Mechanisms of Mitochondrial DNA Deletion Formation

Nissanka, Nadee; Minczuk, Michal; Moraes, Carlos T.

doi:10.1016/j.tig.2019.01.001

Cited by 76 publications

(51 citation statements)

References 83 publications

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“…For the model to be correct, it requires some sort of double-strand break repair system, which remains to be identified. For a detailed discussion of doublestranded breaks and their role in mtDNA deletion formation, we refer to a recent review (Nissanka et al 2019).…”

Section: Deletion Formation In Mitochondrial Dnamentioning

confidence: 99%

Mammalian mitochondrial DNA replication and mechanisms of deletion formation

Falkenberg

Gustafsson

2020

Critical Reviews in Biochemistry and Molecular Biology

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Mammalian mitochondria contain multiple copies of a circular, double-stranded DNA genome (mtDNA) that codes for subunits of the oxidative phosphorylation machinery. Mutations in mtDNA cause a number of rare, human disorders and are also associated with more common conditions, such as neurodegeneration and biological aging. In this review, we discuss our current understanding of mtDNA replication in mammalian cells and how this process is regulated. We also discuss how deletions can be formed during mtDNA replication.

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Section: Deletion Formation In Mitochondrial Dnamentioning

confidence: 99%

Mammalian mitochondrial DNA replication and mechanisms of deletion formation

Falkenberg

Gustafsson

2020

Critical Reviews in Biochemistry and Molecular Biology

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Section: Mtdna Repairmentioning

confidence: 99%

“…If mtDNA degradation is not complete, partially degraded mtDNA molecules can generate mtDNA deletions after NHEJ-mediated DNA ligation (Nissanka et al, 2019). However, it should be underscored that mtDNA deletions can also arise from errors in mtDNA replication such as slipped mispairing (Chen et al, 2011;Nissanka et al, 2019). Slipped-mispairing replication generates large mtDNA deletions that are usually flanked by small direct DNA repeats with identical sequences (Chen et al, 2011;Nissanka et al, 2019).…”

Section: Mtdna Repairmentioning

confidence: 99%

Alteration of mitochondrial DNA homeostasis in drug-induced liver injury

Fromenty

2020

Food and Chemical Toxicology

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Mitochondrial DNA (mtDNA) encodes for 13 proteins involved in the oxidative phosphorylation (OXPHOS) process. In liver, genetic or acquired impairment of mtDNA homeostasis can reduce ATP output but also decrease fatty acid oxidation, thus leading to different hepatic lesions including massive necrosis and microvesicular steatosis. Hence, a severe impairment of mtDNA homeostasis can lead to liver failure and death. An increasing number of investigations report that some drugs can induce mitochondrial dysfunction and drug-induced liver injury (DILI) by altering mtDNA homeostasis. Some drugs such as ciprofloxacin, antiretroviral nucleoside reverse-transcriptase inhibitors and tacrine can inhibit hepatic mtDNA replication, thus inducing mtDNA depletion. Drug-induced reduced mtDNA levels can also be the consequence of reactive oxygen speciesmediated oxidative damage to mtDNA, which triggers its degradation by mitochondrial nucleases. Such mechanism is suspected for acetaminophen and troglitazone. Other pharmaceuticals such as linezolid and tetracyclines can impair mtDNA translation, thus selectively reducing the synthesis of the 13 mtDNA-encoded proteins. Lastly, some drugs might alter the mtDNA methylation status but the pathophysiological consequences of such alteration are still unclear. Drug-induced impairment of mtDNA homeostasis is probably under-recognized since preclinical and post-marketing safety studies do not classically investigate mtDNA levels, mitochondrial protein synthesis and mtDNA oxidative damage. 2 A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t 2. Main features of the mitochondria 2.1. Structure and main components Mitochondria, whose size is ~1 µm, are intracellular organelles with two membranes (namely the outer and the inner membrane) that surround the matrix. This compartment contains numerous enzymes involved in different key oxidative pathways such as mitochondrial fatty acid oxidation (mtFAO) and pyruvate oxidation via the tricarboxylic acid (TCA) cycle. The matrix also contains the mitochondrial DNA (mtDNA) and all the components (e.g. enzymes and transcription factors) mandatory for its replication, transcription, translation and repair. However, this small genome allows only the synthesis of 13 polypeptides of the mitochondrial respiratory chain (MRC), whereas all other mitochondrial proteins (~1700) are encoded by the nuclear DNA and targeted to mitochondria (Area-Gomez and Schon, 2014; Borst and Grivell, 1981). Notably, mitochondria share different major features with bacteria including size, double-membrane structure, mode of mtDNA transcription and some components of the mtDNA translation machinery (Santini et al., 2017; Schon and Fromenty, 2015). These features are due to the fact that the precursors of mitochondria were bacteria that became endosymbiotic residents of "proto-eukaryotic" cells early in our evolutionary history (Pessayre et al., 2010). 2.2. Production of energy One major role of mitochondria is the production of energy so that these organelles...

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“…As such, import of the nucleic acid component for mtDNA transformation and editing appeared to be a hurdle [176]. This difficulty can be overcome by the use of protein-only nucleases that can efficiently be engineered to target the mitochondrial matrix and induce sequence-specific double-strand breaks in mtDNA molecules [177]. This strategy takes advantage of mtDNA heteroplasmy and is based on the cleavage of mtDNA molecules harboring certain sequences (for example, pathological mutations).…”

Section: Mtdna Editingmentioning

confidence: 99%

Mitochondrial Gene Expression and Beyond—Novel Aspects of Cellular Physiology

Kotrys

Szczęsny

2019

Cells

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Mitochondria are peculiar organelles whose proper function depends on the crosstalk between two genomes, mitochondrial and nuclear. The human mitochondrial genome (mtDNA) encodes only 13 proteins; nevertheless, its proper expression is essential for cellular homeostasis, as mtDNA-encoded proteins are constituents of mitochondrial respiratory complexes. In addition, mtDNA expression results in the production of RNA molecules, which influence cell physiology once released from the mitochondria into the cytoplasm. As a result, dysfunctions of mtDNA expression may lead to pathologies in humans. Here, we review the mechanisms of mitochondrial gene expression with a focus on recent findings in the field. We summarize the complex turnover of mitochondrial transcripts and present an increasing body of evidence indicating new functions of mitochondrial transcripts. We discuss mitochondrial gene regulation in different cellular contexts, focusing on stress conditions. Finally, we highlight the importance of emerging aspects of mitochondrial gene regulation in human health and disease.

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Mechanisms of Mitochondrial DNA Deletion Formation

Cited by 76 publications

References 83 publications

Mammalian mitochondrial DNA replication and mechanisms of deletion formation

Mammalian mitochondrial DNA replication and mechanisms of deletion formation

Alteration of mitochondrial DNA homeostasis in drug-induced liver injury

Mitochondrial Gene Expression and Beyond—Novel Aspects of Cellular Physiology

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