in vivo 31 : 511-525 (2017) doi:10.21873/invivo.11090 Review Μitochondrial Membrane Dynamics and Inherited Optic Neuropathies ELENI BAGLI 1,2 , ANASTASIA K. ZIKOU 3, NIKI AGNANTIS 4 and GEORGIOS KITSOS 2 1Institute of Molecular Biology and Biotechnology–FORTH, Division of Biomedical Research, Ioannina, Greece; Departments of 2Ophthalmology, 3Clinical Radiology, and 4Pathology, University of Ioannina, Ioannina, Greece Abstract. Inherited optic neuropathies are a genetically Mitochondria represent a tubular and branched membrane diverse group of disorders mainly characterized by visual loss system playing a fundamental role in several cellular processes and optic atrophy. Since the first recognition of Leber ’s required for the development and maintenance of an organism, hereditary optic neuropathy, several genetic defects altering such as metabolism, apoptosis, ion buffering and autophagy primary mitochondrial respiration have been proposed to (1-3). They reveal a high degree of interconnectivity and contribute to the development of syndromic and non- plasticity, mainly dictated by metabolic status and syndromic optic neuropathies. Moreover, the genomics and developmental stage (4) and, therefore, a constant state of imaging revolution in the past decade has increased mitochondrial network flux is fundamental. This dynamic state diagnostic efficiency and accuracy, allowing recognition of a is achieved through mitochondrial dynamics, a complex link between mitochondrial dynamics machinery and a broad machinery of highly conserved mechanisms, including range of inherited neurodegenerative diseases involving the mitochondrial fusion, fission, transport, interorganellar optic nerve. Mutations of novel genes modifying mainly the communication and mitochondrial quality control ( i.e. balance between mitochondrial fusion and fission have been mitophagy), tuned to a variety of signals and stimuli (5-7), and shown to lead to overlapping clinical phenotypes ranging from well-orchestrated by specific intracellular proteins. isolated optic atrophy to severe, sometimes lethal multisystem The morphology and intracellular distribution of disorders, and are reviewed herein. Given the particular mitochondria vary significantly between tissues and cell types, vulnerability of retinal ganglion cells to mitochondrial being enriched in areas of increased metabolic demand, such dysfunction, the accessibility of the eye as a part of the central as neurons, especially the presynaptic and postsynaptic nervous system and improvements in technical imaging terminals (8). Accordingly, it is not surprising that the concerning assessment of the retinal nerve fiber layer, optic pathogenic mechanism of various neurodegenerative diseases nerve evaluation becomes critical – even in asymptomatic is established through an underlying deficiency of patients – for correct diagnosis, understanding and early mitochondrial energy metabolism (9). However, in recent treatment of these complex and enigmatic clinical entities. years it has been shown that impairment of mitochondrial dynamics also leads to synaptic dysfunction, dendritic and axonal degeneration and consequently to neurodegeneration (10, 11). In this respect, restoration of mitochondrial function has become, for some time now, the priority target of novel This article is freely accessible online. neuroprotective strategies (12). Correspondence to: Niki Agnantis, Department of Pathology, Mitochondrial membrane dynamics, and more specifically University of Ioannina, Stavros Niarchos Avenue, 45500 Ioannina, fission and fusion, are indispensable for mitochondrial Greece. Tel +30 2651007792, Fax: +302651007792, e-mail: distribution and homeostasis. Fusion, the physical merger of [email protected] and Georgios Kitsos, Department of two neighboring mitochondria, is necessary for the functional Ophthalmology, University of Ioannina, Stavros Niarchos Avenue, complementation between individual mitochondria via 45500 Ioannina, Greece. Tel: +30 2651099657, Fax: +30 intermixing and exchanging proteins, respiratory complexes 2651007077, e-mail: [email protected] and mitochondrial DNA (mtDNA) nucleoids (13, 14). It is Key Words: Μitochondrial membrane dynamics, optic neuropathy, continuously counterbalanced by fission, a process necessary OPA1, MFN, DRP1, AFG3L2, SPG7, YME1L, MFF, OPA3, for the appropriate distribution of mitochondria in dividing SLC25A46, ATAD3A, review. cells, as well as their transportation and distribution throughout 511 in vivo 31 : 511-525 (2017) the length of neurons (15). Furthermore, fission is essential for regulated by several post-translational modifications (35, 36). mitophagy, a quality-control mechanism that enables the The recognition of all the implicated molecular players and