# The mechanism of elimination of the mitochondrial DNA replisome

> **NIH NIH R15** · UNIVERSITY OF NORTH FLORIDA · 2021 · $210,164

## Abstract

The mechanism of elimination of the mitochondrial DNA replisome.
Specific Aims: Mitochondria are essential organelles of eukaryotic cells that convert chemical energy from food
into that of the phosphoanhydride bonds of adenosine triphosphate (ATP). The human mitochondrial genome
encodes proteins critical for ATP synthesis, therefore, defects in the maintenance of mitochondrial DNA (mtDNA)
result in energy deprivation and may lead to the development of degenerative disorders involving the heart,
muscles, kidneys, liver and the central nervous system (1-3). For example, Alpers syndrome is characterized by
intractable epilepsy, psychomotor retardation and liver failure that leads to death in early childhood (4,5). Defects
of mtDNA maintenance have also been linked to other prominent disorders such as Parkinson’s and Alzheimer’s
diseases, autism spectrum disorders, diabetes, as well as multiple types of cancer and aging (6-13). The
mechanisms of pathogenesis of mitochondrial diseases are unknown. There is no cure for any of the mtDNA-
associated diseases and only palliative treatment strategies are currently available (14).
 The PI proposes to investigate a putative mechanism that prevents the formation of large-scale deletions
in mtDNA, which are the most common (de novo) defects of the mitochondrial genome (15-17). The mechanism
of deletions formation is unknown, but studies reported to date indicate that they commonly originate from mtDNA
replication stalling, which promotes breakage of DNA strands. Deletions are most likely formed in the process of
DNA breaks repair (18-20). Notably, the absence of specific mitochondrial molecular chaperones and proteases
promotes the destabilization of mtDNA and accumulation of deletions (21-27), which implies their role in
preventing deletions formation. On the other hand, our preliminary results indicate that a stalled mitochondrial
replicative polymerase remains DNA-bound for a significant extent of time, which could be deleterious and likely
requires active elimination. Therefore, we infer that, in normal conditions, dysfunctional mtDNA replisomes are
eliminated by specific chaperones and proteases, which in turn promotes replication restart. In pathological
conditions, the increased frequency of replication stalling (e.g. due to defects of the replicative enzymes) exceeds
the capacity of the putative elimination system resulting in an increase in DNA breaks frequency and the initiation
of the deleterious repair mechanism (we discussed this in detail in a recent review (20)). Notably, it has been
observed that the large-scale deletions accumulate in tissues with age (12,13,28) and, curiously, the activity of
the related chaperones and proteases has been observed to decrease with age as well (29-31). This apparent
correlation calls for the investigation of a causative relationship. In addition, the putative relationship between
chaperones/proteases systems and the accumulation of deletion-bearing (Δ)mtDNA mo...

## Key facts

- **NIH application ID:** 10880042
- **Project number:** 7R15GM139104-02
- **Recipient organization:** UNIVERSITY OF NORTH FLORIDA
- **Principal Investigator:** Grzegorz Leszek Ciesielski
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $210,164
- **Award type:** 7
- **Project period:** 2021-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10880042

## Citation

> US National Institutes of Health, RePORTER application 10880042, The mechanism of elimination of the mitochondrial DNA replisome (7R15GM139104-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10880042. Licensed CC0.

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