# Chemical and Molecular Mechanisms of Mitochondrial DNA Degradation

> **NIH NIH R35** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2024 · $505,485

## Abstract

In higher eukaryotes, mitochondria play multiple roles in bioenergetics, metabolism, and signaling. The
mitochondrial DNA (mtDNA) genome is indispensable for mitochondrial function because it encodes protein
subunits of the oxidative phosphorylation system and a set of transfer and ribosomal RNAs. mtDNA degradation
is an essential mechanism in mitochondrial genomic maintenance and cell signaling. The knowledge regarding
the mechanism of mtDNA degradation remains limited, representing 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 inflammatory and
immunological diseases triggered by cytosolic and cell-free mtDNA. The objective of this project is to delineate
the chemical and molecular basis of damaged mtDNA degradation by identifying the proteins factors and
molecular triggers in mtDNA degradation and characterizing the released mtDNA products. Addressing these
critical knowledge barriers will facilitate the PI’s long-term goal of unraveling the basis of mtDNA turnover and its
role in mitochondrial pathobiology. The application builds on the PI’s expertise in DNA and protein biochemistry,
mechanistic enzymology, and quantitative analysis, and accelerates the progress in an exciting, productive area
of research into mitochondrial biology. The proposed research is grounded in progress from the PI’s and other
laboratories in the field. Recent research from the PI’s laboratory has provided strong chemical, molecular, and
cellular evidence for the involvement of mitochondrial transcription factor A (TFAM) in the degradation of
damaged mtDNA containing abasic (AP) sites. AP sites are ubiquitous DNA lesions and central DNA repair
intermediates. Enzymology studies from the PI’s laboratory have also provided insights into catalytic and kinetic
mechanisms of key proteins in mtDNA maintenance. The proposed research will focus on (i) identifying unknown
protein factors in mtDNA degradation using proteomics and siRNA-based approaches, (ii) clarifying the
molecular triggers of mtDNA degradation using biochemical and cellular assays, and (iii) characterizing the
chemical and molecular properties of fragmented mtDNA using mass spectrometry-based methods. The
expected outcome is that the results from this research will provide new insights into the molecular basis of
mtDNA degradation and shed light on the characteristics of subsequent mtDNA products. The project is
significant because it addresses a critical barrier in the field by providing fundamental knowledge at the molecular
level. In addition, the PI’s commitment to enhancing diversity in the biomedical workforce further the significance
at a minority- and Hispanic-serving institution. Considering the importance of mtDNA in cell signaling and innate
immunity, new insights into mtDNA degradation will not only advance the understanding of...

## Key facts

- **NIH application ID:** 10765165
- **Project number:** 2R35GM128854-06
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Linlin Zhao
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $505,485
- **Award type:** 2
- **Project period:** 2018-09-01 → 2028-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765165

## Citation

> US National Institutes of Health, RePORTER application 10765165, Chemical and Molecular Mechanisms of Mitochondrial DNA Degradation (2R35GM128854-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10765165. Licensed CC0.

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