title: Shared and cell type-specific mitochondrial defects and metabolic adaptations in primary cells from PINK1-deficient mice.
abstract: BACKGROUND
  Mutations in PTEN-induced kinase 1 (PINK1) cause early-onset recessive parkinsonism. PINK1 and Parkin regulate mitochondrial quality control. However, PINK1 ablation in Drosophila and cultured mammalian cell lines affected mitochondrial function/dynamics in opposite ways, confounding the elucidation of the role of PINK1 in these processes.
  
  
  OBJECTIVE
  We recently generated PINK1-deficient (PINK1-/-) mice and reasoned that primary cells from these mice provide a more physiological substrate to study the role of PINK1 in mammals and to investigate metabolic adaptations and neuron-specific vulnerability in PINK1 deficiency.
  
  
  RESULTS
  Using real-time measurement of oxygen consumption and extracellular acidification, we show that basal mitochondrial respiration is increased, while maximum respiration and spare respiratory capacity are decreased in PINK1-/- mouse embryonic fibroblasts (MEF), as is the membrane potential. In addition, a Warburg-like effect in PINK1-/- MEF promotes survival that is abrogated by inhibition of glycolysis. Expression of uncoupling protein-2 is decreased in PINK1-/- MEF and the striatum of PINK1-/- mice, possibly increasing the sensitivity to oxidative stress. Mitochondria accumulate in large foci in PINK1-/- MEF, indicative of abnormal mitochondrial dynamics and/or transport. Like in PINK1-/- Drosophila, enlarged/swollen mitochondria accumulate in three different cell types from PINK1-/- mice (MEF, primary cortical neurons and embryonic stem cells). However, mitochondrial enlargement is greatest and most prominent in primary cortical neurons that also develop cristae fragmentation and disintegration.
  
  
  CONCLUSIONS
  Our results reveal mechanisms of PINK1-related parkinsonism, show that the function of PINK1 is conserved between Drosophila and mammals when studied in primary cells, and demonstrate that the same PINK1 mutation can affect mitochondrial morphology/degeneration in a cell type-specific manner, suggesting that tissue-/cell-specific metabolic capacity and adaptations determine phenotypes and cellular vulnerability in PINK1-/- mice and cells.
authors.affiliation: Department of Anatomy and Neurobiology, University of Kentucky, Lexington, Ky., USA.
authors.forename: Ravi S
authors.initials: RS
authors.lastname: Akundi
authors.forename: Lianteng
authors.initials: L
authors.lastname: Zhi
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Sullivan
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Büeler
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D002478:Cells, Cultured; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure*; D009474:Neurons / Q000378:metabolism*; D061251:Primary Cell Culture; D011494:Protein Kinases / Q000235:genetics*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase