Associate Professor, Stanford University School of Medicine (2019 - Present)
Assistant Professor, Stanford University School of Medicine (2012 - 2019)
Honors & Awards
McCormick and Gabilan Faculty Award, Stanford University (2018-2020)
Parkinson's seed grant, Stanford (2018-2019)
The Archer Award, The Archer Foundation (2016-2018)
Biology V, California Institute of Regenerative Medicine (2014-2017)
Mechanisms of Illness, Chronic Fatigue Initiative (2014-2015)
Klingenstein Fellowship in Neuroscience, Klingenstein Foundation (2013-2018)
Michael J. Fox Foundation Grant Target Validation Spring 2013, Michael J. Fox Foundation (2013-2014)
Gabilan Junior Faculty Fellow, Stanford University (2012-now)
Alfred P. Sloan Research Fellow 2012, Alfred P. Sloan Foundation (2012-2016)
William and Bernice E Bumpus Foundation Innovation Award, William and Bernice E Bumpus Foundation (2011-2014)
NIH Pathway to Independence (K99/R00), NINDS (2009-2014)
Boards, Advisory Committees, Professional Organizations
SAB Chair, CuraX Therapeutic Corporation (2019 - Present)
SAB, Mitokinin LLC. (2018 - Present)
Ph.D, University of Cambridge, Genetics, Neurobiology (2007)
M.D/MSc., China Medical University, Clinical Medicine and Genetics (2003)
Current Research and Scholarly Interests
Mitochondria move and undergo fission and fusion in all eukaryotic cells. The accurate allocation of mitochondria in neurons is particularly critical due to the significance of mitochondria for ATP supply, Ca++ homeostasis and apoptosis and the importance of these functions to the distal extremities of neurons. In addition, defective mitochondria, which can be highly deleterious to a cell because of their output of reactive oxygen species, need to be repaired by fusing with healthy mitochondria or cleared from the cell. Thus mitochondrial cell biology poses critical questions for all cells, but especially for neurons: how the cell sets up an adequate distribution of the organelle; how it sustains mitochondria in the periphery; and how mitochondria are removed after damage. The goal of my research is to understand the regulatory mechanisms controlling mitochondrial dynamics and function and the mechanisms by which even subtle perturbations of these processes may contribute to neurodegenerative disorders.
- Mitochondrial Transport and Function in Neuronal Health and Death
NSUR 81N (Aut)
- Molecular Mechanisms of Neurodegenerative Disease
BIO 267 (Win)
Independent Studies (7)
- Directed Reading in Neurosciences
NEPR 299 (Aut, Win, Spr, Sum)
- Directed Reading in Neurosurgery
NSUR 299 (Aut)
- Early Clinical Experience in Neurosurgery
NSUR 280 (Aut)
- Graduate Research
NEPR 399 (Aut, Win, Spr, Sum)
- Graduate Research
NSUR 399 (Aut)
- Medical Scholars Research
NSUR 370 (Aut)
- Undergraduate Research
NSUR 199 (Aut)
- Directed Reading in Neurosciences
- Prior Year Courses
Graduate and Fellowship Programs
Drosophila VCP/p97 Mediates Dynein-Dependent Retrograde Mitochondrial Motility in Axons.
