# Chemical and Molecular Mechanisms of Mitochondrial DNA Degradation

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2021 · $45,893

## Abstract

PROJECT SUMMARY/ABSTRACT
 Mitochondria are subcellular compartments that are critical for energy production, cell signaling, and the
biosynthesis of protein cofactors in higher eukaryotic cells. The mitochondrial DNA (mtDNA) genome is
indispensable for mitochondrial function because it encodes protein subunits of the oxidative phosphorylation
system and a full set of transfer and ribosomal RNAs. mtDNA degradation is an essential mechanism in
mitochondrial genomic maintenance and a quality control measure to cope with mitochondrial DNA damage
sourced from endogenous and environmental chemicals. The mechanism of mtDNA degradation and factors
involved are poorly understood, which represents a significant knowledge gap. Such knowledge is fundamental
to the understanding of mitochondrial genomic maintenance and pathology, because mtDNA degradation may
contribute to the etiology of mtDNA depletion syndromes and to the activation of the innate immune system by
circulating mtDNA. The objective of this project is to define the chemical and molecular basis of damaged mtDNA
degradation and to clarify the role of a major transcription factor and DNA packaging protein TFAM (mitochondrial
transcription factor A) in DNA degradation and repair. Addressing this critical knowledge gap will facilitate the
PI’s long-term goal of unraveling the basis of mitochondrial DNA turnover and its role in mitochondrial
pathobiology. This project focuses on a ubiquitous DNA lesion and central DNA repair intermediate, i.e. abasic
(AP) sites. The central hypothesis is that TFAM modulates the stability of AP lesions and mediates AP-DNA
degradation. This hypothesis is grounded in both strong preliminary data and empirical evidence. Preliminary
results will be further evaluated by using a combination of quantitative biochemical, computational, and cellular
approaches. Specifically, this research program will delineate the chemical and kinetic basis of TFAM-mediated
AP-DNA destabilization, describe the involvement of TFAM in AP-DNA degradation in human cells, and clarify
the regulatory role of TFAM in mtDNA repair. The expected outcome is that the project will fill a critical knowledge
gap concerning the chemical and molecular mechanisms of mtDNA degradation and novel protein factors
involved in the process. This application builds on the PI’s strong background in DNA and protein biochemistry,
mechanistic enzymology, and quantitative analysis, and accelerates the progress in an exciting area of research
into mitochondrial biology. The significance of this project is that it will define the chemical and molecular basis
of an mtDNA-degradation pathway and the role of TFAM in mtDNA degradation and repair. Considering that AP
sites are key intermediates in mtDNA repair, insights into AP-DNA degradation will have broad implications for
understanding mitochondrial genomic maintenance and instability. New knowledge from this research will
profoundly advance the field of mtDNA maintenance an...

## Key facts

- **NIH application ID:** 10212125
- **Project number:** 3R35GM128854-03S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Linlin Zhao
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $45,893
- **Award type:** 3
- **Project period:** 2018-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212125

## Citation

> US National Institutes of Health, RePORTER application 10212125, Chemical and Molecular Mechanisms of Mitochondrial DNA Degradation (3R35GM128854-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10212125. Licensed CC0.

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