MyVisionTest News Archive
Jun 26, 2009
Mitochondrial DNA and AMD
A new study finds that the mitochondrial (mt)DNA in the retinas of patients with age-related macular degeneration (AMD) contained more single-nucleotide polymorphisms (SNPs) within the control region of the geneome compared to normal retinas. There was an increased frequency of mtDNA SNPs associated with haplogroups J, T and U in patients with AMD. These results implicate mitochondrial alterations in the etiology of AMD.
Mitochondria are the structures located within cells that are responsible for energy production. Mitochondria are, in effect, the powerhouses of the cell. All of the energy requirements of the cell must be fulfilled by the cell's mitochondria. Organs requiring large amounts of energy, such as brain, heart, muscles, and retina, are dramatically affected by mitochondrial dysfunction. Chiefly responsible for energy production, mitochondria are also used in some apoptotic (cell death) pathways that are thought to be involved in the pathologic course of AMD.
Interestingly, mitochondria contain their own DNA (mitochondrial DNA). Because mitochondria are inherited from the mother (the father contributes no mitochondria to their offspring), all mtDNA is maternal. mtDNA is susceptible to oxidative damage and has a higher sequence evolution rate (mutation rate) than does nuclear DNA. Over the past 200,000 years, mtDNA variations have accumulated along maternal lineages.
Haplogroups are increasingly being correlated to a broad spectrum of common diseases. A4917G, a defining polymorphism for the T haplogroup, was reported as an independent predictor of AMD. The mtDNA control region is noncoding but important for mtDNA replication and transcription. Mutations in the control region have been described in patients with Alzheimer’s disease and other disorders associated with oxidative stress.
Methods and Results
Retinas from 10 normal and 11 AMD globes were isolated and analyzed for mtDNA rearrangements by long extension-polymerase chain reaction (LX-PCR) and for the nature and frequency of SNPs in the mtDNA control region by direct sequencing. Blood DNA was extracted from 99 AMD and 92 age-matched control subjects. The sequence variations that define haplogroups H, I, J, K, T, V, X, and U were characterized by PCR, restriction enzyme digestion, and/or sequencing.
LX-PCR of retinal mtDNAs revealed high levels of rearrangements in the patients with AMD and the control subjects, consistent with the decline in mitochondrial function with age. However, the AMD retinas had higher oxidized DNA levels and a higher number of SNPs than controls (P = 0.02). The control region SNPs T16126C and A73G, commonly found in haplogroups J and T, were more frequent in the AMD retinas than in normal retinas. The associations between AMD and haplogroups J and T were confirmed and extended by analysis of blood DNA. SNPs at position a T16126C (J; odds ratio [OR] = 3.66), T16126C+G13368A (JT; OR = 10.27), A4917G+A73G (T4; OR = 5), and T3197C+A12308G (U5; OR = infinity), were all strongly associated with AMD.
Discussion and Conclusions
The retina has one of the highest oxygen consumption rates of any tissue in the body, presumably due to continuous demand for mitochondrial ATP for visual function. The continuous, high exposure of light results in photo and oxidative damage to retinal cells. Since mtDNA damage accumulates with age and is associated with increased mitochondrial oxidative stress, it follows that human retinas would accumulate high levels of mtDNA damage by age 80. The excessive accumulation of age-related somatic mtDNA variations could severely inhibit the mtDNA biosynthetic capacity, inhibit mitochondrial function, and lead to apoptosis.
Consistent with increased mtDNA damage in the AMD retinas, sequencing of the mtDNA control region revealed an increase in the number of variants in AMD retinal mtDNAs versus controls (P = 0.02). Higher levels of SNPs in the mtDNA control region may impair mitochondrial copies and/or the functional efficiency, thereby contributing to decreased energy production and cell death.
Sequencing of the control regions from the AMD retinas revealed that certain haplogroup-associated control region SNPs were more prevalent in the patients with AMD than in the control subjects. Haplogroup J was associated with large, soft drusen, which are recognized risk factors for the development of wet AMD, and haplogroup U was linked to retinal pigment abnormalities.
These results suggest that defects in mitochondrial energy metabolism are important factors in the etiology of AMD. The mtDNA haplogroups associated with reduced mitochondrial ATP production increase the risk of AMD. The investigators hypothesize that as mitochondrial energy production falls below the retinal photoreceptor cell bioenergetic threshold, photoreceptors are destroyed. Ultimately, as mitochondrial energy production falls below the retinal photoreceptor cell bioenergetic threshold, the mitochondrial permeability transition pore (mtPTP) is activated, and photoreceptors are destroyed through the intrinsic apoptosis pathway. This mitochondrial scenario of AMD, may not only explain many of the previously puzzling features of AMD but offers an array of new therapeutic approaches for the disease targeted toward increasing mitochondrial energy production, decreasing mitochondrial ROS, and stabilizing the mtPTP.
