# Understanding mitochondrial mutations that drive human tissue aging

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2024 · $173,788

## Abstract

PROJECT SUMMARY/ABSTRACT
This proposal describes a five-year mentored physician-scientist training program to define the scope and
functional consequences of mitochondrial genome mutations in skin tissue aging. The mitochondrial genome
(mtDNA) is an extranuclear source of genetic variability that regulates critical cell functions. MtDNA is highly
susceptible to mutagenesis, including the development of large deletion mutations. When a mutation is
present, it can affect all copies, or only a fraction of the copies of mtDNA. This portion is referred to as
heteroplasmy. Increased levels of mtDNA mutation heteroplasmy have been frequently reported in aging
tissue. Despite this potential, the scope and consequences of age-related mtDNA mutations are not well
understood due to difficulties in sequencing mtDNA and a paucity of in vitro models, making it challenging to
use these mutations as a metric of aging or to develop targeted interventions. To address these limitations, I
developed a long-read sequencing method to profile mtDNA and an induced pluripotent cell-based system to
study the impact of high mtDNA mutation heteroplasmy in multiple cell types.
 Aged facial skin contains the highest frequency of mtDNA deletion mutations across tissues profiled
and prior work suggests a link between mtDNA and function of skin keratinocyte progenitor cells. Skin thus
offers an appealing system to begin understanding the breadth and consequences of age-associated mtDNA
mutations. I hypothesize that mtDNA alterations are acquired with aging in a tissue specific pattern and directly
contribute to age-associated functional changes. To test this, I will pursue three study aims 1) Map and
determine the tissue specificity of mtDNA mutations in aged skin, 2) Quantify mtDNA genetic diversity in age-
associated neoplasia, and 3) Determine whether high mtDNA mutation heteroplasmy alters the function of
human iPSC-derived keratinocyte progenitor cells. This work will provide foundational knowledge for the study
of mitochondrial genome mutations in aging. The K08 will support me to develop advanced skills in the
identification acquired genomic variation and the use of pluripotent and progenitor cells in the study of aging in
order to become a pioneering physician scientist studying the biology of aging. Dr. Michael Teitell, a world-
renowned expert in the study of mitochondrial metabolism and highly experienced and successful mentor, will
serve as my primary mentor. Dr. Jonathan Wanagat and Dr. Paul Boutros will offer guidance in the study of
mitochondrial genomic variation, Dr. Thomas Rando will offer guidance in the study of progenitor cell aging and
Dr. Phillip Scumpia will guide work studying cutaneous tissue, all as members of my advisory committee. A
K08 award will enable my carving out a unique, critical niche of multidisciplinary research that blends
mitochondrial genomics and regenerative biology at the launch of my career as an independent investigator.

## Key facts

- **NIH application ID:** 10865814
- **Project number:** 1K08AG086582-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Amy R. Vandiver
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $173,788
- **Award type:** 1
- **Project period:** 2024-09-12 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10865814

## Citation

> US National Institutes of Health, RePORTER application 10865814, Understanding mitochondrial mutations that drive human tissue aging (1K08AG086582-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10865814. Licensed CC0.

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