How Does Mitochondrial DNA Contribute to Human Disease


            Mitochondria are organelles found in nearly all eukaryotic cells with approximate size 0.5 to 10µm in diameter which are most famous for their ability to produce Adenosine-5′-triphosphate (ATP) – which is the molecular unit of currency of energy transfer within the cell; by means of oxidative phosphorylation during aerobic respiration. If this is not enough for an organelle, previous reports have also suggested that mitochondria also play a role in cell death, inter-cellular signalling, during cell differentiation and regulation of the cell cycle (Halestrap AP, 2003; McBride HM et al., 2006).

            Mitochondria, according to the “endosymbiosis theory” evolved from Purpurbacteria around 1.5 billion years ago. They are unique in many ways compared to other organelles which exist within the cell. To start, it has its own DNA; has sections which carry out different functions; and the amount of mitochondria differs from tissue to tissue. Starting with the former of these features of the mitochondrion; the human mitochondrial genome is double stranded and circular; is around 16.5 kilobases long and codes for 37 genes. In the case of humans, mtDNA also lacks introns and 93% of it is coding, compared to the nuclear DNA’s value of 3%. Some genes even overlap and the only non-coding region in the mtDNA is the D-loop, which is 1kb long. As one can see it bears a resemblance of a prokaryotic organism’s genome, which suggests the mitochondria could be linked to prokaryotes through evolution – or may even have been a prokaryote itself, supporting the Purpurbacteria theory. Next one is the differences in function between the outer membrane, inner membrane and the matrix. Their jobs are to enclose the organelle and transport essential protein and minerals; synthesize ATP and regulate metabolite passage in to and out of the matrix; and oxidise pyruvate and fatty acids, respectively. Finally, the amount of mitochondria varies between different cell types and even same cell types in different individuals; for example in the case of humans values vary from 200 to 2000 (Robin E.D & Wong R, 1988) depending on the work rate and energy requirements of the respective cell/tissue.

Another interesting fact is that mitochondrial DNA (mtDNA) is only passed on to the offspring maternally. During fertilisation of the ovum – due to the sperm only having enough mitochondria for itself when travelling to the female gamete; the maternal mitochondria vastly outnumbers the mitochondria of the sperm in the zygote, thus leading to (nearly) all the offspring’s mtDNA being inherited from the mother.

Mitochondrial DNA also has its own genetic code different from the “universal” code, where AUA codes for methionine; TGA codes for tryptophan, and AGA and AGG specify stop codons. All these difference aforementioned add up to the fact that mitochondrial genetics is very different from Mendelian genetics nearly in all aspects; take it from how it is inherited to how it replicates. Further analysis into how mtDNA replication and transcription is carried out – which knowledge at present is not up to the levels of nuclear DNA’s replication and transcription mechanisms; will lead to better understanding of mtDNA mutations and their consequences. However DNA polymerase γ is known to play a part in the replication process with the assistance of TFAM – a transcription factor; and a DNA helicase called Twinkle, which work together to form structures called “nucleoids” which are dynamic complexes consisting of several copies of mtDNA and essential maintenance proteins. Nevertheless the mode of replication is not understood properly and several theories are made about it, with the most prominent ones being the “Strand-coupled” and “strand-displacement” models. The former one states that replication starts at the heavy strand first, then with the RNA polymerase moving on to the light strand two-thirds of the way, working in the opposite direction. The latter states the two strands are coordinated in the conventional way. The origin of replication is also a debate issue, as several points in the mitochondrial genome are proposed, including the D-loop. Another problem which complicates matters is the lack of knowledge on how recombination occurs at a cellular (and population) level.

Contrastingly to the replication process, a lot of knowledge is present about the transcriptional machinery of the mitochondria. It is known that transcription occurs on both strands and promoters are present in the D-loop which produce polycistronic precursor RNAs, which is then are processed accordingly to individual tRNA and mRNA molecules. However, how pathogenic mtDNA mutations result in the disruption of transcription, which possibly leads to cellular dysfunction requires further research to give better insight tissue and mutation specific effects.

Functions of the Mitochondrion

            Functions of an organelle can give great insight into what the consequences will be when things start to malfunction in it. The main function of mitochondria is ATP production; this can also be confirmed with the ratio of proteins embedded in the inner membrane for this task – such as proteins involved in ADP phosphorylation, pyruvate decarboxylation and in the Krebs cycle; compared to proteins used in different functions (Taylor SW et al., 2003), such as signalling and apoptosis. After glucose has been reduced to pyruvate in the cytosol, each of these resulting molecules are actively transported through the inner membrane of the mitochondrion in to the matrix. In this enzyme-rich environment, important processes such as the citric acid cycle take place. The process, very generally consists of the pyruvate being oxidised; and with the combination of coenzyme A, acetyl-coenzyme A (acetyl-CoA), carbon dioxide (CO2) and Nicotinamide adenine dinucleotide (NADH) – which is used as a source of electrons for the electron-transport-chain (ETC); are formed; thus leading to ATP synthesis as a result of storage of the energy produced by the ETC process.

