# Molecular Mechanisms of Mitochondrial Biogenesis

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA BERKELEY · 2023 · $318,683

## Abstract

PROJECT SUMMARY
Mitochondria are endosymbiotically-derived double membrane-bound organelles which provide cells with
energy via oxidative respiration. Mitochondria also serve as a major hub for cellular metabolism and are
involved in numerous vital pathways, including cell signaling, innate immune response, and apoptosis.
Dysfunction of mitochondria is implicated in aging and many diseases and is a potential causative factor in
neurodegenerative diseases. Most of >1,000 mitochondrial proteins are encoded by the nuclear genome and
thus are imported from the cytosol shortly after being synthesized as precursors on cytosolic ribosomes. Thus,
mitochondrial protein import is an essential process required for biogenesis and functional maintenance of
mitochondria. The import process is mainly mediated by two universally conserved membrane complexes, the
translocase of the outer membrane (TOM) complex and the translocase of the inner membrane (TIM) complex.
The TOM complex mediates the initial translocation of precursor proteins across the outer mitochondrial
membrane, and the TIM complex further translocates the precursor proteins across the inner mitochondrial
membrane. The TIM complex is also responsible for integration of many integral membrane proteins to the
inner membrane. Currently, it is poorly understood how the TOM and TIM complexes mediate these
translocation processes. In the current proposal, we aim to address central outstanding questions about
protein import mechanisms by the TOM and TIM complexes, using structural, biochemical, and biophysical
approaches. These questions include how the translocase complexes specifically recognize their client
proteins, how they form a path for protein translocation in the membranes, what are the molecular interactions
and forces driving protein translocation, and how the translocase complexes are regulated. In particular, we will
perform several cryo-electron microscopy (cryo-EM) studies to visualize the translocase complexes in different
functional states, including substrate-engaged states, and gain insights into their mechanisms for substrate
engagement and conformational changes. The outcomes of these studies will fundamentally advance our
understanding of mitochondrial biology and provide new insights to develop novel approaches to treat
mitochondrial-associated diseases, such as neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10735778
- **Project number:** 1R01GM147628-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA BERKELEY
- **Principal Investigator:** Eunyong Park
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $318,683
- **Award type:** 1
- **Project period:** 2023-09-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10735778

## Citation

> US National Institutes of Health, RePORTER application 10735778, Molecular Mechanisms of Mitochondrial Biogenesis (1R01GM147628-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10735778. Licensed CC0.

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