# Homeostatic Mechanisms Regulating Mitochondrial Health

> **NIH NIH R35** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2020 · $655,967

## Abstract

Project Summary/Abstract
Mitochondria are essential organelles that are most well-known for being cellular "powerhouses," due to
their role in oxidative phosphorylation (OXPHOS) and other metabolic pathways. In addition, they have
diverse roles in other areas of cell biology, including calcium handling, immunity, cell signaling, and
formation of iron-sulfur clusters. Healthy mitochondria are therefore critical for human health, and many
common diseases are associated with mitochondrial dysfunction. The broad goal of this application is to
understand the mechanisms that control mitochondrial health. There are three mechanisms of particular
interest. First, mitochondrial function depends on continual cycles of fusion and fission. These dynamic
processes serve to homogenize the mitochondrial population within a cell and are critical for maintenance of
the mitochondrial genome, morphology, and respiratory chain activity. Second, mitophagy is a major
mechanism to recognize and remove dysfunctional mitochondria. Third, protein surveillance mechanisms
exist to maintain the quality of the OXPHOS protein complexes that generate cellular energy. The OXPHOS
complexes are composed of protein subunits encoded by two genomes--the nuclear genome and the
mitochondrial genome--and therefore have unique challenges in achieving proper subunit stoichiometry and
assembly. This research program targets gaps in knowledge in each of these three homeostatic
mechanisms. For mitochondrial dynamics, this research program investigates the molecular mechanisms
and physiological functions of fusion and fission. To understand molecular mechanism, structural studies
are used to obtain atomic structures of the key molecules mediating these processes. An example is Opa1,
the molecule that mediates inner membrane fusion. Little is known about how this molecule is able to bring
two inner membranes together and mediate membrane merger. To understand physiological function,
mouse studies will be used to determine the role of mitochondrial fusion and fission. The application
highlights two biological systems--the astrocytes of the nervous system and the male germ cell--in which
mitochondrial fission and/or mitophagy play a prominent role. In the case of male germ cell development,
mutations in mitochondrial dynamics genes lead to distinct stage-specific defects, providing a biological
system in which multiple pathways requiring mitochondrial dynamics can be deciphered. To understand
how the quality of the OXPHOS complexes are maintained, innovative genetic screens in human cells will
be used to identify pathways that sense and degrade excessive subunits. Such quality control mechanisms
have been implicated in lifespan regulation. Taken together, these approaches will provide a deep
understanding of homeostatic mechanisms that maintain mitochondrial health.

## Key facts

- **NIH application ID:** 9983083
- **Project number:** 5R35GM127147-03
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** David C Chan
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $655,967
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983083

## Citation

> US National Institutes of Health, RePORTER application 9983083, Homeostatic Mechanisms Regulating Mitochondrial Health (5R35GM127147-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9983083. Licensed CC0.

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