            Mitochondria also act as “cytosolic buffers” (Rossier, M.F, 2006) for calcium due to their ability to take up any free calcium in the cytosol due to the concentration gradient; contributing to the processes linked with homeostasis of calcium. This is essential for calcium signalling between cells and also for calcium induced apoptosis

            Other proposed functions of the mitochondria are regulation of the transmembrane potential – which drives the production of ATP (Voet, D, et al, 2006); initiation of apoptosis in the cell it is conserved – by activating several pathways which are recognized by lysosomes (Green, D, 1998); regulation of cell proliferation (McBride, HM, 2006); and many more such as steroid synthesis. Furthermore some of mitochondria’s not-so-mentioned functions are carried out only in certain cell types, for example mitochondria in the liver cells contain enzymes which detoxify waste products of the protein metabolisms such as ammonia.

            However being such a useful organelle for the host organism also has it’s down sides for the host; and as mutations in the mtDNA are very likely to be within genes – due to the lack of introns and tandem repeats; since it is easier compared to the nuclear DNA, for even small scale mutations to cause disruption within the mitochondria, which is then bound to affect nearly all interactions occurring in the cell and cause weakening to the host.

Mitochondria and Disease

Approximately 90% of the oxygen consumption within the cell is carried out by the Mitochondria. Most oxygen is reduced to water and around 1-2% of these are converted to superoxide anion radicals. With the action of the superoxide dismutase enzyme, these radicals are converted to hydrogen peroxide which, has the ability – due to it’s viscosity; to freely diffuse throughout the cell and cause decomposition and interfere with important interactions being carried out within the cell (Druzhnya N.M, 2008). Unlike the nuclear DNA, mtDNA does not have “good enough” DNA repair systems – as it lacks the nucleotide excision repair systems; to fully compensate for the damage caused due to the excessive amount of free oxygen radicals being released, because of the electron transport chain nearby. Furthermore, mtDNA is not protected by histones and more rounds of replications occur compared to the nuclear DNA leading to more replicative mutations. Additionally with respect to nuclear DNA replication, during replication much of the genome is single stranded for longer periods making mtDNA more prone to mutation. Moreover due to the mitochondrial membrane potential, a negative charge in the matrix is generated, causing lipophilic cations – which are alkylating agents; to accumulate within the mitochondria and concentrate 1000-fold compared to the cytosolic levels. All these factors lead to the mtDNA having a mutation rate approximately 10 times higher than that of the nuclear DNA, which is not good news considering the importance of its genome to the cell and with nearly all of it being encoded to proteins.

13 of the 37 genes present in the mtDNA code for respiratory proteins, while the rest codes for the other functions abovementioned; thus mutations are most likely to occur within the respiratory genes which will abruptly reduce the ability to synthesize ATP. However ATP synthesis is under the control of both the mtDNA and the nuclear DNA; thus mutations in critical genes in either of these genomes could impair the respiration process. Nonetheless around 1500 proteins which function in mitochondria are encoded by nuclear genes; which are transported into the mitochondria by various protein complexes after being synthesised in the cytosol. This makes mtDNA very much, if not totally dependent on nuclear encoded proteins for its maintenance and transcription. This phenomenon could lead to the symptoms of mitochondrial disorders to show even when nothing seems to be wrong in the mtDNA (Wallace D.C, 2010).

The tissues which require the most ATP are the central nervous, peripheral nervous, gastrointestinal, endocrine and the renal systems as well as the cardiac muscles. With the main job of the mitochondria being ATP synthesis, any mutation in the genes which code for respiratory proteins of the mtDNA are most likely to cause disorder in these systems. Furthermore there is no one way to malfunctioning of the mitochondrial processes; mitochondrial disorders could be caused either by mutations which occur within the genes of mtDNA; or with mutations which damage pathways associated with mitochondrial protein synthesis.

Mitochondrial disorders can have effects on different cells of the body, either to the muscles or to the nerves; and these disorders are named myopathies and neuropathies respectively. Mitochondrial-encephalomyopathy-lactic-acidosis-and-stroke-like-episodes (MELAS), a myopathy which occurs 1 per 13000 in Northern England (Scaglia, F, 2010); its frequency is rising in other parts of the world and there is no tried-and-tested cure for it. It is usually caused by mutations in the NADH dehydrogenase genes such as ND1 and ND5; and is a heteroplasmic disorder – which means both the mutated mitochondria and the normal ones are present in the same cell; with symptoms such as hemiparesis and dementia. It can also be caused by mutations in the transfer RNAs such as TL1, TH and TV as they are essential in the translation of the ND genes. Another common mitochondrial disorder, Leber’s hereditary optic neuropathy (LHON) is a neuropathy caused 90% of the time by mutations in the ND4, ND6 and/or ND1 genes. It is a homoplasmic disorder – which means it arises when all the mitochondria in a cell possess the mutations; with symptoms such as colour blindness and loss of vision. Again, same as the MELAS disorder, the genes responsible for LHON encode for specific NADH dehydrogenases which take part during oxidative phosphorylation. Interesting feature of this disorder is that it shows sex bias as the severity is worse in males compared to females; but how and why this happens is not well understood.

