Electron Microscopy of Mitochondrial Pathology in Central Nervous Diseases. A Review

Orlando J. Castejon

Biological Research Institute, Faculty of Medicine, Zulia University, Maracaibo, Venezuela

*Correspondence to: Dr. Orlando J. Castejon, Biological Research Institute, Faculty of Medicine, Zulia University, Maracaibo, Venezuela.

Copyright © 2019 Dr. Orlando J. Castejon. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction
The fine structural changes of mitochondria and the respiratory system in experimental cerebral edema, and in different neuropathological conditions have been widely reported since the advent of transmission electron microscopy [1-28].

Jonhson et al. (2000) [29] reported the MELAS syndrome characterized by mitochondrial myopathy, encephalopathy, and acute focal severe cerebral edema. Hillered and Chang (1989) [30] found brain mitochondrial swelling induced by arachidonic acid release during cerebral ischemia. Takeuchi et al. (1991) [31] also demonstrated inhibition of mitochondrial respiration by arachidonic acid during brain ischemia. Novikov and Naperstnikov (1994) [17] described profound destructive changes of mitochondria in traumatic brain edema. Numerous studies of neuronal mitochondria after transient and permanent ischemia and anoxia in experimental animals have reported that mitochondria undergo a sequence of profound alterations in structure and function, which contribute to cell death [11,15,16,22,32-54]. Mitochondrial dysfunction has also been implicated in bipolar disorders [55]. Wang et al. (2002) [56] reported mitochondrial swelling after stretch- induced injury. Castejón and Castejón (2004) [57] described swollen clear, dense and degenerated mitochondria in cortical biopsies of human edematous cerebral cortex. Dupuis et al. (2004) reported mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS).

Mitochondrial dysfunction has been widely reported in aging and neurodegenerative diseases, such as Alzheimer´s, Parkinson’s and Huntington’s diseases (Zhu et al., 2006) [3,47,58-82].

Structural and functional damage of mitochondria is currently found in traumatic brain injuries [83-87], mitochondrial encephalomyopathies [88], picrotoxin and kainic acid-induced epilepsy and status epilepticus in rats [89-91], stroke [92], intracerebral hemorrhage [93].

Shukkur et al. (2006) [94] found mitochondrial dysfunction and tau hyperfosforilation in Ts1Cje, a mouse model form of Down Syndrome.

The goal of the present work is to describe the mitochondrial alterations in the soma, myelinated axons, dendrites and synaptic endings of neuronal cells, in the soma and processes of glial cells, and at the level of capillary wall. As a step toward characterizing mitochondria as lethal markers of nerve cell death, this study has been focused to establish mitochondrial alterations and mitochondrial types during neuronal injury associated to human complicated brain trauma with extradural or subdural hematomas or hygromas, brain tumors, vascular anomalies, and congenital hydrocephalus of patients examined in our laboratories of electron microscopy and clinical neuroscience.

Submicroscopic Morphology of Injured Mitochondria in Brain Trauma, Tumors, Vascular Anomalies and Congenital Hydrocephalus
Swollen clear and dense mitochondria are generally observed in pyramidal and non-pyramidal neurons, but swollen clear mitochondria (SCM) predominate in traumatic brain edema, and swollen dense mitochondria (SDM) are more frequently observed in tumors, vascular anomalies and congenital hydrocephalus (Figs. 1-3). SCM are characterized by the low electron density of mitochondrial matrix. and are frequently associated with microtubules and smooth, flattened endoplasmic reticulum cisterns.

Swollen clear and dense mitochondria have been reported in axonal degeneration [95,96], edematous nerve cells [97], endothelial cells [98], oligodendroglial cells [99], swollen pericites [100,101], reactive astrocytes [102,103], and degenerated pre- and postsynaptic endings [96,104] in traumatic human brain edema. According to our studies we have previously postulated the mitochondria as marker of lethal injury [105].

Dark degenerated mitochondria (DDM) exhibiting dense matrix, damage of outer mitochondria membrane, and enlargement of the space between the outer and inner mitochondrial membranes (intermembrane space) are also found (Fig. 4).

