Mitochondrial Genetics of Retinal Disease

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Chapter 32 Mitochondrial Genetics of Retinal Disease

Mitochondrial origins

It is now accepted that the origin of mitochondria within eukaryotes is the result of an endosymbiotic relationship and that mitochondrial (mt) DNAs can be traced to an α-proteobacterial genome.1,2 This theory has been supported by phytogenetic patterns of gene arrangements, small subunit ribosomal RNAs (rRNA) and protein data.3,4 DNA sequencing studies have shown that tremendous variations are still present within mtDNA, with the genome of the protozoan Reclinomonas americana having the most bacteria-like mitochondrial genome and Rickettsia prowazekii the most mitochondria-like eubacterial genome.1 The mtDNA from eukaryote species show remarkable differences in size, ranging from 6 to 60 kb. They also vary in shape, with some eukaryotes having linear mtDNA while others have circular mtDNA.

Mitochondrial structure

Depending on the energy requirement of each cell, the number of mitochondria varies from one to several thousand. Each mitochondrion is divided into compartments that are contained within the outer membrane, and include the intermembrane space, the inner membrane, cristae, and the matrix (Fig. 32.1). The outer membrane is permeable to molecules smaller than 5 kDa, which pass through the lipid bilayer channels called porins (voltage-dependent anion channel) into the intermembrane space. It also contains a translocase of the outer membrane complex involved in the import of resident mitochondrial proteins that are encoded by the nuclear genome and produced in the cytosol.5 The inner membrane has a high content of cardiolipin and its selective permeability allows only specific molecules into the matrix. The surface area is greatly expanded as a result of the numerous invaginations of the inner membrane, known as cristae. Embedded within the inner membrane are many of the enzyme complexes required for adenosine triphosphate (ATP) production and the translocase of the inner membrane complex that is responsible for the import of nuclear-encoded proteins into the matrix. The matrix contains numerous proteins, ribosomes, tRNA, and the mtDNA.

Mitochondrial DNA

Mitochondria are unique in that they have their own DNA that is inherited through the maternal lineage. The human mtDNA forms a closed circle of double-stranded DNA, with 16 569 nucleotide pairs, comprised of two strands that are differentiated by their nucleotide content. The heavy strand is guanine-rich and encodes for 28 genes while the light strand is cytosine-rich and encodes for nine genes. Unlike the nuclear genome, mtDNA contains a unique noncoding control region but no introns. The noncoding mtDNA Dloop has within it the 1121 nucleotide control region that is important for replication and transcription. The coding region of mtDNA codes for 37 genes, including 13 protein subunits essential for oxidative phosphorylation (OXPHOS), two ribosomal RNAs, and 22 transfer RNAs (Fig. 32.2).68 The vast majority of mitochondrial proteins (~1500–2000) that contribute to energy biogenesis4,9 are encoded by nuclear DNA and imported into the mitochondria.

Within a cell there is a single DNA copy of the nuclear genome (nDNA) but multiple copies of mtDNA because there can be thousands of mitochondria per cell, and within each mitochondrion, 1–10 copies of mtDNA. With aging and exposure to oxidative stress, mtDNA molecules can be damaged, which results in a mixture of nonmutated (wild-type) and mutant mtDNA within the same cell. This mixture of damaged and undamaged mtDNA is termed “heteroplasmy.” When cells with heteroplasmic mitochondria divide, the two types of mtDNA are randomly or, in some instances, nonrandomly distributed into the daughter cells.1014 Alternatively, cells may have either a pure mutant mtDNA or pure nonmutant (wild-type) mtDNA population, in which case it is referred to as homoplasmic mtDNA.15 Homoplasmy within a cell indicates that all mtDNA copies are identical. Cells can function only with relatively low levels of heteroplasmy but once this threshold is breached, abnormal function and disease can occur. Although low levels of heteroplasmic mtDNA defects may have an effect on function, the mtDNA changes are not always obvious and special technical approaches are required to ensure their detection. Correlating a phenotype with mtDNA defects can be difficult because the complexity of the phenotype can be influenced by when (time during embryogenesis/development) and where (tissue type) the mutation arises.1618 In addition, environmental factors, such as oxidative stress, can modulate the expression of the phenotype. mtDNA is particularly susceptible to oxidative damage because it resides in the matrix and is in close proximity to sites of reactive oxygen species (ROS) formation. In addition, the mitochondria have a poor DNA repair process and a high transcription rate. Oxidative damage to mtDNA is especially prevalent in very metabolically active tissues such as the retina, brain, and muscle.

Localization of mitochondria within the retina and optic nerve

The retina has one of the highest oxygen consumption rates in the body. To meet the energy demand for vision, the photoreceptor cells have a high concentration of mitochondria within the inner segments (Fig. 32.3). The photoreceptors have high exposure to ultraviolet light and OXPHOS levels, leading to increased ROS formation, which makes these cells a target for mtDNA damage. In vitro studies show that oxidative stress leads to preferential damage of mtDNA compared to nuclear DNA.20 Animal models demonstrate increased mtDNA deletions and damage in aging and degenerating retinas.21,22 Mitochondrial abnormalities, including mtDNA damage, have been found in aging and age-related macular degeneration (AMD) retinas.20,21,2325 The retinal ganglion cells (RGC) with their long axons are also susceptible to mitochondrial damage. In RGCs, the mitochondria are present around the nucleus and along the axons but they tend to accumulate just anterior to the lamina cribrosa (Fig. 32.2).26 The numbers of RGCs and their axons are significantly decreased in Leber’s hereditary optic neuropathy and glaucoma.27,28 This may be related to lower energy production caused by mtDNA damage and dysfunction.

Influences of mtdna ON cell function

Influences of mtDNA upon cell function can be classified into ancient adaptive polymorphic changes (haplogroups), recent mutations, and somatic mtDNA changes.29 Examples of each are presented below.

Ancient inherited mtDNA variants representing populations (haplogroups)

Definition of haplogroups

Haplogroups are mtDNA sequence polymorphism variations that have occurred over more than 150 000 years and correlate with the geographic origins of populations traced through the maternal lineages. The oldest haplogroups are from Africa and with geographic migration and climate adaptations, European, Asian, and Native American haplogroups have evolved.4 Each haplogroup has related patterns of mtDNA sequences (haplotypes) that represent that population. If the specific single polynucleotide polymorphism (SNP) variants representing the haplogroup are found in the mtDNA Dloop, it can affect the replication and transcription rates. If within the coding region, the SNP variants can be nonsynonymous (amino acid changing), which can potentially alter efficiencies of energy production, causing ROS formation, apoptosis, and cell death. This means that each haplogroup, with its different set of SNPs, can produce unique bioenergetic as well as biochemical properties. Haplogroups increasingly are being correlated with a broad spectrum of common diseases, including age-related diseases, such as Parkinson’s disease and Alzheimer’s disease.3040

Association of haplogroups with AMD and other eye diseases

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