            Since the 1980’s, mutations within the mtDNA were reported to be pathogenic (Druzhnya N.M, 2008) and an increasing number of diseases have been linked to mtDNA since then, such as cancer and premature aging syndromes. It has been also observed that mitochondrial disorders show variance in severity – as the number of mitochondria which carry mutations varies from person to person. Furthermore, how these mutations are passed on to the offspring also varies as the gametes do not have the same ratio of normal and mutated mitochondria within them, due to random segregation of the mitochondria. This leads to some gamete having homoplasmic cells with all-normal or all-mutated; or having heteroplasmic cells with different ratios of both mitochondria present within the cell. Homoplasmic cells with all-normal are very likely not to show mitochondrial disorders whereas the opposite is true for the all-mutated cells. Matters are complicated in heteroplasmic ones; as there is usually a threshold to where the symptoms of the disease is not shown. If the offspring of a person with heteroplasmic disorder are born normal – without any mitochondrial disorders; there is a good chance that the amount of damaged mitochondria which he/she inherited from his/her mother will increase later on in life leading to mitochondrial disorders; or the severity of the disorder could worsen as time passes in offspring who show mild symptoms. One thing that complicates matters even further is the genetic bottleneck – a temporary reduction in population size that causes the loss of genetic variation; which occurs during development of primary oocytes. This only adds to the difficulty when a clinician is predicting the outcome of the offspring, whether they are going to be affected or not.

            Other studies report that damage to the mtDNA could possibly be particularly devastating to permanently differentiated cells such as neurons (Ly and Verstreken, 2006), as mitochondria are an essential part of the synapses – which are essential to neuron functions; since they provide the energy needed for their roles within the body, which is to pass electrical (and/or chemical) signals throughout the nervous system and enable movement (and sense). Neurogenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are caused due to progressive loss of neurons through necrosis and apoptosis. Reports have shown that accumulation of mutations and deletions in the mtDNA were found in patients suffering from AD and PD (Wallace C.D, 2005; Mancuso, M et al., 2009), so again there is strong evidence that mtDNA plays a role in the development of neurodegenerative diseaseses.

            Moving on to cancers which have been the “main killers” in human history; all forms of cancers have been linked with mtDNA damage (Copeland et al., 2002). Carew and Huang have reported that mtDNA mutations – especially in the D-loop; play a major role in cancer initiation (Carew and Huang, 2002). Furthermore functional mtDNA can play an essential role in tumour apoptosis (Petros et al., 2005), thus indicating another important role of mitochondria in cancer initiation and development since the opposite is true for a dysfunctional mtDNA. This matter requires exhaustive investigation as there is indication from a lot of studies but none goes further than saying the two are linked. Details of how dysfunctional mtDNA leads to tumours, is still unknown.

No feature of the mitochondrial disorders seem to make things easy for researchers and clinicians; for example patients with mtDNA disease rarely have a common phenotype which would be used as a foundation for clinicians to build their knowledge on. These varieties of pheotype can lead to the diagnosis being looked elsewhere. A typical example for this is diabetes, which are very common conditions and in some cases mutated mtDNA has a role in them. However these types of disorders – the ones that are seen as caused due to mtDNA; are a mere fraction of the total number of diabetes which are being reported (Taylor, R & Turnbull, D; 2005). This leads to the importance of mtDNA being overlooked and is the reason why not many mtDNA disorders are screened due to not being seen as practical and economical.

Mitochondria and Ageing

            Many studies have linked aging with diseases, especially to cancer. As people get older the frequency of cancers seem to increase exponentially compared to younger people (Chan, D.C, 2006); this is why tackling ageing is seen as a way of preventing diseases by many scientists nowadays.

The debate of whether aging is a programmed process – determined by changes in gene regulation; or is it a process of accumulation of mutations, seems to never stop but many stay on the side of the latter. Out of the several theories of aging, mitochondria is linked especially to the free-radical theory of aging which, states that accumulation of oxidative damage is the basis of ageing; and since mitochondria are the main sources of oxidative radicals, this theory is directly linked with mtDNA.

