# Molecular mechanisms underlying mitochondria-lysosome membrane contact sites in neuronal function and neurodegeneration

> **NIH NIH R00** · NORTHWESTERN UNIVERSITY · 2022 · $249,000

## Abstract

Both mitochondria and lysosomes are critical for regulating neuronal metabolism and function, and dysfunction
of both organelles has been implicated in multiple neurodegenerative diseases including Parkinson’s and
Charcot-Marie-Tooth (CMT) disease. However, the interplay between these two organelles in regulating
neuronal homeostasis and driving neurodegeneration are still not well understood. Inter-organelle membrane
contacts form between two different organelles and are critical sites for mediating organelle dynamics,
metabolite exchange and signaling, but whether mitochondria and lysosomes form similar membrane contact
sites to regulate their functional crosstalk was previously unknown. I recently identified the formation and
regulation of mitochondria-lysosome membrane contact sites which represent a new pathway for the
bidirectional regulation of mitochondria and lysosomes, but the role of these contact sites in neurons has not
yet been explored. Importantly, further elucidating the neuronal role of mitochondria-lysosome contacts
provides important insight into coupled mitochondrial and lysosomal function in neurons and potential
pathways for their coupled dysfunction in multiple neurodegenerative diseases. In this project, I propose to
investigate the molecular mechanisms underlying mitochondria-lysosome contact function in healthy and
diseased neurons during both the K99 and R00 phases using long-term cultures of human induced pluripotent
stem cell (iPSC)-derived neurons grown on micropatterned substrates to facilitate organelle imaging via
advanced microscopy techniques including super-resolution imaging, electron microscopy and high spatial and
temporal resolution live cell microscopy. In Aim 1, I will investigate how mitochondria-lysosome contacts
regulate neuronal health and homeostasis by examining 1) the bidirectional relationship between mitochondrial
trafficking and mitochondria-lysosome contacts in axons, and 2) the role of contacts in regulating calcium and
lipid dynamics and exchange between mitochondria and lysosomes in neurons. Moreover, as lysosomal Rab7
GTP hydrolysis from GTP-bound state to GDP-bound state driven by a mitochondrial GAP (GTPase activating
protein) regulates mitochondria-lysosome contact dynamics, disruption of Rab7 may contribute to
neurodegeneration by misregulating contact dynamics and downstream lysosomal and mitochondrial function.
In Aim 2, I will investigate the role of Rab7-mediated mitochondria-lysosome contact misregulation in the
neurodegeneration of two diseases genetically and functionally linked to both mitochondrial and lysosomal
dysfunction: 1) Parkinson’s disease in which various familial genes disrupt Rab7 GTP state, and 2) CMT as
autosomal dominant mutations in Rab7 result in CMT Type 2B. Together, the proposed research and career
plan offers important new training in experimental techniques and disease modeling, which are essential for my
transition to independence and for ultimately achie...

## Key facts

- **NIH application ID:** 10267212
- **Project number:** 5R00NS109252-04
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Yvette Wong
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10267212

## Citation

> US National Institutes of Health, RePORTER application 10267212, Molecular mechanisms underlying mitochondria-lysosome membrane contact sites in neuronal function and neurodegeneration (5R00NS109252-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10267212. Licensed CC0.

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