Frontiers in cell and developmental biology
2020; 8: 256
Valosin-containing protein (VCP), also called p97, is an evolutionarily conserved and ubiquitously expressed ATPase with diverse cellular functions. Dominant mutations in VCP are found in a late-onset multisystem degenerative proteinopathy. The neurological manifestations of the disorder include frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In these patients, long motor neuron axons could be particularly susceptible to defects in axonal transport. However, whether VCP has a physiological function in maintaining axonal transport and whether this role is impaired by disease-causing mutations remains elusive. Here, by employing live-imaging methods in Drosophila larval axons and performing genetic interaction experiments, we discover that VCP regulates the axonal transport of mitochondria. Downregulation of VCP enhances the retrograde transport of mitochondria and reduces the density of mitochondria in larval axons. This unidirectional motility phenotype is rescued by removing one copy of the retrograde motor dynein heavy chain (DHC), or elevating Miro which facilitates anterograde mitochondrial movement by interacting with the anterograde motor kinesin heavy chain (KHC). Importantly, Miro upregulation also significantly improves ATP production of VCP mutant larvae. We investigate human VCP pathogenic mutations in our fly system. We find that expressing these mutations affects mitochondrial transport in the same way as knocking down VCP. Our results reveal a new role of VCP in mediating axonal mitochondrial transport, and provide evidence implicating impaired mitochondrial motility in the pathophysiology of VCP-relevant neurodegenerative diseases.
View details for DOI 10.3389/fcell.2020.00256
View details for PubMedID 32373611
View details for PubMedCentralID PMC7186335
Miro1 Marks Parkinson's Disease Subset and Miro1 Reducer Rescues Neuron Loss in Parkinson's Models.
The identification of molecular targets and pharmacodynamic markers for Parkinson's disease (PD) will empower more effective clinical management and experimental therapies. Miro1 is localized on the mitochondrial surface and mediates mitochondrial motility. Miro1 is removed from depolarized mitochondria to facilitate their clearance via mitophagy. Here, we explore the clinical utility of Miro1 for detecting PD and for gauging potential treatments. We measure the Miro1 response to mitochondrial depolarization using biochemical assays in skin fibroblasts from a broad spectrum of PD patients and discover that more than 94% of the patients' fibroblast cell lines fail to remove Miro1 following depolarization. We identify a small molecule that can repair this defect of Miro1 in PD fibroblasts. Treating patient-derived neurons and fly models with this compound rescues the locomotor deficits and dopaminergic neurodegeneration. Our results indicate that tracking this Miro1 marker and engaging in Miro1-based therapies could open new avenues to personalized medicine.
View details for DOI 10.1016/j.cmet.2019.08.023
View details for PubMedID 31564441
Alpha-synuclein delays mitophagy and targeting Miro rescues neuron loss in Parkinson's models.
Alpha-synuclein is a component of Lewy bodies, the pathological hallmark of Parkinson's disease (PD), and is also mutated in familial PD. Here, by extensively analyzing PD patient brains and neurons, and fly models, we show that alpha-synuclein accumulation results in upregulation of Miro protein levels. Miro is a motor/adaptor on the outer mitochondrial membrane that mediates mitochondrial motility, and is removed from damaged mitochondria to facilitate mitochondrial clearance via mitophagy. PD patient neurons abnormally accumulate Miro on the mitochondrial surface leading to delayed mitophagy. Partial reduction of Miro rescues mitophagy phenotypes and neurodegeneration in human neurons and flies. Upregulation of Miro by alpha-synuclein requires an interaction via the N-terminus of alpha-synuclein. Our results highlight the importance of mitochondria-associated alpha-synuclein in human disease, and present Miro as a novel therapeutic target.
View details for PubMedID 29923074
Phosphorylation of MCAD selectively rescuesPINK1deficiencies in behavior and metabolism.
Molecular biology of the cell
PINK1 is a mitochondria-targeted kinase, whose mutations are a cause of Parkinson's disease. We set out to better understand PINK1's effects on mitochondrial proteinsin vivoUsing an unbiased phosphoproteomic screen inDrosophila, we found that PINK1 mediates the phosphorylation of MCAD, a mitochondrial matrix protein critical to fatty acid metabolism. By mimicking phosphorylation of this protein in aPINK1null background, we restoredPINK1null's climbing, flight, thorax, and wing deficiencies. Due to MCAD's role in fatty acid metabolism, we examined the metabolic profile ofPINK1null flies, where we uncovered significant disruptions in both acylcarnitines and amino acids. Some of these disruptions were rescued by phosphorylation of MCAD, consistent with MCAD's rescue ofPINK1null's organismal phenotypes. Our work validates and extends the current knowledge of PINK1, identifies a novel function of MCAD, and illuminates the need for and effectiveness of metabolic profiling in models of neurodegenerative disease.