Although mtDNA is only 1% of the total DNA present within the cell, its contribution is far greater than expected; this is especially the case in the ageing process (Trifunovic, A, 2006). Mutations accumulate within the mtDNA as time passes – especially in the D-loop region which contains the only two promoters existing in the mitochondrial genome; and leads to deficiencies within the oxidative phosphorylation activity of the mitochondria, and it return leads to even more radicals being produced, thus more mtDNA damage occurs (Oliveira, T.M, 2010). This exponential increase in oxidative damage leads to cellular dysfunction due to energy insufficiency, signalling defects, apoptosis and replicative senescence; and leads to ageing, which increases chances of disease initiation; and finally, leads to death.

The most common mutation reported within the mtDNA is a 4977bp deletion – which is also known as the “common deletion”; interrupts several mitochondrial complexes involved in the electron transport chain. This mutation has been linked directly with ageing as the frequency of the deletions has been detected many more times – sometimes 1000 fold in different regions of the brain; compared to younger people. Ageing associated deletions of the mtDNA have also been detected in other vertebrates and even invertebrates, such as the monkeys, mice and nematodes. More and more deletions connected with ageing are being detected as time passes (Wallace, D.C, 2010).


Mitochondrial disorders are not well understood compared to other diseases, which does not help when developing prevention and cure. However there is evidence that increasing enzyme activity by exercising leads to “satellite cells” being incorporated into muscle fibres, which contributes to muscle growth. This can lead to the ratio of damaged mtDNA to normal mtDNA being lowered as there are more normal cells being produced and not reaching the threshold for heteroplasmic disorders; and not reaching 100% in the case of homoplasmic disorders. Caveats of these types of treatments would be whether this could lead to more of the mutated mtDNA being produced; and whether mouse models would be appropriate for humans.

This is why new pathways are being taken and “allotopic expression” – which is the expression of a gene in a different cellular compartment to its target location; is seen as the way to complement dysfunctional mitochondrial proteins. The aim would be to promote the encoding of a mitochondrial gene in the nucleus, and with the use of conjugation add a localisation signal to the protein which will cause it to be transported to the mitochondria. This strategy is being tried on the ND4 protein to complement mutations which cause LHON at present.

Finally there is the mutations which are pathogenic to the host, such as the 8993T>G which has been shown to lead to increased oxidative radical production; however inhibition of oxidative phosphorylation pathway due to free radicals (because of pathogenic mutations) has been reversed with the use of antioxidants (Taylor, R & Turnbull, D; 2005).

Conclusion & Discussion

            It has been nearly 30 years since the human mitochondrial genome was sequenced by the Sanger group and substantial progress is being made all the time. There are still gaps in the knowledge even on basic processes such as replication, transcription and translation which are essential if cure and prevention is to be found for mitochondrial disorders. Also the importance of mtDNA cannot be understood fully, until a better insight into how repair mechanisms of mtDNA function and are regulated; how the malfunctioning of certain genes lead to disease and ageing; and to which extent the obtained information can be used in curing and preventing the appropriate diseases. More emphasis has to be given towards mtDNA repair systems as there is enormous amount of information about the nuclear DNA repair mechanisms and only so little about the former (Tuppen, A.L et al., 2010). However there is a lot of progress being made and the mitochondrial genome is being annotated and mapped for humans as well as a variety of species – which can speed up research due to homology of genes in different organisms.

It is known why mtDNA is more susceptible to carcinogens and oxidative radicals compared to nuclear DNA, which has definitely changed the perspective of how scientists see the mitochondria and how it is a key player when searching for clues on causes of novel and known diseases. Furthermore with the mitochondria and its genome being such an important organelle for humans, now special attention is paid to it as it is bound to have a role in nearly all diseases due to its multifunctional manner.

There is great evidence that mtDNA plays a central role in the ageing process (Trifunovic, A, 2006). If ways to interfere with this “vicious” cycle were to be found, the ageing process could be slowed down – or even stopped; leading to more healthier individual with less chance of picking up diseases and developing cancers. However this issue still needs further research, as there debates about the ageing process itself, let alone which factors play a role in it.

Another debate about mtDNA is whether it is connected to obesity too. This has been proposed by Wallace et al in 2003 who stated that alterations in mitochondrial coupling efficiency – caused by differences in mitochondrial proteins; determines the ratio of calories which are used to generate ATP against the ones that are used to generate heat. When the proportion of the latter is lowered, more energy is stored as fat. To link this with diseases, it is a known phenomenon that overweight individuals are more likely die of heart strokes and develop disorders and cancers.

As one can see there is a lot to be found out and discovered about the organelle as well as its genome; before significant cures and prevention strategies are developed. Future therapeutic strategies to combat diseases could and should have a lot to do with mtDNA.

Useful Links

–          Human Mitochondrial Genome Database:

–          Human Mitochondrial Protein Database:


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