Role of ocular blood flow in normal tension glaucoma.

Background: Normal tension glaucoma (NTG) is a multifactorial disease in the pathogenesis of which intraocular pressure (IOP)-independent factors play a key role. Main text: There is considerable evidence that impairment of the ocular blood flow (OBF) is involved both in the onset and progression of this disease. With the development of the hypothesis of OBF in NTG, various imaging techniques have been developed to evaluate the OBF and blood vessels. Moreover, vascular dysregulation, which is a main factor in Flammer syndrome, was frequently observed in NTG patients. Disturbed OBF leads to increased oxidative stress, which plays an important role in the pathogenesis of glaucomatous optic neuropathy. These results suggested that IOP-independent management may provide alternative treatment options for NTG patients. Conclusions: In this review, we mainly focus on the mechanisms of the abnormal OBF in NTG.

Endosomal disentanglement of a transducible artificial transcription factor targeting endothelin receptor A.

Cell-penetrating peptides (CPPs) hold great promise for intracellular delivery of therapeutic proteins. However, endosomal entrapment of transduced cargo is a major bottleneck hampering their successful application. While developing a transducible zinc finger protein-based artificial transcription factor targeting the expression of endothelin receptor A, we identified interaction between the CPP and the endosomal membrane or endosomal entanglement as a main culprit for endosomal entrapment. To achieve endosomal disentanglement, we utilized endosome-resident proteases to sever the artificial transcription factor from its CPP upon arrival inside the endosome. Using this approach, we greatly enhanced the correct subcellular localization of the disentangled artificial transcription factor, significantly increasing its biological activity and distribution in vivo. With rational engineering of proteolytic sensitivity, we propose a new design principle for transducible therapeutic proteins, helping CPPs attain their full potential as delivery vectors for therapeutic proteins.

Treatment of Glaucoma Patients with Flammer Syndrome.

Flammer syndrome (FS) describes a phenotype characterized by the presence of primary vascular dysregulation along with a number of symptoms and signs. Although most people with FS are healthy, FS favors the occurrence of certain diseases, such as normal tension glaucoma. This is because disturbed autoregulation makes the eye more sensitive to intraocular pressure (IOP) spikes or blood pressure drops. Treatment of FS is generally appropriate when patients either suffer greatly from their symptoms or if we can assume that it has contributed to a disease. In glaucoma, this may be the case if the glaucoma damage progresses despite well-controlled IOP. Both the still sparse scientific studies and our long clinical experience suggest that FS-targeted therapy not only relieves the symptoms of FS but also slows the progression of glaucoma damage in selected cases. This description is intended not only to help affected patients but to also motivate clinicians and researchers to conduct therapy studies to confirm or refute our observations.

Retinal venous pressure is decreased after anti-VEGF therapy in patients with retinal vein occlusion-related macular edema.

PURPOSE: The pathomechanism leading to retinal vein occlusion (RVO) is unclear. Mechanical compression, thrombosis, and functional contractions of veins are discussed as the reasons for the increased resistance of venous outflow. We evaluated changes in the retinal venous pressure (RVP) following intravitreal injection of anti-vascular endothelial growth factor (VEGF) agent to determine the effect on RVO-related macular edema. METHODS: Twenty-six patients with RVO-related macular edema (16 branch RVOs [BRVOs] and 10 central RVOs [CRVOs], age 72.5 ± 8.8 years) who visited our hospital were included in this prospective study. Visual acuity (VA), intraocular pressure (IOP), central retinal thickness (CRT) determined by macular optical coherence tomography, and RVP measured using an ophthalmodynamometer were obtained before intravitreal injection of ranibizumab (IVR) and 1 month later. RESULTS: Comparison of the BRVOs and CRVOs showed that VA was significantly improved by a single injection in BRVOs (P < 0.0001; P = 0.1087 for CRVOs), but CRT and RVP were significantly decreased without significant difference in IOP after the treatment in both groups (P < 0.0001). CONCLUSION: The anti-VEGF treatment resulted in a significant decrease in the RVP, but the RVP remained significantly higher than the IOP. An increased RVP plays a decisive role in the formation of macula edema, and reducing it is desirable.

Endothelin-1 traps as a potential therapeutic tool: from diabetes to beyond?

There is substantial research on the vasoactive peptide endothelin (ET)-1 in physiology, as well as in pathology. In fact, pathologically elevated levels of ET-1 have been found in several disease states, such as various cardiovascular diseases, different cancers, some neurodegenerative disorders, as well as in diabetes. Here, we describe and discuss ET-1, its importance in different diseases, and the potential therapeutic effects of ET-traps in the treatment of these diseases. Previous in vitro and in vivo research (in the diabetes disease space) demonstrated that ET-traps potently and significantly prevent the induction of different markers of diabetes-related pathology. This included induction of extracellular matrix (ECM) proteins (collagen 4α1 and fibronectin), which are pathologically elevated in diabetes. The ET-traps prevented induction of these and brought a significant return to non-diabetic levels. We also discuss the merits of using ET-traps over the currently used endothelin receptor antagonists (ERAs) and previously used therapeutic antibodies.

Effects of the Glaucoma Drugs Latanoprost and Brimonidine on Corneal Temperature.