View details for PubMedID 29563254
PINK1 Phosphorylates MIC60/Mitofilin to Control Structural Plasticity of Mitochondrial Crista Junctions.
Mitochondrial crista structure partitions vital cellular reactions and is precisely regulated by diverse cellular signals. Here, we show that, in Drosophila, mitochondrial cristae undergo dynamic remodeling among distinct subcellular regions and the Parkinson's disease (PD)-linked Ser/Thr kinase PINK1 participates in their regulation. Mitochondria increase crista junctions and numbers in selective subcellular areas, and this remodeling requires PINK1 to phosphorylate the inner mitochondrial membrane protein MIC60/mitofilin, which stabilizes MIC60 oligomerization. Expression of MIC60 restores crista structure and ATP levels of PINK1-null flies and remarkably rescues their behavioral defects and dopaminergic neurodegeneration. In an extension to human relevance, we discover that the PINK1-MIC60 pathway is conserved in human neurons, and expression of several MIC60 coding variants in the mitochondrial targeting sequence found in PD patients in Drosophila impairs crista junction formation and causes locomotion deficits. These findings highlight the importance of maintenance and plasticity of crista junctions to cellular homeostasis in vivo.
View details for PubMedID 29456190
Drosophila MIC60/Mitofilin Conducts Dual Roles in Mitochondrial Motility and Crista Structure.
Molecular biology of the cell
MIC60/mitofilin constitutes a hetero-oligomeric complex on the inner mitochondrial membranes to maintain crista structure. However, little is known about its physiological functions. Here, by characterizing Drosophila MIC60 mutants, we define its roles in vivo We discover that MIC60 performs dual functions to maintain mitochondrial homeostasis. In addition to its canonical role in crista membrane structure, MIC60 regulates mitochondrial motility, likely by influencing protein levels of the outer mitochondrial membrane protein Miro that anchors mitochondria to the microtubule motors. Loss of MIC60 causes loss of Miro and mitochondrial arrest. At a cellular level, loss of MIC60 disrupts synaptic structure and function at the neuromuscular junctions. The double roles of MIC60 in both mitochondrial crista structure and motility position it as a crucial player for cellular integrity and survival.
View details for PubMedID 28904209
Functional Impairment in Miro Degradation and Mitophagy Is a Shared Feature in Familial and Sporadic Parkinson's Disease.
Cell stem cell
Mitochondrial movements are tightly controlled to maintain energy homeostasis and prevent oxidative stress. Miro is an outer mitochondrial membrane protein that anchors mitochondria to microtubule motors and is removed to stop mitochondrial motility as an early step in the clearance of dysfunctional mitochondria. Here, using human induced pluripotent stem cell (iPSC)-derived neurons and other complementary models, we build on a previous connection of Parkinson's disease (PD)-linked PINK1 and Parkin to Miro by showing that a third PD-related protein, LRRK2, promotes Miro removal by forming a complex with Miro. Pathogenic LRRK2G2019S disrupts this function, delaying the arrest of damaged mitochondria and consequently slowing the initiation of mitophagy. Remarkably, partial reduction of Miro levels in LRRK2G2019S human neuron and Drosophila PD models rescues neurodegeneration. Miro degradation and mitochondrial motility are also impaired in sporadic PD patients. We reveal that prolonged retention of Miro, and the downstream consequences that ensue, may constitute a central component of PD pathogenesis.
View details for DOI 10.1016/j.stem.2016.08.002
View details for PubMedID 27618216
View details for PubMedCentralID PMC5135570
Elevated Energy Production in Chronic Fatigue Syndrome Patients.
