Mitochondrial genetics and human systemic hypertension.

Evolution of biological processes is fascinating and more so the evolutionary reduction of mitochondrial genome. A proteobacterium that invaded the nucleus-containing host cell 1.5 billion years ago, as would the endosymbiotic model surmises,1 ended up enslaved and yet became the essence of life of the invaded cell. And, if so, the invader could not have had a genome that was comprised of only 16 569 base pairs (bp), coding for only 13 proteins, 22 transfer (t)RNAs, and 2 ribosomal (r)RNAs (NC_012920).2,3 Such a small size would seem to be incompatible with survival of a free-living organism as the smallest known bacterial genome is that of Carsonella Ruddi, which is 159 662 bp, ie, 10 times the size of mitochondrial genome, and codes for 182 proteins. Yet, C Ruddi is not a free-living organism but rather an endosymbiont.4 On the contrary, obligate intracellular lifestyle can exist with as little as 5386 bp, as for X174, which is smallest known genome.5 If indeed this organelle, ie, the mitochondrion, was one time a free-living organism with a much larger genome, then, how did it shrink its genome size to the current size and manage to survive? The generation of ATP through oxidative phosphorylation, one of the several mitochondrial functions, alone involves 89 genes and requires a much larger genome to sustain that the mitochondrial (mt)DNA affords.6 Apparently, the invader could not escape from the evolutionary pressure imposed by the host environment and a symbiotic life. Consequently, mitochondria gradually streamlined its genome by relaxed selection of the genes that were superfluous to its survival. Through yet-to-be defined mechanisms the invader seems to have transferred thousands of its genes, particularly those that mutated during mtDNA replication, to nuclear (n)DNA wherein they reside as genes or pseudogenes.7,8 Moreover, mtDNA has a number of exceptions to the universal genetic code, which could render its DNA unrecognizable to transcription and translational machinery of the host cells.9 Hence, to survive and to function, mitochondria became dependent on host’s nuclear genome to code for a thousand or so protein that constitutes mitochondrial proteome.10,11 Despite a symbiotic life, nonetheless, the invader maintained its partial independence in binary fission and genomic replication from the host cell. The processes in mitochondria, although coregulated with the energy demand of the host cell and partially with the cell cycle, occur at much faster rates than those in the hosts. Consequently, each mitochondrion contains two to ten copies of its genome and each cell encompasses hundreds to thousands copies of mitochondria. The faster rate of mtDNA replication, however, is not without consequences, particularly, in an environment that is high in reactive oxygen species (ROS). The rare error rates of DNA replication and editing enzymes increase in the presence of oxidative modified nucleotides and enzymes. Hence, mtDNA has 16 times higher mutation accumulation rate than the nDNA.12 Mutations could initiate a vicious cycle of impaired mitochondrial functions, increased ROS, higher error rates of DNA polymerases and editing enzymes and further accumulation of mutated mtDNA. Given the presence of thousands of copies of mtDNA in each cell, mutations generate an admixture of wild type and mutant mtDNA, which is referred to as heteroplasmy, as opposed to homoplasmy, when all copies of mtDNA are identical. Heteroplasmy in mtDNA in somatic cells, as the mitochondria replicates, increases with age. Accordingly mitochondrial mutations and dysfunctions have been implicated in various age-dependent phenotypes including cellular senescence and metabolic disorders.13 Likewise, most pathogenic mtDNA mutations are heteroplasmic. However, phenotypic consequences of heteroplasmic mtDNA vary according to effects on mitochondrial functions (mutation type and involved gene) and the characteristics of the host cells, such as their energy dependence and metabolism. Thus, the heteroplasmic threshold that causes a phenotype is expected to be lower for organs such as heart, skeletal muscle, brain and endocrine glands that have high dependence on electron chain transport for ATP generation. An intriguing aspect of mtDNA mutations is maternal (matrilineal) inheritance.14 Whereas sperm and ovum nDNA equally contribute to composition of nDNA in a fertilized zygote, mtDNA almost exclusively is inherited from the ovum. The biological rationale and basis for the uniparental inheritance of mtDNA are not fully understood. Nonetheless, a few copies of paternal mtDNA that might enter the zygote during fertilization neither multiply nor recombine with the ovum mtDNA through homologous recombination but rather are tagged with ubiquitin for degradation.15 Perhaps, the evolutionary pressure has so meticulously optimized reconstitutions of the oxidative phosphorylation complexes that any homologous recombination between different sets of mtDNA or reconstitution of different sets of 13 mitochondrial polypeptides are not compatible with functional mitochondria.16 Alternatively, dilution by a shear number of mtDNA in each ovum, which is estimated to be several hundred thousands as opposed to a few hundred copies of mtDNA in the sperm, offers a simple explanation. The process, nevertheless, restricts the opportunity for homologous recombination between 2 sources of mtDNA and, consequently, The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Center for Cardiovascular Genetics, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center and Texas Heart Institute, Houston. Correspondence to A. J. Marian, MD, Center for Cardiovascular Genetics, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Sciences Center, 6770 Bertner St, Suite C900A, Houston, TX 77030. E-mail [email protected] (Circ Res. 2011;108:784-786.) © 2011 American Heart Association, Inc.