This review is focused on retinopathy caused by primary genetic mitochondrial disorders, although mitochondrial dysfunction may be an important pathogenetic component of other retinopathies. Present in virtually all eukaryotes, mitochondria are double-membraned organelles with a central role as the powerhouses of the cell
[1]. They are in fact the major source of the high-energy phosphate molecule, adenosine triphosphate (ATP), synthesized by the mitochondrial respiratory chain (MRC) through the process of oxidative phosphorylation (OXPHOS)
[2]. ATP is required for all active processes in the cell, and ATP deficiency leads to cellular dysfunction and ultimately cell death. ATP is synthesized by mitochondrial oligomycin-sensitive, proton (H
+)-dependent ATP synthase, (also termed as complex V, cV), which is a multi-subunit structure embedded in the IMM and strictly linked to the MRC. Since cV can also act in reverse mode, i.e., as an ATPase which hydrolyses ATP into ADP + Pi, and this is in fact the usual way it is measured spectrophotometrically, it is also called oligomycin-sensitive mitochondrial ATPase. The MRC and the H
+-ATPase/synthase stores the energy liberated through respiration, i.e., the stepwise flow of electrons extracted by oxidative catabolism from nutrient-derived substrates, as ATP and transfers it through the MRC complexes cI or cII, to cIII and eventually to cIV, due to mobile electron shuttles, Coenzyme Q (from cI-cII to cIII) and cytochrome c (from cIII to cIV). In turn, cIV (cytochrome c oxidase, COX), fixates the electrons to molecular O
2, the final “electron sink” of the pathway, converting it into H
2O. The energy liberated by this electronic current is exploited by cI, cIII, and cIV to pump protons across the inner mitochondrial membrane (IMM). As a result, energy is conserved generating a mitochondrial membrane potential, MtMP, which is composed of a proton concentration gradient (∆pH) and an electrostatic gradient, more negative outside, but more positive inside, the IMM (∆Ψ). The MtMP provides the proton-motive force (∆
p)
[3][4] that drives the rotational engine of H
+-ATP synthase, by exploiting the protons flowing from the outside to the inside of the IMM through the subunit A channel, to ultimately cause the condensation of ADP and Pi into ATP. In addition to ATP production through OXPHOS, ∆
p can also be dissipated into heat, a crucial function, especially in homeothermic animals, which is controlled by uncoupling proteins
[5]. In addition, the MtMP provides energy for numerous other processes, such as trafficking of Ca
2+, Fe
2+, and other important ions, reactive oxygen and nitrous oxygen species (ROS and NOS) production, mitochondrial protein translocation, etc. A host of other pathways residing within mitochondria can modify and influence OXPHOS, and OXPHOS abnormalities can in turn generate signals triggering either homeostatic pathways, e.g., mitochondrial biogenesis, or execution programs, e.g., mitophagy, which eliminates some impaired parts, or the whole spent organelle, or apoptosis, which eliminates the dysfunctional cell altogether
[6]. This complex metabolic network is largely based on the repertoire of the entire mitochondrial proteome, summing up to approximately 1500 proteins in mammals
[7]. Mitochondria contain their own DNA (mitochondrial DNA, mtDNA), which in mammals is a 16.5 kb circular molecule of double-stranded DNA that encodes 13 polypeptides and 24 RNAs (22 transfer tRNAs and two ribosomal rRNAs), essential for in situ protein synthesis. This is also needed because the genetic code of mtDNA differs in different phyla, including vertebrates, from the universal code, which makes the two genomes, nuclear and mitochondrial, reciprocally untranslatable. MtDNA polypeptides are all subunits of four OXPHOS complexes (c), namely cI (
n. 7), cIII (
n. 1), cIV (
n. 3) and cV (
n. 2), where they interact with over 70 nucleus-encoded protein subunits and several non-protein prosthetic groups
[8]. Additional nucleus-encoded factors are essential for mtDNA maintenance and expression, as well as for MRC formation and activity.
Mitochondrial disorders are in fact clinical entities associated with the ascertained or allegedly genetic defects of mitochondrial OXPHOS
[10]. Tissue and organ functions where energy demand is high, such as neurons and muscle fibres, critically depend on adequate ATP supply. This explains why primary mitochondrial disorders usually cause neurodegeneration and/or muscle weakness, in children and adults
[11]. However, specific mitochondrial syndromes may involve any other organ, either individually or in combination with brain and muscle dysfunction. The double genetic contribution and the complexity of the OXPHOS-related biochemical network account for the extreme clinical and genetic heterogeneity of mitochondrial disorders. In addition, many pathogenic mtDNA mutations are heteroplasmic, that is, they co-exist with a variable percentage of wild-type (wt) mtDNA, and this proportion can differ from tissue to tissue and in each individual
[12], partly dictating the clinical outcome and the tissue-specific involvement in different subjects. Because of polyplasmy, the transmission of mutant vs. wt-mtDNA is largely dependent on the stochastic distribution of the organelles during mitosis in somatic cells, as well as meiotic divisions in female germ cells, and on the capacity of different tissues to work out effective selection against OXPHOS-defective cells. Thus, the same mutation, for instance the 3243G > A transition in the gene encoding mt-tRNA
Leu(UUR), can be associated with a virtually disease-free individual when the percentage of heteroplasmy in critical tissues is low or cause a range of different clinical syndromes, from relatively benign hearing loss and type 2 diabetes, to late-onset myopathy, to a devastating juvenile or infantile syndrome known as mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)
[13]. Although individually rare, when taken as a group primary mitochondrial disorders are a frequent category of monogenic diseases (~1 affected individual in 4300 live births in Europe)
[14]. However, the number of individuals carrying a mtDNA mutation in a percentage below the clinical threshold is probably much higher, around 1 in 500 live births.