Journal of nature and science
2016; 2 (10)
Chronic Fatigue Syndrome (CFS) is a debilitating disease characterized by physical and mental exhaustion. The underlying pathogenesis is unknown, but impairments in certain mitochondrial functions have been found in some CFS patients. To thoroughly reveal mitochondrial deficiencies in CFS patients, here we examine the key aspects of mitochondrial function in blood cells from a paired CFS patient-control series. Surprisingly, we discover that in patients the ATP levels are higher and mitochondrial cristae are more condensed compared to their paired controls, while the mitochondrial crista length, mitochondrial size, shape, density, membrane potential, and enzymatic activities of the complexes in the electron transport chain remain intact. We further show that the increased ATP largely comes from non-mitochondrial sources. Our results indicate that the fatigue symptom in this cohort of patients is unlikely caused by lack of ATP and severe mitochondrial malfunction. On the contrary, it might be linked to a pathological mechanism by which more ATP is produced by non-mitochondrial sources.
View details for PubMedID 27747291
View details for PubMedCentralID PMC5065105
PINK1-mediated phosphorylation of Miro inhibits synaptic growth and protects dopaminergic neurons in Drosophila.
2014; 4: 6962-?
Mutations in the mitochondrial Ser/Thr kinase PINK1 cause Parkinson's disease. One of the substrates of PINK1 is the outer mitochondrial membrane protein Miro, which regulates mitochondrial transport. In this study, we uncovered novel physiological functions of PINK1-mediated phosphorylation of Miro, using Drosophila as a model. We replaced endogenous Drosophila Miro (DMiro) with transgenically expressed wildtype, or mutant DMiro predicted to resist PINK1-mediated phosphorylation. We found that the expression of phospho-resistant DMiro in a DMiro null mutant background phenocopied a subset of phenotypes of PINK1 null. Specifically, phospho-resistant DMiro increased mitochondrial movement and synaptic growth at larval neuromuscular junctions, and decreased the number of dopaminergic neurons in adult brains. Therefore, PINK1 may inhibit synaptic growth and protect dopaminergic neurons by phosphorylating DMiro. Furthermore, muscle degeneration, swollen mitochondria and locomotor defects found in PINK1 null flies were not observed in phospho-resistant DMiro flies. Thus, our study established an in vivo platform to define functional consequences of PINK1-mediated phosphorylation of its substrates.
View details for DOI 10.1038/srep06962
View details for PubMedID 25376463
View details for PubMedCentralID PMC4223694
The meaning of mitochondrial movement to a neuron's life
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
2013; 1833 (1): 184-194
Cells precisely regulate mitochondrial movement in order to balance energy needs and avoid cell death. Neurons are particularly susceptible to disturbance of mitochondrial motility and distribution due to their highly extended structures and specialized function. Regulation of mitochondrial motility plays a vital role in neuronal health and death. Here we review the current understanding of regulatory mechanisms that govern neuronal mitochondrial transport and probe their implication in health and disease. This article is part of a Special Issue entitled: Mitochondrial dynamics and physiology.
View details for DOI 10.1016/j.bbamcr.2012.04.007
View details for Web of Science ID 000313932100019
View details for PubMedID 22548961
View details for PubMedCentralID PMC3413748
PINK1 and Parkin Target Miro for Phosphorylation and Degradation to Arrest Mitochondrial Motility
2011; 147 (4): 893-906
Cells keep their energy balance and avoid oxidative stress by regulating mitochondrial movement, distribution, and clearance. We report here that two Parkinson's disease proteins, the Ser/Thr kinase PINK1 and ubiquitin ligase Parkin, participate in this regulation by arresting mitochondrial movement. PINK1 phosphorylates Miro, a component of the primary motor/adaptor complex that anchors kinesin to the mitochondrial surface. The phosphorylation of Miro activates proteasomal degradation of Miro in a Parkin-dependent manner. Removal of Miro from the mitochondrion also detaches kinesin from its surface. By preventing mitochondrial movement, the PINK1/Parkin pathway may quarantine damaged mitochondria prior to their clearance. PINK1 has been shown to act upstream of Parkin, but the mechanism corresponding to this relationship has not been known. We propose that PINK1 phosphorylation of substrates triggers the subsequent action of Parkin and the proteasome.