In the swollen astrocytic cytoplasm, SCM, SDM, and DDM are seen, but DDM are predominantly observed, suggesting a major vulnerability of astrocytic mitochondria to anoxic-ischemic conditions. Clear and dense mitochondrial populations exhibiting calcium granules, continuous inner and outer mitochondrial membranes, intact cristae with dilated intracristal space, and fragmentation or absence of mitochondrial cristae are found in severe brain edema [57].

Marked mitochondrial matrix swelling was earlier reported by Garcia et al. (1977) [9] after middle cerebral artery occlusion. Mitochondria with increased density of matrix and paracrystalline inclusions have been reported by Saraiva et al. (1985) [23] in Alzheimer disease. According to Hillered and Chang (1989) [30] and Takeuchi et al. (1991) [31], brain mitochondrial swelling is induced by the release of arachidonic acid during ischemia and inhibition of mitochondrial respiration. Mitochondrial swelling and vacuolization was reported by Ellis et al. (1995) [7] after stretch- induced injury in brain cultured cells. Increased matrix density of mitochondria and deposit of electron dense material was reported by Solenski et al. (2002) [25] after severe ischemic/ reperfusion conditions.

At the level of degenerated myelinated axons, SCM and SDM are also distinguished. As illustrated in figure 5, some mitochondria exhibited a dense band occupying the intermembrane space.

In brain trauma, tumors and congenital malformations, varicose swollen dendrites exhibit clear, round and elongated mitochondria with fragmented cristae (Fig. 6).

Mitochondrial abnormalities in cortical dendrites also were reported by Paula-Barboza et al. (1984) in early forms of subacute sclerosing panencephalitis.

At the level of axosomatic synapses upon non-pyramidal nerve cells, vacuolated SDM in the presynaptic endings and SCM with discontinuities of mitochondrial membranes in the postsynaptic soma surface are seen in brain tumors (Fig. 7).

At the level of the neuropil, the astrocytic processes show a heterogeneous population of mitochondria with evident signs of calcium sequestration (Fig. 8).

Calcium accumulation in mitochondria was reported by Gutierrez-Diaz et al. (1985) [11] and Hossman et al. (1985) [12] after cerebral ischemia, and by Hagberg (2004) [43] after hypoxia -ischemia.

The perivascular astrocytic end-feet display also SCM, SDM, and DDM. In severe edema associated to brain trauma and tumors, isolated astrocytic processes surrounded by proteinaceous edema fluid are observed showing SCM, SDM, and DDM [57]. Dense degenerated mitochondria are observed in congenital hydrocephalus at the level of perivascular astrocytic end-feet (Fig. 9).

Swollen clear mitochondria have been reported in congenital hydrocephalus and Arnol-Chiari malformation [106-108].

In swollen and dark hydropic oligodendroglial cells, SCM and SDM are mainly observed in the soma, and also in the neighboring astrocytic processes (Fig 10).

Al the level of open or collapsed capillaries, SCM and SDM are seen with intact cristae and continuous inner and outer mitochondrial membrane (Fig 11), mainly localized at the organelle zone of endothelial cells. DDM are also found in collapsed capillaries with signs of increased transendothelial transport.

Hyperglicemia during cerebral ischemia results in marked changes in endothelial cell morphology and mitochondrial swelling [109].

The swollen pericytes embedded in the capillary basement membrane exhibit also SCM and SDM (Fig. 12).

Swollen clear mitochondria were found in pericyte cells in traumatic brain edema [101].

