Impaired mitochondrial transport and Parkin-independent degeneration of respiratory chain-deficient dopamine neurons in vivo

• Published in: Proceedings of the National Academy of Sciences - PNAS 2011-08, Vol.108 (31), p.12937-12942
• Main Authors: Sterky, Fredrik H, Lee, Seungmin, Wibom, Rolf, Olson, Lars, Larsson, Nils-Göran
• Format: Article
• Language: English
• Subjects: Animals; Axonal transport; Axons; Axons - metabolism; Biological Sciences; Blotting, Western; Brain; Cell aggregates; Dopamine; Dopamine - metabolism; Electron transport; electron transport chain; Enzymes; Female; Genetic mutation; HeLa Cells; Humans; Immunohistochemistry; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Male; Medicin och hälsovetenskap; Membrane potential; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Fluorescence; Mitochondria; Mitochondria - genetics; Mitochondria - metabolism; Mitochondrial Diseases - genetics; Mitochondrial Diseases - metabolism; Mitochondrial Diseases - pathology; Mitochondrial DNA; Movement disorders; Neurodegeneration; Neurodegenerative diseases; Neurons; Neurons - metabolism; Neurons - pathology; Parkin protein; Parkinson disease; Parkinson's disease; patients; phenotype; Protein Transport; Recruitment; Respiration; respiratory rate; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1103295108

Mitochondrial dysfunction is heavily implicated in Parkinson disease (PD) as exemplified by the finding of an increased frequency of respiratory chain-deficient dopamine (DA) neurons in affected patients. An inherited form of PD is caused by impaired function of Parkin, an E3 ubiquitin ligase reported to translocate to defective mitochondria in vitro to facilitate their clearance. We have developed a reporter mouse to assess mitochondrial morphology in DA neurons in vivo and show here that respiratory chain deficiency leads to fragmentation of the mitochondrial network and to the formation of large cytoplasmic bodies derived from mitochondria. Surprisingly, the dysfunctional mitochondria do not recruit Parkin in vivo, and neither the clearance of defective mitochondria nor the neurodegeneration phenotype is affected by the absence of Parkin. We also show that anterograde axonal transport of mitochondria is impaired in respiratory chain-deficient DA neurons, leading to a decreased supply of mitochondria to the axonal terminals.