Mitochondrial dysfunction underlying outer retinal diseases
Introduction
Mitochondria are crucial and ubiquitous intracellular organelles and the major source for cellular energy production through oxidative phosphorylation, thereby providing most of the adenosine triphosphate (ATP) requirements of eukaryotic cells (Schrier and Falk, 2011, Yu-Wai-Man et al., 2011) (see Fig. 1). These energy producing organelles consist of an outer and inner membrane that defines two distinct compartments, more specifically an intermembrane space and an internal matrix space (Yu-Wai-Man et al., 2011). Mitochondrial oxidative phosphorylation resides in the inner mitochondrial membrane, in which the invaginations, called cristae, greatly improve the surface area for ATP generation. The electron transport chain in the inner membrane is the site of oxidative phosphorylation and consists of a five-complex chain of polypeptides, in which the first four complexes oxidize NADH and FADH2 through a controlled series of redox reactions, while complex V phosphorylates ADP to ATP (Fig. 1). Ubiquinone, also known as coenzyme Q (Co Q), and cytochrome complex (cyt C) are cofactors of the electron transport chain that act as electron shuttles and importantly contribute to the mitochondrial respiratory chain function. Defects in these complexes and/or cofactors may lead to diminished mitochondrial ATP production and an increased formation of reactive oxygen species (ROS) (Fraser et al., 2010). Next to their main function as ATP producers, mitochondria fulfill important critical functions to preserve cell integrity and survival, by means of scavenging ROS, mitochondrial dynamics (fission and fusion), the regulation of calcium homeostasis, nucleotide metabolism, and the biosynthesis of amino acids, cholesterol and phospholipids (Falk, 2010, Schrier and Falk, 2011). As such, malfunctioning of this critical organelle leads to severe impairment of tissue homeostasis and cellular dysfunction, mainly characterized by defects in bio-energetic processes and mitochondrial dynamics, increased apoptosis and augmented oxidative stress, but also by accumulation of mutated mitochondrial DNA (mtDNA) (Procaccio et al., 2014, Golden and Melov, 2001). Notably, mitochondria have their own genome, semi-autonomously replicating and transcribing their mtDNA in the internal matrix space (Druzhyna et al., 2008). The structural proteins that form the oxidative phosphorylation system are encoded by both mtDNA and nuclear DNA (nDNA), indicating the importance of both genomes in the structure and function of the mitochondrial respiratory complexes (Calvo et al., 2006, Fraser et al., 2010). The increment in oxidative stress and associated mitochondrial disturbances are vastly associated with increasing age (Raha and Robinson, 2000). Indeed, the free radical theory as the most outspoken hypothesis to explain ageing together with mitochondria as the principle source of ROS, suggests that ageing in mammals is highly correlated with an accumulation of deteriorated mtDNA and a decrease in respiratory chain function, as a result of hyperproduction of intracellular ROS (Trifunovic and Larsson, 2008, Payne and Chinnery, 2015). Although mitochondrial dysfunction with age is well described, also other processes/proposed theories may cause cellular ageing, such as heterochromatin formation, endoplasmic reticulum stress, telomere attrition, etc. (Liu, 2014, Musumeci et al., 2017, Chandrasekaran et al., 2016). Nevertheless, mitochondria are suggested to serve a prominent role in the complicated web of processes leading to cellular and organismal ageing, and as such to age-related disorders (Kauppila et al., 2017).
Malfunctioning of the oxidative phosphorylation system and other mitochondrial dysfunctions are characteristic for mitochondrial diseases, which are generally described as either of primary or secondary origin.
Primary mitochondrial disorders result from (inherited) mutations located in the mtDNA or the nDNA and will cause a direct malfunctioning of the organelle. Compared to nDNA, mtDNA is more prone to mutations because it lacks protective histones and certain DNA repair mechanisms, and is therefore more sensitive to ROS (Filler et al., 2014, Paasche et al., 2000). The mitochondrial genome is mainly transferred via maternal inheritance, i.e. the transmission of mtDNA from the mother to her children with no paternal mtDNA contribution (Fraser et al., 2010). nDNA mutations, which are always associated with Mendelian inheritance, may cause mitochondrial dysfunction by deteriorating nuclear genes that control the stability of mtDNA and as such lead to large-scale deletions in mtDNA (Fraser et al., 2010). Of note, a conservative estimate of the prevalence of all primary mitochondrial diseases manifesting in the central nervous system (CNS) is 1:5000, making them among the most common inherited neurological disorders (Gorman et al., 2015).
Secondary mitochondrial disorders are primarily affected by external mechanisms such as environmental factors or pharmacological toxins that can deteriorate mtDNA, produce ROS and might as such cause accumulation of damaged mitochondria. Mitochondrial dysfunction underlies many CNS disorders as a result of disturbed antioxidant defenses and defective quality-control mechanisms, i.e. (un)controlled mitochondrial fission and fusion processes and aberrant autophagic removal of mitochondria, termed mitophagy, needed to eliminate old and damaged mitochondria (Youle and Van Der Bliek, 2012, Filler et al., 2014, Punzo et al., 2012). In association with this, functional and/or ultrastructural abnormalities of mitochondria are extensively evidenced in the CNS, including the retina, largely because of their high-energy demanding neurons (Haas et al., 2007, Pagano et al., 2014). Indeed, mitochondrial dysfunction has been reported as a characteristic hallmark in a variety of chronic CNS diseases, including autoimmune diseases (e.g. multiple sclerosis), psychiatric disorders, (e.g. autism) (Morris and Berk, 2015), but also in age-related neurodegenerative diseases, including Alzheimer's and Parkinson's disease (Fukae et al., 2007, Maruszak et al., 2006, Moreira et al., 2008, Onyango and Khan, 2006, Onyango et al., 2006, Luo et al., 2015, Bhat et al., 2015), glaucoma and Age-related Macular Degeneration (AMD) (Jarrett et al., 2008, Feher et al., 2006, Liang and Godley, 2003, Chrysostomou et al., 2013, Barot et al., 2011, Osborne, 2010).
