Autophagy in the limelight. Dr. Yoshinori Ohsumi wins the 2016 Nobel Prize in Physiology or Medicine!
Manish won first place and a cash prize for his molecular, biochemical and live neuron imaging study of mitochondrial calcium dysregulation in the mutant LRRK2 neuron model.
Jason received a $1000 travel award for his exciting discovery that the "Sensitivity of Mitochondrial Respiratory Chain Complex I to Toxin Inhibition is Activity-Dependent in Neurons," from the American Association of Neuropathologists at the annual meeting in Denver, CO.
He was also awarded a $10,000 Pathology Postdoctoral Research Training Program (PPRTP) research grant from "a very competitive group of applications," which will allow him to collect preliminary data on respiratory chain post-translational modifications to support a K99/R00 application.
Ed will be honored by the ASCI, the premier scientific association for physician-scientists, with a $500 award at its annual meeting on April 25! I had nominated him for the 2015 Young Physician-Scientist Award based on his novel discoveries as a recently independent investigator that the autophagy protein beclin1 has additional roles sorting surface amyloid precursor protein for plasma membrane autophagy and endolysosomal degradation. Such work has implications both for our basic understanding of alternative pathways for plasma membrane degradation, and for Alzheimer's disease mechanisms Congratulations, Ed!
Ed just received notification that his K08 application, entitled NMDA receptor trafficking by the autophagy regulatory protein berlin 1 will be funded!
Two of his papers have also recently been accepted -- one on mutant LRRK2 electrophysiology in BBA-Molecular Basis of Disease from his work in our lab, and a new paper from his lab on transcriptional regulation of beclin 1 complexes in Autophagy.
A great Spring - 3 papers accepted in 4 weeks! Part 1 - the balance of mitochondrial biogenesis and mitophagy in PD: Dual roles for ERK1/2
Kent Wang's study of a novel phosphorylation site on the mitochondrial transcription factor TFAM comes full circle from the first Chu Lab research paper by Scott Kulich 13 years ago.
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:
The lecture, SOS: Mitochondrial Distress Signals in Parkinson's Disease, was preceded by the awarding of a bronze medallion by Dean Levine. A celebratory dinner banquet at the Monterey Bay Fish Grotto was attended by multiple members of the Martinez family, members of the Oury-Chu family and lab groups, and colleagues in Pathology, Neuropathology and Neurosurgery.
Ruben's paper on non-mitochondrial functions of PINK1 is now out in Journal of Neurochemistry.
Key findings include the concept that PINK1 does not just sense dysfunctional mitochondria, but is released from healthy mitochondrial as a signal to promote dendritic growth and differentiation.
Click below to read what Nektarios Tavernarakis & Vassiliki Nikoletopoulou: F1000 Cell Biology, and Zu-Hang Sheng & Rajat Puri: F1000 Neuroscience had to say about our study on Cardiolipin externalization to the outer mitochondrial membrane acts as an elimination signal for mitophagy in neuronal cells . http://f1000.com/prime/718109987
Other studies noted by the F1000 Biology or F1000 Medicine were:
Bioenergetics of neurons inhibit the translocation response of Parkin following rapid mitochondrial depolarization by Van Laar et al. in Sarah Berman's lab.
Regulation of the autophagy protein LC3 by phosphorylation by Cherra et al. of the Chu lab.
Optical coherence tomography grading correlates with MRI T2 mapping and extracellular matrix content by Bear et al. in Constance Chu's lab.
Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission by Dagda et al. of the Chu lab.
News and Press Releases