. A cluster of metabolic defects caused by mutation in a mitochondrial tRNA. Science. 2004 Nov 12;306(5699):1190-4. PubMed.


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  1. In the present study, the authors report that a cluster of metabolic defects are caused by mutation in a mitochondrial tRNA (Wilson et al., 2004). They identified a homoplasmic mutation substituting cytidine for uridine immediate 5’ to mitochondrial rRNA isolucine anticodon. They note that uridine is almost invariate of a large number of species because of its role in stabilizing the anticodon loop. The authors found that hypertension and dyslipidemia occur in patients who have inherited this mutation. This was described in a large kindred which had a syndrome consisting of hypertension, hypercholesterolemia and hypomagnesemia. The phenotype appeared to be inherited along the maternal lineage. These findings are of great interest. The findings would have been stronger if the authors had actually cultured fibroblasts or made cybrids to demonstrate that this mutation does indeed cause mitochondrial dysfunction. Nevertheless, the findings are of potential great importance because of the “metabolic syndrome” which occurs in up to one-quarter of the U.S. adult population. The “metabolic syndrome” includes diabetes, insulin resistance, obesity, and hypercholesterolemia. These are the major risk factors for cardiac disease and stroke. Diabetes also has a number of other life-threatening consequences, such as renal failure and peripheral neuropathy, which can be extremely painful.

    Overall, about 70 pathology-related mutations in mt tRNA genes have been identified; at least eight different point mutations within genes for mt tRNAIle are correlated with pathologies, chiefly with cardiomyopathy and ophthalmoplegia (cf Kelley et al., 2001). Regarding particularly mt tRNAIle, most of the mutations destabilize this tRNA species and/or interfere with its binding to mitochondrial elongation factors (Kelley et al., 2001; Hino et al., 2004). The newly found mutation described in this article is different in that it is the first one affecting the highly conserved uridine of anticodon of mt tRNAIle. According to the authors, a mutation in this single base may severely impair the binding of tRNA to ribosome.

    How does it result in pathological changes? One of the possibilities might actually be a decrease in efficiency of mitochondrial protein synthesis. This would result in an increase in energy expenditure for mitochondrial self-maintenance and an overall decrease in efficiency of oxidative metabolism in general. Protein biosynthesis costs minimum four ATP molecules per peptide bond formed (two for the aminoacylation of the appropriate tRNA and two for each elongation cycle on the ribosome. There are also some incurrent costs of a degradation of proteins. Less efficient binding of one of the tRNAs to ribosome may result in higher probability of premature termination of polypeptide chains at the level of isoleucine. That would elevate the overall metabolic cost of protein synthesis, thereby increasing caloric intake by a mitochondrion for its own self-maintenance, etc. Instantaneously, this would be insignificant; in a long run, it would sum up to a quite sizeable extraneous caloric intake that is proportional to both the degree of inefficiency of protein synthesis caused by this tRNA mutation, and to a tissue-specific mitochondrial protein turnover rate. If we still believe that a caloric restriction has something to do with an individual’s lifespan, an increase in metabolically futile caloric intake may be viewed quite negatively in terms of living a long and healthy life.

    The link to hypomagnesemia, hypertension, and hypercholesterolemia based on a mitochondrial point mutation is unexpected, and not previously seen in other mitochondrial disorders. There is a clear link between mitochondrial point mutations and diabetes mellitus. For instance, 1 percent of all diabetics harbor the MELAS mutation. There is recent strong evidence implicating mitochondrial dysfunction in normal aging. In a study recently published in Nature, the authors produced genetically engineered mice that carried mutations in an enzyme called mtDNA polymerase PolgA (Trifunovic et al., 2004). This enzyme is involved in both copying and proofreading mtDNA. The authors eliminated the proofreading capability. This then resulted in a marked increase in mtDNA point mutations. Point mutations were common in several enzymes. For instance, cytochrome b had a three- to fivefold increase in single nucleotide substitutions, which were widely dispersed throughout the gene. By eight weeks, mutant animals had about nine mutations per 10 kilobases of DNA, while normal mice had less than one. This markedly accelerated aging in these mice. By 25 weeks of age, the mice showed premature aging. They stopped gaining weight and became bald. They developed low bone mineral density resulting in curved spines, a clinical sign of osteoporosis. Half of the animals died by 48-61 weeks, which is much sooner than a typical mouse which lived to approximately two years. There was a reduction in the activity of enzymes involved in the respiratory chain and in the production of ATP in these mice. This is extremely strong data implicating mtDNA mutations in normal aging.