View details for DOI 10.1016/j.cell.2011.10.018
View details for Web of Science ID 000296902300021
View details for PubMedID 22078885
The Mechanism of Ca2+-Dependent Regulation of Kinesin-Mediated Mitochondrial Motility
2009; 136 (1): 163-174
Mitochondria are mobile organelles and cells regulate mitochondrial movement in order to meet the changing energy needs of each cellular region. Ca(2+) signaling, which halts both anterograde and retrograde mitochondrial motion, serves as one regulatory input. Anterograde mitochondrial movement is generated by kinesin-1, which interacts with the mitochondrial protein Miro through an adaptor protein, milton. We show that kinesin is present on all axonal mitochondria, including those that are stationary or moving retrograde. We also show that the EF-hand motifs of Miro mediate Ca(2+)-dependent arrest of mitochondria and elucidate the regulatory mechanism. Rather than dissociating kinesin-1 from mitochondria, Ca(2+)-binding permits Miro to interact directly with the motor domain of kinesin-1, preventing motor/microtubule interactions. Thus, kinesin-1 switches from an active state in which it is bound to Miro only via milton, to an inactive state in which direct binding to Miro prevents its interaction with microtubules. Disrupting Ca(2+)-dependent regulation diminishes neuronal resistance to excitotoxicity.
View details for DOI 10.1016/j.cell.2008.11.046
View details for Web of Science ID 000262318400023
View details for PubMedID 19135897
IMAGING AXONAL TRANSPORT OF MITOCHONDRIA
METHODS IN ENZYMOLOGY, VOL 457: MITOCHONDRIAL FUNCTION, PARTB MITOCHONDRIAL PROTEIN KINASES, PROTEIN PHOSPHATASES AND MITOCHONDRIAL DISEASES
2009; 457: 319-333
Neuronal mitochondria need to be transported and distributed in axons and dendrites in order to ensure an adequate energy supply and provide sufficient Ca(2+) buffering in each portion of these highly extended cells. Errors in mitochondrial transport are implicated in neurodegenerative diseases. Here we present useful tools to analyze axonal transport of mitochondria both in vitro in cultured rat neurons and in vivo in Drosophila larval neurons. These methods enable investigators to take advantage of both systems to study the properties of mitochondrial motility under normal or pathological conditions.
View details for DOI 10.1016/S0076-6879(09)05018-6
View details for Web of Science ID 000266544100018
View details for PubMedID 19426876
Drosophila spichthyin inhibits BMP signaling and regulates synaptic growth and axonal microtubules
2007; 10 (2): 177-185
To understand the functions of NIPA1, mutated in the neurodegenerative disease hereditary spastic paraplegia, and of ichthyin, mutated in autosomal recessive congenital ichthyosis, we have studied their Drosophila melanogaster ortholog, spichthyin (Spict). Spict is found on early endosomes. Loss of Spict leads to upregulation of bone morphogenetic protein (BMP) signaling and expansion of the neuromuscular junction. BMP signaling is also necessary for a normal microtubule cytoskeleton and axonal transport; analysis of loss- and gain-of-function phenotypes indicate that Spict may antagonize this function of BMP signaling. Spict interacts with BMP receptors and promotes their internalization from the plasma membrane, implying that it inhibits BMP signaling by regulating BMP receptor traffic. This is the first demonstration of a role for a hereditary spastic paraplegia protein or ichthyin family member in a specific signaling pathway, and implies disease mechanisms for hereditary spastic paraplegia that involve dependence of the microtubule cytoskeleton on BMP signaling.
View details for DOI 10.1038/nn1841
View details for Web of Science ID 000244175200012
View details for PubMedID 17220882