Ann Lab Med.  2015 Jan;35(1):1-14. 10.3343/alm.2015.35.1.1.

Mitochondrial DNA Aberrations and Pathophysiological Implications in Hematopoietic Diseases, Chronic Inflammatory Diseases, and Cancers

• Kim HR
• Won SJ
• Fabian C
• Kang MG
• Szardenings M
• Shin MG

• KMID: 2363141
• DOI: http://doi.org/10.3343/alm.2015.35.1.1

Abstract

Mitochondria are important intracellular organelles that produce energy for cellular development, differentiation, and growth. Mitochondrial DNA (mtDNA) presents a 10- to 20-fold higher susceptibility to genetic mutations owing to the lack of introns and histone proteins. The mtDNA repair system is relatively inefficient, rendering it vulnerable to reactive oxygen species (ROS) produced during ATP synthesis within the mitochondria, which can then target the mtDNA. Under conditions of chronic inflammation and excess stress, increased ROS production can overwhelm the antioxidant system, resulting in mtDNA damage. This paper reviews recent literature describing the pathophysiological implications of oxidative stress, mitochondrial dysfunction, and mitochondrial genome aberrations in aging hematopoietic stem cells, bone marrow failure syndromes, hematological malignancies, solid organ cancers, chronic inflammatory diseases, and other diseases caused by exposure to environmental hazards.

Keyword

mtDNA; Aberrations; Diseases

MeSH Terms

DNA, Mitochondrial/*genetics/metabolism
Hematologic Diseases/genetics/*pathology
Humans
*Inflammation
Mitochondria/genetics
Mutation
Neoplasms/genetics/*pathology
Oxidative Stress
Reactive Oxygen Species/metabolism
DNA, Mitochondrial
Reactive Oxygen Species

Figure

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  Fig. 1 Phylogenetic tree of 70 unrelated Korean individuals based on direct sequencing results of mitochondrial DNA (mtDNA) control region. The study population exhibited marked mtDNA sequence diversity. The percent identification distribution was 17.7 to 99.9 among healthy Korean donors.

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  Fig. 2 Demonstration of the difficulties involved in sequencing the homopolymeric C (poly-C) tracts in mitochondrial DNA (mtDNA) control region. Many mtDNA length heteroplasmies are localized in the hypervariable (HV) 2 poly-C tract, which is located between nucleotide positions (np) 303 and 315 (303CCCCCCCTCCCCC315 which is abbreviated as 7CT5C) (A and C). Another poly-C tract variant is located between np 16184 and 16193 (16184CCCCCTCCCC 16193, 5CT4C) in the HV1 region (B and D). This intractability against sequencing beyond these poly-C tracts in the HV regions is most likely attributable to the existence of more than one length of mtDNA.

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  Fig. 3 Schematic diagram of the heme biosynthetic pathway. Heme synthesis begins in the mitochondria, and after several intermediate steps in the cytoplasm, returns to the mitochondria.

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  Fig. 4 Schematic representation of aging hematopoietic stem cells (HSCs) and disease phenotypes. Instabilities of nuclear and mitochondrial genomes, and their altered transcriptions, including epigenetic changes, are associated with HSC aging, resulting in the development of age-related diseases.Abbreviations: mtDNA, mitochondrial DNA; ROS, reactive oxygen species; HSC, hematopoietic stem cell.

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  Fig. 5 Schematic representation of mtDNA mutations in hematopoietic stem/progenitor cells and their clonal expansion. mtDNA mutations arise in hematopoietic stem cells as a result of intracellular reactive oxygen species (ROS). These mutations are clonally expanded into progenitor cells and daughter cells.

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