    Furthermore, in collaboration with Doug Wallace and Pinar Coskun, we recently found that there was a marked increase in point mutations in the control region of mtDNA from AD brains (Coskun et al., 2004). In the AD brain, 65 percent had the T414G gene mutation, while this mutation was absent in all controls. Cloning and sequencing of the mtDNA control region from patient and control brains show that there was an average 63 percent increase in heteroplasmic mtDNA control region mutations, and in subjects older than 80 years, there was a 130 percent increase in these mutations. This was associated with a reduction in the ND6 complex 1 transcript as well as the mtDNA content.

    We previously used a PCR cloning sequencing strategy to show a significant increase in a number of mtDNA point mutations in the brains of elderly subjects as compared to younger subjects (Lin et al., 2002). The average aggregate mutational burden in elderly subjects was 2 x 10 to the minus from mutations per base and a 60 percent change in amino acid. This correlated to a reduction in cytochrome oxidase activity.

    There is, therefore, increasing evidence for mtDNA mutations in both normal aging in neurodegenerative diseases. The present study showing that mtDNA mutations may also be associated with the “metabolic syndrome” is of great interest, further linking mtDNA mutations to normal aging. The fact that the mutation described in the present report caused elevated cholesterol and hypertension would potentially implicate it in increasing the risk of AD, since epidemiological studies have demonstrated that both of these abnormalities can increase the risk of AD.


    . Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10726-31. PubMed.

    . The pathogenic A4269G mutation in human mitochondrial tRNA(Ile) alters the T-stem structure and decreases the binding affinity for elongation factor Tu. Genes Cells. 2004 Mar;9(3):243-52. PubMed.

    . Fragile T-stem in disease-associated human mitochondrial tRNA sensitizes structure to local and distant mutations. J Biol Chem. 2001 Apr 6;276(14):10607-11. PubMed.

    . High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain. Hum Mol Genet. 2002 Jan 15;11(2):133-45. PubMed.

    . Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004 May 27;429(6990):417-23. PubMed.

    . A cluster of metabolic defects caused by mutation in a mitochondrial tRNA. Science. 2004 Nov 12;306(5699):1190-4. PubMed.

  2. These results are quite exciting and underscore the importance of mitochondrial genome mutations in what otherwise seem to be sporadic diseases associated with aging (atherosclerosis, diabetes, dementia, etc.).

    The significance of the paper, aside from the description of a large kindred plagued by a novel homoplasmic mitochondrial DNA (mtDNA) tRNA mutation which produces a hypertensive, dyslipidemic phenotype, is that Wilson et al. point towards a putative genetic etiology for hypertension in the general population. Epidemiological studies have consistently identified a maternal inheritance effect in hypertension and hypercholesterolemia that resembles the results seen in this kindred. In combination with the numerous reports on the accumulation of mtDNA mutations that invariably occurs with age (mitochondrial microheteroplasmy), the results of Wilson et al. provide a salient genetic etiology for hypertension and dyslipidemia (and thus, atherosclerosis) in the general population.

    Hypertension and hypercholesterolemia are well accepted to play a role in age-associated dementia. The relationship between cholesterol and Alzheimer disease is an active area of study where the results of Wilson et al. may begin to shift attention towards mitochondrial dysfunction.

