Functional Impairment in Miro Degradation and Mitophagy Is a Shared Feature in Familial and Sporadic Parkinson's Disease.
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.
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Chung-Han
CH
Hsieh
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
Atossa
A
Shaltouki
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Neurosciences Graduate Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
Ashley E
AE
Gonzalez
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Alexandre
A
Bettencourt da Cruz
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Lena F
LF
Burbulla
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Erica
E
St Lawrence
Parkinson's Institute and Clinical Center, Sunnyvale, CA 94085, USA.
Birgitt
B
Schüle
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Dimitri
D
Krainc
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Theo D
TD
Palmer
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: xinnanw@stanford.edu.
Xinnan
X
Wang
D000818:Animals; D001369:Axons / Q000378:metabolism; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000378:metabolism; D004331:Drosophila melanogaster / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D063306:Mitophagy; D009043:Motor Activity; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000150:complications / Q000378:metabolism / Q000473:pathology; D000066829:Neuroprotection; D010300:Parkinson Disease / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D011485:Protein Binding; D011494:Protein Kinases / Q000378:metabolism; D059748:Proteolysis; D034622:RNA Interference; D015398:Signal Transduction; D013312:Stress, Physiological; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D024101:Mitochondrial Proteins; D011494:Protein Kinases; D044767:Ubiquitin-Protein Ligases; D020741:rho GTP-Binding Proteins; D000099202:PTEN-Induced Putative Kinase; C111567:parkin protein; C495280:LRRK2 protein, human; C473124:RHOT1 protein, human