Read more...
Invest Ophthalmol Vis Sci. 2009;50:2966–2974
A new study finds that the mitochondrial (mt)DNA in the retinas of patients with age-related macular degeneration (AMD) contained more single-nucleotide polymorphisms (SNPs) within the control region of the geneome compared to normal retinas. There was an increased frequency of mtDNA SNPs associated with haplogroups J, T and U in patients with AMD. These results implicate mitochondrial alterations in the etiology of AMD. Mitochondria are the structures located within cells that are responsible for energy production. Mitochondria are, in effect, the powerhouses of the cell. All of the energy requirements of the cell must be fulfilled by the cell's mitochondria. Organs requiring large amounts of energy, such as brain, heart, muscles, and retina, are dramatically affected by mitochondrial dysfunction. Chiefly responsible for energy production, mitochondria are also used in some apoptotic (cell death) pathways that are thought to be involved in the pathologic course of AMD.
Haplogroups are increasingly being correlated to a broad spectrum of common diseases. A4917G, a defining polymorphism for the T haplogroup, was reported as an independent predictor of AMD. The mtDNA control region is noncoding but important for mtDNA replication and transcription. Mutations in the control region have been described in patients with Alzheimer’s disease and other disorders associated with oxidative stress.
Methods and Results
Retinas from 10 normal and 11 AMD globes were isolated and analyzed for mtDNA rearrangements by long extension-polymerase chain reaction (LX-PCR) and for the nature and frequency of SNPs in the mtDNA control region by direct sequencing. Blood DNA was extracted from 99 AMD and 92 age-matched control subjects. The sequence variations that define haplogroups H, I, J, K, T, V, X, and U were characterized by PCR, restriction enzyme digestion, and/or sequencing.
LX-PCR of retinal mtDNAs revealed high levels of rearrangements in the patients with AMD and the control subjects, consistent with the decline in mitochondrial function with age. However, the AMD retinas had higher oxidized DNA levels and a higher number of SNPs than controls (P = 0.02). The control region SNPs T16126C and A73G, commonly found in haplogroups J and T, were more frequent in the AMD retinas than in normal retinas. The associations between AMD and haplogroups J and T were confirmed and extended by analysis of blood DNA. SNPs at position a T16126C (J; odds ratio [OR] = 3.66), T16126C+G13368A (JT; OR = 10.27), A4917G+A73G (T4; OR = 5), and T3197C+A12308G (U5; OR = infinity), were all strongly associated with AMD.
Discussion and Conclusions
The retina has one of the highest oxygen consumption rates of any tissue in the body, presumably due to continuous demand for mitochondrial ATP for visual function. The continuous, high exposure of light results in photo and oxidative damage to retinal cells. Since mtDNA damage accumulates with age and is associated with increased mitochondrial oxidative stress, it follows that human retinas would accumulate high levels of mtDNA damage by age 80. The excessive accumulation of age-related somatic mtDNA variations could severely inhibit the mtDNA biosynthetic capacity, inhibit mitochondrial function, and lead to apoptosis.
Consistent with increased mtDNA damage in the AMD retinas, sequencing of the mtDNA control region revealed an increase in the number of variants in AMD retinal mtDNAs versus controls (P = 0.02). Higher levels of SNPs in the mtDNA control region may impair mitochondrial copies and/or the functional efficiency, thereby contributing to decreased energy production and cell death.
Sequencing of the control regions from the AMD retinas revealed that certain haplogroup-associated control region SNPs were more prevalent in the patients with AMD than in the control subjects. Haplogroup J was associated with large, soft drusen, which are recognized risk factors for the development of wet AMD, and haplogroup U was linked to retinal pigment abnormalities.
These results suggest that defects in mitochondrial energy metabolism are important factors in the etiology of AMD. The mtDNA haplogroups associated with reduced mitochondrial ATP production increase the risk of AMD. The investigators hypothesize that as mitochondrial energy production falls below the retinal photoreceptor cell bioenergetic threshold, photoreceptors are destroyed. Ultimately, as mitochondrial energy production falls below the retinal photoreceptor cell bioenergetic threshold, the mitochondrial permeability transition pore (mtPTP) is activated, and photoreceptors are destroyed through the intrinsic apoptosis pathway. This mitochondrial scenario of AMD, may not only explain many of the previously puzzling features of AMD but offers an array of new therapeutic approaches for the disease targeted toward increasing mitochondrial energy production, decreasing mitochondrial ROS, and stabilizing the mtPTP.
Read more...
Invest Ophthalmol Vis Sci. 2009;50:2966–2974
