# Structure/Function of Complex II Oxidoreductase

> **NIH NIH R01** · NORTHERN CALIFORNIA INSTITUTE/RES/EDU · 2020 · $672,518

## Abstract

PROJECT SUMMARY/ABSTRACT
Mitochondrial Complex II, also known as succinate dehydrogenase (SDH) is a membrane-bound
heterotetramer (SDH-ABCD) whose four subunits are encoded by nuclear DNA. Complex II has a dual function
in the cell by linking two essential energy-producing processes. As part of the TCA cycle the hydrophilic
SDHAB domain oxidizes succinate to fumarate. This oxidation generates electrons that are transferred
through the Fe-S clusters of the SDHB subunit to reduce ubiquinone within the SDHCD membrane domain to
provide reducing equivalent to the electron transport chain needed for energy generation. As a key metabolic
enzyme malfunction of Complex II is associated with debilitating neurodegenerative diseases and tumor
formation. Although a significant amount of information is available on the structure and function of mature
Complex II, there is gap in our understanding of how the enzyme assembles into a functional complex. In this
project we will identify how various assembly factors work together to insert the flavin (FAD) and Fe-S redox
centers into the SDHAB subunits and how this process is coordinated to assemble a functional Complex II.
Aim 1: Our recent progress has provided insight into how assembly chaperones interact with the bacterial
SdhA subunit to form the covalent FAD linkage needed for catalysis. We will expand on these findings to show
how substrates enable protein domain movements to activate this assembly process and control catalysis in
both bacterial SdhA and human SDHA subunits. This will be accomplished by x-ray crystallography, SAXS,
and double electron electron resonance (DEER) spectroscopy of different intermediate assembly states.
Aim 2: It is known that the Fe-S containing subunit requires specific assembly factors to incorporate its
clusters. In this aim we investigate how the human SDHB (or bacterial SdhB) subunit incorporates its three
unique Fe-S clusters localized into two separate protein domains. We also will determine whether the unique
Complex II assembly chaperones assist with the insertion of the Fe-S clusters, or whether they stabilize the
protein intermediates for interaction with the rest of the cellular Fe-S assembly machinery.
Aim 3: Either malfunction of Complex II assembly or disassociation of the assembled complex during
ischemia/reperfusion can contribute pathologies in mitochondrial function. In this aim we reveal mechanisms
of how the SDHA and SDHB subunits form a functional subcomplex and aberrant activities associated with
accumulation of the SDHAB subcomplex. A focus of this aim is how assembly factors and other proteins
control the potentially deleterious reactive oxygen species that can be formed from the SDHAB subcomplex.

## Key facts

- **NIH application ID:** 9844945
- **Project number:** 5R01GM061606-18
- **Recipient organization:** NORTHERN CALIFORNIA INSTITUTE/RES/EDU
- **Principal Investigator:** Gary Cecchini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $672,518
- **Award type:** 5
- **Project period:** 2001-07-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9844945

## Citation

> US National Institutes of Health, RePORTER application 9844945, Structure/Function of Complex II Oxidoreductase (5R01GM061606-18). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9844945. Licensed CC0.

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