Light and dense mitochondria have been earlier reported by Ikrenyi et al. (1976) [13] in postmortem specimens. These authors correlate the light type of mitochondria with the non-functional homogeneous type, and the dense form of mitochondria with the functional state. More recently, Solenski et al. (2002) [25] reported dense cortical neuronal mitochondria exposed to severe ischemic/reperfusion conditions, whereas increasing loss of mitochondrial density with pronounced swelling are observed in permanent ischemia. Such findings suggest that the SCM type is related with the transient ischemic process of brain trauma, the formation of subdural hematoma or hygroma, and the associated vasogenic and cytotoxic brain edema. The SDM type is more frequently found in sustained and permanent nerve cell ischemia, such as in brain tumors, vascular anomalies and congenital hydrocephalus. In addition, we have found in severe brain edema enlargement of intracristal space and fragmentation of cristae, which are extension of inner mitochondrial membrane. The above mentioned findings indicate that mitochondria show significantly different pattern of injury, express by electron density changes of mitochondrial matrix. This observation is probably related with mitochondrial matrix protein aggregation, which could be responsible by its osmiophilic property at the electron microscopy level. The fragmentation of the mitochondrial cristae suggest that oxidative phosphorylation of ADP, the precursors of the high-energy phosphate bond of ATP, no longer occurs. In addition, suppose an interruption of mitochondrial membrane intracellular transport, which cause respiration-dependent extrusion of H+ and accumulation of Ca2+ from the cytoplasm (Lehninger, 1971) [110]. During ischemia the lack of oxygen blocks oxidative metabolism so there is no enough energy to maintain the membrane potential require to drive Ca2+ uptake into the mitochondria [111]. However, in brain edema mitochondria can accumulate excessive amounts of Ca2+ and become overloaded. When this occurs, mitochondria undergo a high permeability transition of the inner mitochondrial membrane [112,113], release Ca2+, and become swollen and uncoupled [114] thereby loosing the ability to produce ATP, and leading to nerve cell death. Therefore, neuronal death by necrosis or apoptosis depend of mitochondrial function [115]. Presumably the different pathological entities examined in the present study induce a high conductance permeability transition pore or megachannel [116,117] in the inner mitochondrial membrane, which causes mitochondrial swelling. In this context mitochondrial swelling should be considered as an epiphenomenon preceding nerve cell death [22].

Glutamate excitotoxicity is the process whereby a massive glutamate release occurs in the central nervous system in response to ischemia or related trauma leading to a delayed, predominantly ischemic cell death of neurons. Mitochondria accumulate much of the post-ischemic calcium entering the neurons via the chronically activated N-methyl-D-aspartate receptors [48,111,118], contributing to excitotoxicity.

Nitric oxide and its derivative peroxinitrite inhibit mitochondrial respiration (complexes I, II and V). NOinduced inhibition of respiration in brain nerve terminals results in rapid glutamate release, which might also contribute to neurotoxicity. Peroxinitrite also causes opening of the mitochondrial permeability transition pore, resulting in release of cytochrome c, which might then trigger apoptosis [119].

Impaired brain mitochondrial respiration and decreased cytochrome oxidase activity have been found after delayed onset of neurologic deterioration following anoxia/ischemia [27,53]. Novikov and Sharov (1991) [17] and Sharov and Novikov (1992) [24] reported that the rate of oxidation decrease in mitochondria in toxic and traumatic edema.

Lipid peroxidation occurs also in brain edema following ischemia and hypoxia [38,120-122], which could be responsible for the mitochondrial membrane damage. The mitochondrial generation of superoxide anions is enhanced during anoxia and reoxigenation [118,120]. Mitochondrial electron transport also generates reactive oxygen intermediates (ROI). A large increase of ROI induce collapse of mitochondrial membrane potential and neuronal cell death [30,54,120,123]. The elevated intracellular Ca2+ and exposure to fatty acids, which alter the physical properties of mitochondrial membranes and inhibition of mitochondrial respiratory components, may enhance this leak of ROI from mitochondria. Cytochrome C is released from mitochondria into the cytosol contributing to mitochondrial dysfunction and promoting ischemic neuronal injury and delayed nerve cell death [49,124]. In addition, respiratory inhibition, release of pyridine nucleotides, and loss of intramitochondrial glutathione necessary for detoxification of peroxides [125].

The amplification of oxidative stress and Ca2+ loading culminates in necrotic cell death [126]. Releasing of cytochrome C induces to downstream consequences of specific caspase activation and apoptosis [90,127- 129]. Mitochondrial are therefore pivotal regulators of cell death through their role in energy production and calcium homeostasis, their capacity to release apoptogenic proteins, and to produce reactive oxygen species [130].

