Research – Yvette Wong Lab

The Yvette Wong lab focuses on these areas of research:

Inter-organelle contact sites: What are the mechanisms and functions regulating mitochondria-lysosome contacts in cellular &neuronal homeostasis?
Neurodegenerative diseases: How do defects in organelle dynamics contribute to neurodegeneration in Parkinson’s, Charcot-Marie-Tooth, ALS & Alzheimer’s disease?
Super-resolution microscopy: How can we uncover new cellular pathways using super-resolution live cell microscopy?

1) Inter-organelle contact sites: Mechanisms and functions regulating mitochondria-lysosome contact sites

What we know: Mitochondria and lysosomes are important cellular organelles, which can directly tether together at inter-organelle contact sites known as mitochondria-lysosome contacts, allowing for their bidirectional crosstalk (Nature 2018). Rab7 GTP hydrolysis mediates mitochondria-lysosome contact untethering, and contacts regulate both mitochondrial fission and inter-mitochondrial contact untethering events (Nature 2018; Dev Cell 2019), resulting in lysosomal regulation of mitochondrial network dynamics. Conversely, mitochondria also regulate lysosomal tethering dynamics via a Mid51/Fis1 oligomerization complex which couples together Rab7 and Drp1 GTP hydrolysis machinery (J Cell Biol 2022). Contacts further mediate calcium transfer between lysosomes and mitochondria via TRPML1 (PNAS 2020) and regulate amino acid homeostasis (Science Advances 2023). Thus, while mitochondria-lysosome contact sites play key roles in both health and disease (recently reviewed in: Trends in Neurosci 2022; J Cell Biol 2023), whether there are additional roles and regulators of mitochondria-lysosome contact sites is still not known.

Ongoing studies: We are interested in exploring new mechanisms and functions of mitochondria-lysosome contacts, to better understand basic cellular homeostasis. We are currently using human cell lines to i) identify new regulators of contact sites using proteomic studies, ii) explore additional functions of these contact sites, and iii) study novel interactions between other organelles and mitochondria-lysosome contacts.

2) Neurodegenerative diseases: Defective organelle dynamics in Parkinson’s, CMT, ALS and Alzheimer’s disease

What we know: Mitochondrial and/or lysosomal dysfunction are functionally and genetically linked to many neurodegenerative disorders including Parkinson’s, Charcot-Marie Tooth (CMT), ALS and Alzheimer’s disease. Mitochondria-lysosome contact sites are misregulated in different genetic models of Parkinson’s disease (Nature Comm 2021; Science Advances 2023) and mitochondria-lysosome contact site dynamics are also disrupted in the peripheral neuropathy Charcot-Marie Tooth disease (CMT2B) linked to mutations in Rab7 (Dev Cell 2019; PNAS 2023). However, whether these contact sites are disrupted in other human disorders remain to be explored.

Ongoing studies: We are interested in understanding the role of mitochondria-lysosome contact sites in neurodegenerative diseases, to ultimately identify pathways and potential therapeutic targets in disease pathogenesis. We are investigating both mitochondria-lysosome contact and other organelle dynamics in neurons and in disease models of i) Parkinson’s and Charcot-Marie Tooth, ii) other neurodegenerative diseases such as ALS and Alzheimer’s, and iii) lysosomal storage diseases and mitochondrial disorders.

3) Super-resolution microscopy: Identifying new cellular pathways and dynamics using live-cell imaging.

What we know: Using live cell imaging, we previously identified multiple new organelle events, including the dynamics of autophagy receptor recruitment during parkin-mediated mitophagy (PNAS 2014), actin cycling around mitochondrial sub-populations (Nature Comm 2016). We have also used structured illumination microscopy (SIM) super-resolution imaging to study mitochondria-lysosome contact site tethering (Nature 2018). However, our understanding of the full complexity of organelle interactions and dynamics is still incomplete.

Ongoing studies: We are interested in using super-resolution and live-cell microscopy techniques to identify new cellular dynamics/pathways, to help advance our understanding of cellular/neuronal function and their misregulation in human diseases. We are excited to i) identify new events occurring at the organelle level, ii) explore the regulation of these pathways, and iii) study how these dynamics are disrupted in neurodegenerative and other diseases.