The discovery that ERK1/2 directly phosphorylates TFAM at S177 to selectively interfere with TFAM promoter binding and transcription, while not affecting non-selective mtDNA binding and packaging, explains how chronic complex I inhibition triggers a deficit in regenerative biosynthesis of the mitochondrial respiratory chain.
This answers in part questions posed by the Kulich study and subsequent studies: Why is sustained ERK1/2 activation as seen in the 6-OHDA and MPP+ models of Parkinson disease and in sporadic and mutant LRRK2 Parkinson disease patient brains harmful to neurons? What is mitochondrially activated ERK1/2 doing? Why is mitophagy harmful in certain contexts, such as these three models, but beneficial in other contexts?
The answer appears to be that sustained ERK1/2 activation, driven by mitochondrial oxidative stress or by dominant mutation in LRRK2, concurrently triggers mitochondrial clearance by mitophagy and suppression of mitochondrial biogenesis. Remaining questions include characterization of other ERK1/2 dependent phosphorylation sites, direct study of mitochondrial biogenesis in the LRRK2 model, and identification of specific molecular targets by which ERK1/2 triggers mitophagy.
Read it here: Mitochondrion, 2014, in press. Click on blue words for links to web articles.
Prior lab studies of ERK1/2 in Parkinson Disease:
- SM Kulich & CT Chu. (2001) Sustained extracellular signal-regulated kinase activation by 6-hydroxydopamine: Implications for Parkinson's disease. J Neurochem 77: 1058-1066.
- JH Zhu, SM Kulich, TD Oury & CT Chu. (2002) Cytoplasmic aggregates of phosphorylated extracellular signal-regulated protein kinases in Lewy body diseases. Am J Pathol 161: 2087-2098.
- JH Zhu, F Guo, J Shelburne, S Watkins & CT Chu. (2003) Localization of phosphorylated ERK/MAP kinases to mitochondria and autophagosomes in Lewy body diseases. Brain Pathol, 13: 473-481.
- JH Zhu, C Horbinski, F Guo, S Watkins, Y Uchiyama & CT Chu (2007). Regulation of autophagy by extracellular signal regulated protein kinases during 1-methyl-4-phenylpyridinium injury. Am J. Pathol, 170: 75-86.
- SM Kulich, C Horbinski, M Patel & CT Chu. (2007) 6-Hydroxydopamine induces mitochondrial ERK activation. Free Rad Biol Med. 43: 372-383.
- ED Plowey, SJ Cherra III, Y-J Liu & CT Chu (2008) Role of autophagy in G2019S-LRRK2-associated neurite shortening in differentiated SH-SY5Y cells. J Neurochem 105: 1048-1056.
- RK Dagda, J Zhu, SM Kulich & CT Chu. (2008) Mitochondrially localized ERK2 regulates mitophagy and autophagic cell stress. Autophagy, 4: 770-782.
- J Zhu, A Gusdon, H Cimen, B Van Houten, E Koc & CT Chu. (2012) Impaired mitochondrial biogenesis contributes to depletion of functional mitochondria in chronic MPP+ toxicity. Cell Death Dis 3: e312. doi: 10.1038/cddis.2012.46.
- Review Articles
- CT Chu, DJ Levinthal, SM Kulich, EM Chalovich, and DB DeFranco (2004) Oxidative neuronal injury: The dark side of ERK 1/2. Eur J Biochem, 271: 2060-2066.
- J Zhu, KZQ Wang & CT Chu. (2013) After the banquet: Mitochondrial biogenesis, mitophagy and cell survival. Autophagy 9: 1663-76.
- M Verma, EK Steer & CT Chu. (2013) ERKed by LRRK2: A cell biological perspective on hereditary and sporadic Parkinson’s disease. Biochim Biophys Acta (Molecular Basis of Disease) In press.