Clinical Neuroscience Studies of Mitochondrial Dysfunction
Mitochondrial dysfunction has been reported in most neurodegenerative diseases. These anomalies include bioenergetic defect, respiratory chain-induced oxidative stress, defects of mitochondrial dynamics, increase sensitivity to apoptosis, and accumulation of damaged mitochondria with instable mitochondrial DNA [131].

Disturbances in mitochondrial functioning are key factors leading to neuroinflammation and neurodegeneration. Mitochondria have been increasingly linked to the pathogenesis of many neurological disorders, including multiple sclerosis (MS). [132]. The contemporary data indicate that the axonal degeneration in multiple sclerosis largely results from the activation of Ca2+-dependent proteases and from misbalance of ion homeostasis caused by energy deficiency. [133]. There is accumulating evidence highlighting the central role of mitochondrial dysfunction in axonal degeneration and associated neurodegeneration [134]. Loss of mitochondrial activity leads to primary mitochondrial diseases and may contribute to neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. Mitochondria communicate with the cell through mitochondrial retrograde signaling pathways. These signaling pathways are triggered by mitochondrial dysfunction and allow the organelle to control nuclear gene transcription [67]. Convincing evidence demonstrates oxidative stress as a prominent feature in Alzheimer disease (AD) and Parkinson Disease (PD) and links oxidative stress to the development of neuronal death and neural dysfunction, which suggests a key pathogenic role for oxidative stress in both AD and PD [135].

Nissanka and Moraes (2018) analyze the current knowledge in the field of mtDNA and neurodegeneration, the debate about ROS as a pathological or beneficial contributor to neuronal function, bona fide mtDNA diseases, and insights from mouse models of mtDNA defects affecting the central nervous system.

There are several diseases that have a mitochondrial origin such as chronic progressive external ophthalmoplegia (CPEO) and the Kearns- Sayre syndrome (KSS), myoclonic epilepsy with ragged-red fibers (MERRF), mitochondrial encephalomyopathy, lactic acidosis and strokelike episodes (MELAS), Leber’s hereditary optic neuropathy (LHON), the syndrome of neurogenic muscle weakness, ataxia and retinitis pigmentosa (NARP), and Leigh’s syndrome [136].

Mutations of novel genes modifying mainly the balance between mitochondrial fusion and fission have been shown to lead to overlapping clinical phenotypes ranging from isolated optic atrophy to severe, sometimes lethal multisystem disorders [137]. Emerging Evidence points to an important role for mitochondrial dysfunction in the pathogenesis and progression of lysosomal storage diseases (LSD-associated neurodegeneration). Mitochondrial dysfunction in LSD is characterized by alterations in mitochondrial mass, morphology and function. Disturbed mitochondrial metabolism in the CNS may lead to excessive production of mitochondrial reactive oxygen species and dysregulated calcium homeostasis. These metabolic disturbances ultimately result in mitochondria-induced apoptosis and neuronal degeneration [138,139].

Concluding Remarks
The present review analyzes the presence of three injured mitochondrial morphological patterns in the human edematous cerebral cortex of patients with complicated brain trauma associated with subdural hematomas or hygroma, brain tumors, vascular anomalies, and congenital hydrocephalus. Swollen clear (SCM), swollen dense (SDM), and dark degenerated (DDM) mitochondria are described. SCM were predominantly found in traumatic brain edema. SDM and DDM were frequently observed in sustained permanent ischemia induced by brain tumors, vascular anomaly and congenital hydrocephalus. SCM exhibit low electron dense mitochondrial matrix, enlarged intracristal space and continuity of outer and inner mitochondrial membranes. SDM show high electron dense matrix and swollen intact or fragmented cristae. DDM display overall high electron density of matrix and mitochondrial membranes. The role of anoxicischemic conditions of brain parenchyma, calcium overload, lipid peroxidation and reactive oxygen species, glutamate excitotoxicity, cytochrome C release, and nitric oxide and its derivatives are discussed in relation with mitochondrial dysfunction and nerve cell death. The injured mitochondrial patterns are considered markers of lethal nerve cell injury.

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