    For several years, mitochondria and mtDNA have been an active though relatively ignored area of research amongst the AD community despite the role mitochondria play in cell death and oxidative stress. Two recent reports are beginning to reverse this trend. The first is a study that identified D-Loop (Displacement-Loop, the control region of mtDNA) mutations that segregate with AD (Coskun et al., 2004); the second is a study that localized the entire γ-secretase complex, the complex in part responsible for cleaving Aβ, in mitochondria of AD brain (Hansson et al., 2004). These studies complement reports that have shown that amyloid binds and inhibits the mitochondrial enzyme ABAD (Lustbader et al., 2004) and that a splice isoform of IDE (insulin degrading enzyme) is also targeted to mitochondria where it may mitigate amyloid degradation (Leissring et al., 2004). Using cybrid technology, our group was able to induce Aβ deposition in cell culture by simply transferring the mitochondrial genome of AD patients. In this blinded study, age-matched controls failed to deposit appreciable Aβ, implying that increased APP processing and Aβ deposition in cell culture were caused specifically by the mitochondrial genome, and the subsequent mitochondrial dysfunction (Khan, 2000).

    The discovery of mitochondrial microheteroplasmy by Lin et al. (2002) opens a new field in neurodegeneration and aging research. It appears that in addition to the homoplasmic mutations found in rare familial cases such as the present study, all adults have thousands of low-level mutations (each individually present in 1-2 percent of genomes), which add to a significant total mutational burden. In the elderly, almost all copies of mtDNA have at least one amino acid-changing mutation, raising the question of whether the mutational burden has an impact on pathology.

    These findings support the relevance of mitochondrial dysfunction and somatic mtDNA mutations to AD pathogenesis and ought to shift the research focus of the AD community. Unfortunately, research on mtDNA is plagued with technical hurdles, most notably, the difficulty in analysis of heteroplasmic mutations and a lack of a vector that enables direct manipulation of mtDNA. Our group achieved some progress in analysis of microheteroplasmic mutations (Smigrodzki), and we believe we are now in the position to formulate a general outline of a hypothesis which could provide a comprehensive explanation for a wide range of pathological phenomena, from early onset mitochondrial disease, to age-related conditions. We posit that the interaction between focal, inherited or early acquired mtDNA microheteroplasmy, and age-related mtDNA microheteroplasmy, with other modifying factors, may explain the levels of maternal inheritance and the mechanism of AD, as well as other phenomena (please see Swerdlow and Khan, 2004). Promising results in manipulating the mitochondrial genome have been recently achieved by us, and may lead to the development of targeted therapies replacing entire mitochondrial genomes (for invited research update, please see Khan and Bennett, 2004).

    Thank you for allowing me to comment on this exciting new research finding.

    See also:

    Hansson et al. J Biol Chem. 2004 Sep 28.


    . Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10726-31. PubMed.

    . Alzheimer's disease cybrids replicate beta-amyloid abnormalities through cell death pathways. Ann Neurol. 2000 Aug;48(2):148-55. PubMed.

    . Development of mitochondrial gene replacement therapy. J Bioenerg Biomembr. 2004 Aug;36(4):387-93. PubMed.

    . Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria. Biochem J. 2004 Nov 1;383(Pt. 3):439-46. PubMed.

    . High aggregate burden of somatic mtDNA point mutations in aging and Alzheimer's disease brain. Hum Mol Genet. 2002 Jan 15;11(2):133-45. PubMed.

    . ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Science. 2004 Apr 16;304(5669):448-52. PubMed.

    . High frequency of mitochondrial complex I mutations in Parkinson's disease and aging. Neurobiol Aging. 2004 Nov-Dec;25(10):1273-81. PubMed.

    . A "mitochondrial cascade hypothesis" for sporadic Alzheimer's disease. Med Hypotheses. 2004;63(1):8-20. PubMed.

    . Nicastrin, presenilin, APH-1, and PEN-2 form active gamma-secretase complexes in mitochondria. J Biol Chem. 2004 Dec 3;279(49):51654-60. PubMed.

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