Basso 2015 Abstract MiPschool London 2015
|Parkin dependent regulation of ER-Mitochondia tethering via MFN ubiquitination.|
Event: MiPschool London 2015
Parkin loss of function mutations are the major cause of autosomal recessive juvenile parkinsonism. Parkin is an E3 ubiquitin ligase  that is selectively recruited to damaged mitochondria where it ubiquitinates outer mitochondria membrane (OMM) protein Mitofusin (MFN) [2,3]. PINK1, a protein kinase and also a PD related gene, controls Parkin translocation . PINK1/Parkin dependent ubiquitination of MFN is a prerequisite for stress-induced mitophagy, a process by which mitochondria are selectively eliminated via autophagy. In mammals, Parkin both ubiquitinates MFN1 and MFN2. Despite their high level of homology, MFN1 and MFN2 have distinct physiological functions. While MFN1 in cooperation with OPA1, regulates mitochondrial fusion, MFN2 has a role in connecting ER to mitochondria , by creating a molecular bridge that is essential for lipids and calcium exchange and for the regulation of calcium dependent cell death. Drosophila is a well-established model organism for Parkinson’s Disease studies. The Drosophila evolutionary ancestor of mammalian MFN2 is called MARF. We found that in PINK1 or Parkin deficient fly cells, ER-mito interaction is impaired suggesting that PINK/Parkin dependent ubiquitination of MARF might be required for ER-mito tethering. We also found that under stressful conditions, the pattern of MARF ubiquitination changes, leading to the disappearance of the ubiquitinated MARF isoforms and the concomitant increase in the steady state levels of MARF. This process is dependent on Calcium (Ca2+) and Ca2+-activated protein phosphatase Calcineurin. Interestingly, analysis of the most common Charcot Marie Tooth (CMT) disease-mutated MFN proteins, which are leading to dominantly inherited disease characterized by degeneration of peripheral sensory and motor axons, revealed that ubiquitination is impaired in all the disease-mutated MFN. Although the mechanism by which mutations in MFN lead to neuropathy has not yet been elucidated, MFN2R94Q mutant was previously shown to not to be able to correct ER-mito tethering in MFN2-/- MEFs .
The purpose of this project is to understand the physiological role of PINK1/Parkin-dependent ubiquitination of MARF in the regulation of ER-mitochondria tethering and its relevance in the neurodegenerative pathways controlling dopaminergic neurons loss.
Labels: Pathology: Parkinson's
1-Dulbecco-Telethon Inst, Venetian Inst Mol Med, Padova, Italy. - email@example.com
2-Dept Biol, Univ Padova
3-Inst IRCCS Ospedale San Camillo, Lido di Venezia
- Shimura H, Hattori N, Kubo Si, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T (2000) Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nat Genet 25:302-5.
- Ziviani E, Tao RN, Whitworth AJ (2010) Drosophila parkin requires PINK1 for mitochondrial translocation and ubiquitinates mitofusin. Proc Natl Acad Sci USA 107:5018-23.
- Tanaka A, Cleland MM, Xu S, Narendra DP, Suen DF, Karbowski M, Youle RJ (2010) Proteasome and p97 mediate mitophagy and degradation of mitofusins induced by Parkin. J Cell Biol 191:1367-80.
- De Brito OM, Scorrano L (2008) Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456:605-10.