elimination of damaged mitochondria by autophagosomes, and their exact role in fission/fusion has not been elucidated yet for the distribution of mtDNA nucleoids (16). and remains an area of intense investigation. Accumulative The association and balance between mitochondrial fusion evidence suggests that the role of mitochondrial dynamic and fission, and selective mitophagy, are intricate and tightly proteins regarding fusion and fission machinery is not that coordinated (17, 18). By altering the delicate balance between distinguishable. Mitochondrial fusion proteins, such as OPA1, opposing fusional and fissional forces and modifying the can regulate mitochondrial fission (30), and DRP1-dependent architecture of the organelle itself, in particular the cristae, changes in mitochondrial morphology, on the other hand, which house the protein complexes of the oxidative might control MFNs and OPA1 (37). Furthermore, recent phosphorylation system, the cell has been shown to regulate studies have pinpointed the importance of epigenetic and post- cell proliferation (19) and energy metabolism (4, 20, 21). translational modifications of the known key players DRP1, Four large guanosine-5’-triphosphate hydrolases (GTPases), MFNs and OPA1 in the regulation of their function (25, 35, members of the dynamin superfamily located in the cytosol or 36, 38, 39). Remarkably, mutations in several of these inner (IMM) and outer (OMM) mitochondrial membranes, regulatory proteins (usually involved in protein processing) mediate mitochondrial fusion and fission. Specifically, optic have been identified lately as causal gene products of atrophy 1 (OPA1), and mitofusins 1 and 2 (MFN1 and -2) syndromic or nonsyndromic inherited optic neuropathies. mediate mitochondrial fusion (22), while dynamin-related Inherited optic neuropathies are a clinically and genetically protein 1 (DRP1) is essential for fission (23). heterogenous group of disorders, characterized by typically Mitochondrial fusion is necessarily a multistep process, since bilateral, symmetrical, irreversible reduced visual acuity, color at least two distinct membrane fusion events occur. The OMM vision deficits, visual field defects and the clinical appearance and IMM, which delineate a mitochondrion, merge with the of optic atrophy (40). The clinical spectrum usually varies even corresponding membranes on another mitochondrion. These between the members of the same family and, in some cases, events result in mixing of the membranes, the intermembrane individuals develop additional neurological complications space (IMS), and the matrix. MFN1 and MFN2 are highly indicating a greater vulnerability of the central nervous system conserved and have been identified as mediators of OMM (CNS) in susceptible mutation carriers (41). Therefore, besides fusion (24). OPA1 on the other hand is involved in IMM fusion isolated optic neuropathies, optic atrophy is recognized as a and morphology of mitochondrial cristae (25-27). It is prominent feature in many neurodegenerative diseases caused synthesized within the cytoplasm as a pre-protein and once by primary mitochondrial dysfunction. However, because of transported into the mitochondria undergoes proteolytic the heterogeneity and the highly variable phenotypes of these cleavage to generate long (L-OPA1) and short (S-OPA1) disorders, their diagnosis becomes a challenging task. isoforms of OPA1 (28). This OPA1 processing is reported to be Moreover genotype-phenotype correlations are usually highly regulated by several mitochondrial proteases including speculative, probably because of tissue-specific expression of presenilin-associated rhomboid-like (PARL) (25), mitochondrial different isoforms of the affected protein, secondary ATPases associated with diverse cellular activities (m-AAA) unrecognized genetic factors and insufficient knowledge proteases (paraplegin and ATPase family gene 3-like protein 2- concerning the multi-factorial process of mitochondrial AFG3L2) (29), the mitochondrial inner membrane AAA (i- dynamics. However, during the last few years there has been AAA) protease yeast mitochondrial escape (YME1)-like 1 an expansion of data concerning the phenotypic and genotypic ATPase (YME1L) and the membrane-bound metallopeptidase spectrum of these disorders because of improved diagnostic with activities overlapping with the m-AAA protease (OMA1) imaging [magnetic resonance imaging (MRI), optical (30). Mutations in MFN2 and OPA1 gene were initially reported coherence tomography (OCT)] and molecular technology as being responsible for the rare neurodegenerative diseases (DNA sequencing, transgenic animal models etc. ). As a result, Charcot-Marie-Tooth subtype 2A (CMT2A) and autosomal a greater understanding of the complex molecular mechanisms