A diagram of mtDNA highlighting gene loci and their products. Source: wikipedia.org
Mitochondria are subcellular organelles (present in every human cell type except red blood cells) and provide the majority of the cell’s energy requirements in the form of adenosine-5-triphosphate. In addition to this major function, mitochondria are essential to a number of other cellular processes including apoptosis. Mitochondria are unique among all other organelles in that they possess their own DNA entirely separate from the DNA contained within the nucleus of the cell. The nucleus contains only a single copy of the nuclear DNA (nDNA), whereas a mitochondrion contains numerous copies of its mitochondrial DNA (mtDNA) and when the number of mitochondria contained in a single cell (upwards of 1,000 in some cell types) is taken into account, the total number of mtDNA duplicates in any one cell can be enormous.
Not only is this mtDNA entirely separate from the nDNA, it is also radically different in its structure and composition. Mitochondrial DNA is miniscule from a genomics standpoint, being only around 16,000 base pairs in size. To put that into perspective, the nDNA stands at over 3,000,000,000 base pairs. To add to that, mtDNA is circular in shape whilst nDNA is linear and open ended. In this regard the mtDNA is very similar to the genetic material often found in bacteria, a similarity that has helped prompted some interesting theories on the origin of the mitochondria, such as that described by Professor David Wilkie that mitochondria are actually the “descendants” of bacteria that invaded cells many thousands of years ago. As a result of its size, mtDNA encodes only a small number of products (consisting of 13 proteins, 22 tRNAs and 2 rRNAs), the genetic information for which is carried on a total of 37 genes [1]. Whilst being relatively small mtDNA is hugely efficient; only 7% of all nDNA encodes a protein whereas this number is 97% in the DNA of mitochondria. Despite its efficiency mtDNA cannot independently produce the multitude of protein subunits required by the mitochondria and works in concert with the nDNA to ensure correct mitochondrial function. However, the precise molecular mechanisms by which the mitochondrial and nuclear genomes interact to produce complexes I, III, IV and V are poorly understood at present.
The 37 gene products encoded by mtDNA are each involved in the production of the electron transport chain (ETC); the machinery required by the mitochondrion to generate ATP. In combination with around 70 gene products of nDNA, 13 mtDNA genes contribute protein sub-units to the enzymatic machinery required to produce ATP. ETC complexes I, III, IV and ATP synthase each contain mtDNA-derived sub-units; the only ETC component that does not is complex II [2]. The sub-units encoded by mtDNA represent only a small proportion of those required; the mitochondrion relies heavily on gene products of the nDNA, both as components of the ETC and the machinery required for their production.
The 14 mtDNA genes that are not responsible for encoding a protein sub-unit encode 22 tRNAs and 2 rRNAs, each of which is specifically involved in the transcription and translation of the 13 aforementioned genes into their products. Like the protein sub-units encoded by mtDNA, this gene expression machinery cannot function without the aid of numerous nDNA encoded proteins. Various tRNA-related enzymes, ribosomal proteins and factors involved in the regulation of protein synthesis act in concert with the mitochondrial tRNA and rRNA to effectively synthesise mtDNA gene products [2].
Replication and transcription of the mtDNA is controlled primarily by a region of non-coding DNA called the displacement loop or D-loop. This region forms the origin for replication of the mtDNA during cellular division; it is also the site of promoter regions involved in the transcription of the mitochondrial genome, hence it is central to the function of the mitochondrion [3].
It has been shown that alterations to the D-loop and moreover alteration to mtDNA as a whole may have a link to multiple cancers [4]. This correlation is indicative of the role that mitochondrial dysfunction seems to play in disease. As a result of the fundamental role of mitochondria in cellular function the clinical conditions arising from their dysfunction are broad and varied. So-called ‘mitochondrial diseases’ may result in a wide range of symptoms including neurological, musculoskeletal, respiratory and gastrointestinal pathologies [1]. Perhaps most interestingly is the implication of mitochondrial dysfunction in age-related diseases [5]. It has been demonstrated that the capacity for ATP production declines with age as a result of mtDNA mutations that have accumulated throughout the course of an individual’s life-span. This loss of mitochondrial ‘fitness’ shows a correlation with age-related conditions, even to the extent that a possible link between mtDNA fidelity and human life length has been proposed [5]. The role of mitochondria in disease pathogenesis is an area of considerable interest; by-products of oxidative phosphorylation (namely reactive oxygen species and reactive nitrogen species) have been linked to cellular damage and the role of mtDNA in age-related pathological processes has become well accepted. A new focus has been given to an apparent link between mitochondrial dysfunction and important neurological diseases such as Alzheimer’s disease [6], lending hope to further insight into the condition and the possibility of a potential treatment in the future.
Mitochondrial DNA plays a critical role in the life and replication of the cell. Without it, energy production sufficient to power the most important processes in most eukaryotic cells would not be possible. Conversely, alterations in base pair sequence, mas well as mutations and deletions in mtDNA have been shown to correlate with numerous human disease states. Nevertheless, new insights into the mechanisms underlying these “mitochondrial diseases” have recently given hope that in the future molecular medicine and the use of stem cell technologies may be able to correct and reverse the course of the pathophysiology observed in these diseases and provide long-lasting alleviation from symptoms and ultimately a cure.
References & Further Reading
1 – Chial, H. & Craig, J. (2008) mtDNA and Mitochondrial diseases. Nature Education 1(1) (link to article)
2 – Suzuki, T., Nagai, A. & Suzuki T. (2011) Human mitochondrial tRNAs: Biogenesis, function, structural aspects, and diseases. Annual Review of Genetics 45 (link to article)
3 – Florentz, C., Sohm, B., Troen-Tóth, P., et al. (2003) Human Mitochondrial tRNAs in Health and Disease. Cellular and Molecular Life Sciences 60(7) (link to article)
4 – Chatterjee, A., Mambo, E. & Sidransky, D. (2006) Mitochondrial DNA mutations in human cancer. Oncogene 25 (link to article)
5 – Desler, C., Lise Marcker, M., Singh, K. K., et al. (2011) The importance of mitochondrial DNA in aging and cancer. Journal of Aging Research 2011 (link to article)
6 – Schon, E. A. & Przedborski, S. (2011) Mitochondria: The next (neurode)generation. Neuron 70(6) (link to article)
Mitochondrial Me 
