Mitochondrial Heteroplasmy Shifting as a Potential Biomarker of Cancer Progression.

Cancer is a serious health problem with a high mortality rate worldwide. Given the relevance of mitochondria in numerous physiological and pathological mechanisms, such as adenosine triphosphate (ATP) synthesis, apoptosis, metabolism, cancer progression and drug resistance, mitochondrial genome (mtDNA) analysis has become of great interest in the study of human diseases, including cancer. To date, a high number of variants and mutations have been identified in different types of tumors, which coexist with normal alleles, a phenomenon named heteroplasmy. This mechanism is considered an intermediate state between the fixation or elimination of the acquired mutations. It is suggested that mutations, which confer adaptive advantages to tumor growth and invasion, are enriched in malignant cells. Notably, many recent studies have reported a heteroplasmy-shifting phenomenon as a potential shaper in tumor progression and treatment response, and we suggest that each cancer type also has a unique mitochondrial heteroplasmy-shifting profile. So far, a plethora of data evidencing correlations among heteroplasmy and cancer-related phenotypes are available, but still, not authentic demonstrations, and whether the heteroplasmy or the variation in mtDNA copy number (mtCNV) in cancer are cause or consequence remained unknown. Further studies are needed to support these findings and decipher their clinical implications and impact in the field of drug discovery aimed at treating human cancer.

Three-parent babies: Mitochondrial replacement therapies.

The mitochondria are intracellular organelles, and just like the cell nucleus they have their own genome. They are extremely important for normal body functioning and are responsible for ATP production - the main energy source for the cell. Mitochondrial diseases are associated with mutations in mitochondrial DNA and are inherited exclusively from the mother. They can affect organs that depend on energy metabolism, such as skeletal muscles, the cardiac system, the central nervous system, the endocrine system, the retina and liver, causing various incurable diseases. Mitochondrial replacement techniques provide women with mitochondrial defects a chance to have normal biological children. The goal of such treatment is to reconstruct functional oocytes and zygotes, in order to avoid the inheritance of mutated genes; for this the nuclear genome is withdrawn from an oocyte or zygotes, which carries mitochondrial mutations, and is implanted in a normal anucleated cell donor. Currently, the options of a couple to prevent the transmission of mitochondrial diseases are limited, and mitochondrial donation techniques provide women with mitochondrial defects a chance to have normal children. The nuclear genome can be transferred from oocytes or zygotes using techniques such as pronuclear transfer, spindle transfer, polar body transfer and germinal vesicle transfer. This study presents a review of developed mitochondrial substitution techniques, and its ability to prevent hereditary diseases.

Data on association of mitochondrial heteroplasmy and cardiovascular risk factors: Comparison of samples from Russian and Mexican populations.

Despite the fact that the role of mitochondrial genome mutations in a number of human diseases is widely studied, the effect of mitochondrial heteroplasmy in the development of cardiovascular disease has not been adequately investigated. In this study, we compared the heteroplasmy levels of mtDNA from leukocytes for m.3256C>T, m.3336T>C, m.12315G>A, m.5178C>A, m.13513G>A, m.14459G>A, m.14846G>A, m.15059G>A, m.652insG and m.1555A>G mutations in CVD-free subjects and CVD patients in samples derived from Russian and Mexican populations. It was demonstrated that heteroplasmy level of m.5178C>A was associated with CVD in Russian men, and m.14459G>A - in Russian women. Mitochondrial heteroplasmy level of m.13513G>A and m.652insG were associated with CVD in Mexican men, and only m.652insG- in Mexican women. The levels of heteroplasmy for mitochondrial mutations m.3336T>C, m.5178C>A, m.14459G>A, m.14846G>A and m.1555A>G were significantly higher in CVD-free Mexican men, and for m.3256C>T, m.3336T>C, and m.14459G>A - in CVD-free Mexican women.

Causes and Consequences of Rapidly Evolving mtDNA in a Plant Lineage.

Understanding mechanisms of coevolution between nuclear and mitochondrial (mt) genomes is a defining challenge in eukaryotic genetics. The angiosperm genus Silene is a natural system to investigate the causes and consequences of mt mutation rate variation because closely related species have highly divergent rates. In Silene species with fast-evolving mtDNA, nuclear genes that encode mitochondrially targeted proteins (N-mt genes) are also fast-evolving. This correlation could indicate positive selection to compensate for mt mutations, but might also result from a recent relaxation of selection. To differentiate between these interpretations, we used phylogenetic and population-genetic methods to test for positive and relaxed selection in three classes of N-mt genes (oxidative phosphorylation genes, ribosomal genes, and "RRR" genes involved in mtDNA recombination, replication, and repair). In all three classes, we found that species with fast-evolving mtDNA had: 1) elevated dN/dS, 2) an excess of nonsynonymous divergence relative to levels of intraspecific polymorphism, which is a signature of positive selection, and 3) no clear signals of relaxed selection. "Control" genes exhibited comparatively few signs of positive selection. These results suggest that high mt mutation rates can create selection on N-mt genes and that relaxed selection is an unlikely cause of recent accelerations in the evolution of N-mt genes. Because mt-RRR genes were found to be under positive selection, it is unlikely that elevated mt mutation rates in Silene were caused by inactivation of these mt-RRR genes. Therefore, the causes of extreme increases in angiosperm mt mutation rates remain uncertain.