Importantly, the large number of pathologies in which primary or secondary mitochondrial disruption leads to oxidative damage, raises the need for a better understanding of the genetic and molecular mechanisms underlying mitochondrial dysfunction, and drives the search for novel therapies to reduce or prevent mitochondrial oxidative damage.
The number of mitochondria varies among organisms, tissues and cell types, but they are always abundantly represented in highly metabolically active tissues, such as the cardiac conduction system, cardiac and skeletal muscles, and the CNS, including retina and optic nerve. Particularly the retinal pigment epithelium (RPE) cells, the photoreceptors and the Müller glia, contain a high number of mitochondria (Jarrett et al., 2008, Stone et al., 2008, Germer et al., 1998a, Fraser et al., 2010, Skytt et al., 2016, Toft-Kehler et al., 2017). Mitochondria concentrate at the most external ends of RPE cells, photoreceptors and Müller glia, i.e. respectively at the basement membrane, at the cilium of the photoreceptors and at the outer feet. Of note, Germer et al., 1998a, Germer et al., 1998b showed via electron microscopy (EM) that Müller cells from vascularized retinas contain numerous mitochondria along the entire length of the cells, while EM analysis of avascular retinas from e.g. rabbit or guinea pig, revealed only a few mitochondria at the distal end of Müller glia, directed towards the choroid (Germer et al., 1998b, Germer et al., 1998a, Paasche et al., 2000). On the other hand, a more recent publication of Stone et al. (2008) clearly demonstrated via EM analysis that mitochondria are highly concentrated at the distal end of the Müller glia in the adult mammalian retina, irrespective of its vasculature (Stone et al., 2008). Also the photoreceptor inner segments are packed with mitochondria (Fig. 1). This spatial mitochondrial distribution within these outer retinal cells can be interpreted as the result of their migration towards sources of oxygen, thus towards the choriocapillaris (Stone et al., 2008). Mitochondrial dysfunction in photoreceptors and RPE cells is well known to underlie outer retinal pathologies, as being described below. Hence, altered RPE energy metabolism is implicated in retinal pathogenesis and has a profound influence on cell phenotype and photoreceptor viability. Dysfunctional mitochondria in Müller glia have been suggested to importantly contribute to inner retinal disorders, such as glaucoma and diabetic retinopathy (Skytt et al., 2016, Vecino et al., 2016). In addition, a recent review by Toft-Kehler et al. (2017) summarizes the current evidence indicating that mitochondrial dysfunction in Müller glia and oxidative stress are importantly associated with inner retinal diseases (Toft-Kehler et al., 2017). Nevertheless, their contribution to outer retinal disorders remains largely elusive in literature. However, as mitochondria are found in high numbers in photoreceptors, RPE and Müller glia, making these cells highly vulnerable to mtDNA defects and oxidative damage, it seems of utmost importance to elucidate mitochondrial defects in these cells as potential contributors to outer retinal disorders. Within this review, we will list disorders related to the outer retina and RPE that are already associated with loss of functional and structural mitochondria. We first provide an overview of primary mitochondrial disorders, e.g. Neuropathy Ataxia Retinitis Pigmentosa (NARP) Syndrome, Kearns-Sayre Syndrome (KSS) and spastic paraplegia type 15 (SPG15). Then, we will summarize the recent findings concerning mitochondrial dysfunction as an essential contributor to the pathogenesis of secondary mitochondrial disorders, focusing on outer retinal diseases, including AMD, Stargardt disease, cone-rod dystrophies (CRD) and Retinitis Pigmentosa (RP).
Section snippets
Primary mitochondrial disorders of the outer retina
The primary mitochondrial disorders Dominant Optic Atrophy (DOA) and Leber Hereditary Optic Neuropathy (LHON) are both genetic disorders that primarily deteriorate the inner retina. Outer retinal disorders, primarily caused by mitochondrial dysfunctions, are rare. However, both spastic paraplegia type 15, a pigmentary maculopathy also known as Kjellin syndrome, as well as pigmentary retinopathies, such as NARP and KSS are characterized by initial RPE degeneration (Schrier and Falk, 2011). Due
Secondary mitochondrial disorders of the outer retina
Many prevalent ocular diseases of the outer retina, such as photoreceptor dystrophies and AMD, do not originate from mutations in mtDNA, but are, at least partly, characterized by increased ROS production and oxidative damage, finally leading to mitochondrial impairment in the RPE, the photoreceptors or both. In association with this, the eye is constantly exposed to radiation, chemicals and other environmental insults, such as smoking, which all strongly promote mitochondrial oxidative stress (
Summary
Evidence linking mitochondrial dysfunction to (chronic) CNS disorders is increasing over the last decades. Notably, both primary and secondary mitochondrial dysfunctions also seem to play a prominent role in a wide range of ocular pathologies, including outer retinopathies, which are characterized by dysfunction of photoreceptors, RPE cells or both. The outer retina is known to have a high metabolic demand, which is associated with a large number of mitochondria in the RPE and photoreceptors
Acknowledgments
The authors have no conflict of interest. We thank Karel Haesevoets for graphic design of Fig. 1. This work was supported by grants from the Flemish Institute (G.05311.10 [LM]) for the promotion of Scientific Research (IWT and FWO) and the Research Council of KU Leuven (KU Leuven BOF-OT/10/033 [LM]).
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