Elsevier

Gene

Volume 354, 18 July 2005, Pages 169-180
Gene

Review
The mitochondrial genome in human adaptive radiation and disease: On the road to therapeutics and performance enhancement

https://doi.org/10.1016/j.gene.2005.05.001Get rights and content

Abstract

The human mitochondrial genome consists of approximately 1500 genes, 37 encoded by the maternally inherited mitochondrial DNA (mtDNA) and the remainder encoded in the nuclear DNA (nDNA). The mtDNA is present in thousands of copies per cell and encodes proteins that are essential components of the mitochondrial energy generation pathway, oxidative phosphorylation (OXPHOS). OXPHOS generates heat to maintain our body temperature and ATP to do work. The mitochondria also produce much of the cellular reactive oxygen species (ROS) and can initiate apoptosis through activation of the mitochondrial permeability transition pore (mtPTP) in response to energy deficiency and oxidative damage. Mitochondrial ROS mutates the mtDNA and mtDNA mutations have been associated with a wide range of age-related diseases including neurodegenerative diseases, cardiomyopathy, diabetes and various cancers. The cellular accumulation of mtDNA mutations may also be the aging clock. Ancient mtDNA variants have also been adaptive and may influence individual health today. Mutations in nDNA-encoded mitochondrial genes can also disrupt OXPHOS, alter mtDNA replication, and affect mitochondrial division. In an effort to treat mitochondrial disease, both metabolic and genetic interventions have been attempted. Metabolic interventions have been directed at increasing energy output, reducing ROS production and stabilizing the mtPTP. Genetic therapies have attempted introduction of nucleic acids into the mitochondrion, nDNA-mitochondrial genes into the nucleus, and mtDNA-encoded genes into the nucleus. These therapeutic approaches might also be used to enhance performance, but we must be careful that catering to short term individual interests might undermine our capacity to adapt and survive.

Introduction

The mitochondrion of the modern human cell is the product of an ancient symbiosis in which an oxidative bacterium took up residence in the proto-nucleated cell that had developed motility and endocytosis. Following this initial symbiotic event, most of the genes of the mitochondrion were transferred to the nuclear DNA (nDNA) where they now reside, are replicated and transcribed. The resulting nDNA-encoded mitochondrial mRNAs are then translated on cytosolic ribosomes into proteins which are selectively imported into the mitochondrion. This mitochondrial protein import is frequently mediated by an amino terminal targeting peptide which is removed on entrance of the polypeptide into the mitochondrial matrix.

Over the millennia, the mitochondrion became increasingly specialized to provide the energy of the cell. By contrast, the proto-nucleated cell increasingly elaborated genes to drive the cellular differentiation that defines our bodies. Since life is structure animated by energy, the mitochondrion still remains central to human health. As a consequence, it is becoming increasingly clear that alterations in mitochondrial genes have been critical for human adaptation to different global environments and that ancient and recent mtDNA mutations are associated with a wide spectrum of degenerative diseases, cancer and aging.

Section snippets

Mitochondrial function

Mitochondria generate energy by burning hydrogen derived from the carbohydrates and fats of our diet with the oxygen that we breathe to generate energy and water (H2O) by the process of oxidative phosphorylaton (OXPHOS; Wallace and Lott, 2002). In endotherms like humans, the energy that is released is used to maintain body temperature and to generate ATP. The reducing equivalents (electrons) from dietary calories are collected by the tricarboxylic acid (TCA) cycle and β-oxidation and

The nature of the mitochondrial genome

The human mtDNA is a circular molecule of approximately 16, 569 nucleotide pairs (nps) (Fig. 2). It retains the mitochondrial genes for the small (12S) and large (16S) ribosomal RNAs (rRNA) and the 22 transfer RNAs (tRNAs) necessary to translate the 13 mtDNA polypeptides. The mtDNA uses a simplified and modified genetic coded. Key modifications of the mtDNA genetic code include the use of the opal stop codon (UGA) as a second tryptophan codon and the absence of a tRNA for the AGG and AGA codons

Genetics of the nDNA mitochondrial genes and disease mutations

Mutations in the nDNA-encoded mitochondrial genes can result in mitochondrial defects that create a diverse array of clinical problems with an underlying Mendelian mode of inheritance. These nDNA mutations can affect structural and assembly genes of OXPHOS, genes involved in mtDNA maintenance, and genes affecting mitochondrial fusion and mobility (Wallace and Lott, 2002, DiMauro, 2004).

Severe mutations in the structural genes of OXPHOS enzyme subunits often result in Leigh Syndrome, a

Genetics of the mtDNA and its role in degenerative diseases, cancer and aging

While the nDNA-encoded mitochondrial genes are inherited, replicated, transcribed and translated like other nDNA genes; the biology and genetics of the mtDNA genes is totally different. Consequently, the genetics of the mitochondrion is uniquely complex.

In vertebrates, the mtDNA is inherited exclusively through the mother. Moreover, each cell harbors thousands of copies of the mtDNA, which can either be pure normal (homoplasmic wildtype), a mixture of mutant and normal (heteroplasmic), or

Therapeutic approaches to mitochondrial disease

Deficiencies in mitochondrial function might be treated by either metabolic or genetic therapies.

Mitochondrial gene therapy

Mitochondrial diseases could also be treated by gene therapy. Mitochondrial gene therapy might include both somatic therapy to ameliorate symptoms and germline therapy to eliminate maternally-inherited pathogenic mutations.

Mitochondrial therapeutics and performance enhancement

It is now clear that not all mtDNA variation is deleterious. Indeed, about 25% of all ancient mtDNA variation appears to have caused functional mitochondrial changes and thus been adaptive. Those mtDNA variants that are adapted to warm climates have mtDNA variants that result in tightly coupled OXPHOS, thus maximizing ATP output and minimizing heat production. The presence of these mtDNAs permits maximum muscle performance but also predispose sedentary individuals that consume excess calories

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