authors.initials: DZ
authors.lastname: Loesch
authors.affiliation: Discipline of Microbiology, Department of Physiology Anatomy and Microbiology, School of Life Sciences, College of Science Health and Engineering, La Trobe University, Melbourne, Victoria 3086, Australia P.Fisher@latrobe.edu.au.
authors.forename: Paul R
authors.identifier: 0000-0003-1884-6306
authors.initials: PR
authors.lastname: Fisher
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000328:Adult; D000367:Age Factors; D002461:Cell Line, Transformed; D019069:Cell Respiration; D018628:Gene Dosage; D016678:Genome; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism* / Q000473:pathology*; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D010085:Oxidative Phosphorylation; D010101:Oxygen Consumption; D010300:Parkinson Disease / Q000097:blood / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012372:ROC Curve; D017382:Reactive Oxygen Species / Q000378:metabolism; D012044:Regression Analysis; D012720:Severity of Illness Index
chemical_list: D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases
keywords: AMPK; ATP; Complex I; Lymphoblast; Lymphocyte; Mitochondria; OXPHOS; Oxidative stress; Parkinson's disease; ROS; Respiration