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Human Mitochondrial Mutations and Repair

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Plant Mitochondria

Part of the book series: Advances in Plant Biology ((AIPB,volume 1))

Abstract

One of the unique features of mitochondria is that they have their own genome. Mitochondrial DNA, just like its counterpart in the nucleus, is constantly exposed to damaging agents such as ionizing radiation, environmental toxins, as well as many therapeutic drugs. Mitochondrial DNA is also the main target of endogenous ROS. Oxidative damage and mutations are common in mtDNA. A wide spectrum of pathogenic mutations of mtDNA has been demonstrated and associated with common diseases such as diabetes, neurodegeneration, cancer, and aging. Although some of these mutations are inherited, more and more attention is being focused on the accumulation of mitochondrial DNA mutations in somatic cells, particularly terminally differentiated cells. Mutations can be the results of unrepaired damage to mtDNA. Evidence now clearly shows that mitochondria contain the machinery to repair the damage to their genomes caused by certain endogenous or exogenous damaging agents. In this review we provide general information about the human mitochondrial genome and susceptibility of mtDNA to damage, show the association of human mtDNA mutations with aging and diseases, describe the pathways and the proteins involved in mammalian mtDNA repair in normal and pathologic states, and discuss how modulation of mtDNA repair could be a powerful tool to better understanding of the biologic significance of mtDNA repair mechanisms for cellular defenses.

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Abbreviations

4NQO:

4-Nitroquinoline-1 Oxide

8-oxoG:

8-Oxoguanine

AD:

Alzheimer’s Disease

ALS:

Amyotrophic Lateral Sclerosis

APE:

Apurinic/Apyrimidinic Endonuclease

ATP:

Adenosine Triphosphate

BER:

Base Excision Repair

bp:

Base Pair

COX:

Cytochrome C Oxidase

DR:

Direct Repair/Reversal

dsb:

Double Strand Break

ETC:

Electron Transport Chain

HD:

Huntington’s Disease

HR:

Homologous Recombination

LPBER:

Long-Patch Base Excision Repair

MELAS:

Mitochondrial Encephalopathy Lactic Acidosis and Stroke

MERRF:

Myoclonic Epilepsy with Ragged Red Fibers

MGMT:

O6-Methy Guanine DNA Methyltransferase

MMR:

Mismatch Repair

MnSOD:

Manganese Superoxide Dismutase

MPG:

N-Methylpurine DNA Glycosylase

mtDNA:

Mitochondrial DNA

mtSSB:

Mitochondrial Single Stranded Binding Protein

MYH:

MutY Homolog DNA Glycosylase

nDNA:

Nuclear DNA

NER:

Nucleotide Excision Repair

NHEJ:

Nonhomologous End Joining

OGG1:

8-Oxo-Guanine DNA Glycosylase

PD:

Parkinson’s Disease

pol γ:

DNA Polymerase Gamma

ROS:

Reactive Oxygen Species

SOD:

Superoxide Dismutase

TFAM:

Transcriptional Factor A

tg:

Thymine Glycol

tRNA:

Transfer RNA

UNG:

Uracil DNA Glycosylase

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  1. Department of Cell Biology and Neuroscience, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA

    Nadiya M. Druzhyna

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  2. Glenn L. Wilson
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  1. Botanisches Institut, Universität Kiel, Olshausenstr. 40, Kiel, 24098, Germany

    Frank Kempken

Glossary

Base excision repair (BER):

Is a cellular mechanism that repairs damaged DNA. It is primarily responsible for removing small, non-helix distorting base lesions from genome. BER is important for removing damaged bases that could otherwise cause mutations by mispairing or lead to breaks in DNA during replication.

Mitochondrial DNA:

Mitochondria have a small genome that, in mammals generally takes the form of covalently closed circles approximately 16 kb in circumference. The mitochondrial genome encodes 13 proteins that are essential for oxidative phosphorylation, 22 tRNAs, and 2 rRNAs.

Mutations:

Are permanent changes in the DNA sequence of a cell’s genome. Mutations in a gene’s DNA sequence either have no effect, alter the amino acid sequence of the protein encoded by the gene, or prevent the gene from functioning.

Reactive oxygen species (ROS):

Molecules or ions formed by the incomplete one-electron reduction of oxygen. These reactive oxygen intermediates include singlet oxygen; superoxides; peroxides; hydroxyl radical; and hypochlorous acid. They contribute to the microbicidal activity of phagocytes, regulation of signal transduction and gene expression, and the oxidative damage to nucleic acids, proteins, and lipids.

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Druzhyna, N.M., Wilson, G.L., LeDoux, S.P. (2011). Human Mitochondrial Mutations and Repair. In: Kempken, F. (eds) Plant Mitochondria. Advances in Plant Biology, vol 1. Springer, New York, NY. https://doi.org/10.1007/978-0-387-89781-3_19

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