PURPOSE: The aim of this study was to investigate the effects of the glaucoma drugs latanoprost, brimonidine, and the combination of both on the central corneal temperature (CT) of healthy subjects by means of infrared thermography. Changes of the central CT may reflect changes of ocular blood flow. METHODS: Before application and during 2 hours after the application of latanoprost, brimonidine, or the combination of both in one eye, the CT in both eyes of 40 healthy subjects was measured repeatedly. RESULTS: Brimonidine reduced CT by approximately 0.5°C. This effect was statistically significant (P < 0.0001). Latanoprost, however, had a very small and insignificant influence (P = 0.47). Accordingly, the combination of brimonidine and latanoprost also reduced CT up to 0.5°C, and this effect was statistically significant (P < 0.0001). CONCLUSIONS: Brimonidine, but not latanoprost, had a significant effect on central CT. This cooling effect of brimonidine is most probably due to a drug-induced reduction of blood circulation in the ciliary body and iris and to a certain extent also to a reduction of blood flow in the fundus of the eye. TRANSLATIONAL RELEVANCE: This study shows evidence that thermography of the cornea provides indirect information on the influence of drugs on the blood flow to the anterior segment of the patient's eye.

Residual vision activation and the brain-eye-vascular triad: Dysregulation, plasticity and restoration in low vision and blindness - a review.

Vision loss due to ocular diseases such as glaucoma, optic neuropathy, macular degeneration, or diabetic retinopathy, are generally considered an exclusive affair of the retina and/or optic nerve. However, the brain, through multiple indirect influences, has also a major impact on functional visual impairment. Such indirect influences include intracerebral pressure, eye movements, top-down modulation (attention, cognition), and emotionally triggered stress hormone release affecting blood vessel dysregulation. Therefore, vision loss should be viewed as the result of multiple interactions within a "brain-eye-vascular triad", and several eye diseases may also be considered as brain diseases in disguise. While the brain is part of the problem, it can also be part of the solution. Neuronal networks of the brain can "amplify" residual vision through neuroplasticity changes of local and global functional connectivity by activating, modulating and strengthening residual visual signals. The activation of residual vision can be achieved by different means such as vision restoration training, non-invasive brain stimulation, or blood flow enhancing medications. Modulating brain functional networks and improving vascular regulation may offer new opportunities to recover or restore low vision by increasing visual field size, visual acuity and overall functional vision. Hence, neuroscience offers new insights to better understand vision loss, and modulating brain and vascular function is a promising source for new opportunities to activate residual vision to achieve restoration and recovery to improve quality of live in patients suffering from low vision.

Data on the involvement of endothelin-1 (ET-1) in the dysregulation of retinal veins.

Retinal vein occlusion (RVO) is a common vascular disease of the retina; however, the pathogenesis of RVO is still unclear. Branch RVO (BRVO) commonly occurs at the arteriovenous crossing and it was formerly believed that the diseased artery mechanically compresses the vein. However, it has been reported that the retinal vein runs deep beneath the artery at the arteriovenous crossing in eyes with an arterial overcrossing, and the venous lumen often appears to be preserved, even at the arteriovenous crossing, as shown by optical coherence tomography. Paques et al. [1] found venous nicking without arteriovenous contact using adaptive optics imaging. Thus, we investigated the potential role of a dysregulation of the retinal vein. While the pathogenesis of retinal vein occlusion (RVO) is still unclear, systemic hypertension and increased level of endothelin-1 (ET-1) are known risk factors (Flammer and Konieczka, 2015) [2]. We focused on the behavior of retinal veins in spontaneous hypertensive rats (SHR). Then, one of the retinal veins became exceptionally constricted and was nearly occluded (Fig. 1), and the chorioretinal blood flow significantly decreased in the retinas of SHRs following the intravenous injection of ET-1. In addition, immunoreactivity to ET-A receptor was higher in SHR retinas than in control (WKY; Wistar Kyoto rat) retinas (Fig. 2). The protein levels of ET-A receptor and HIF-1 were also significantly higher in SHR retinas than in WKY retinas (Fig. 3). We observed vasoactivity of retinal veins; a retinal venous constriction (Kida et al., 2018) [3]. This supports the hypothesis that ET-1 can constrict retinal veins, thus increasing retinal venous pressure, and that ET-1 may even contribute to the pathogenesis of RVO.

Vasoactivity of retinal veins: A potential involvement of endothelin-1 (ET-1) in the pathogenesis of retinal vein occlusion (RVO).

PURPOSE: Whilst the pathogenesis of retinal vein occlusion (RVO) is still unclear, systemic hypertension and increased level of endothelin-1 (ET-1) are known risk factors. Therefore, we studied the influence of ET-1 on the retinal veins in hypertensive rats. METHODS: We focused on the behavior of retinal veins in spontaneous hypertensive rats (SHR). To determine whether ET-1 was associated with the blood flow in eyes of SHRs, the chorioretinal blood flow in the rats was assessed using laser speckle flowgraphy (LSFG-Micro, Softcare, Fukuoka, Japan) before and after an intravenous injection of ET-1 under general anesthesia. In addition, retinas from SHRs and age-matched normotensive Wistar-Kyoto rats (WKYs) were removed, and retinal sections were immunostained for the ET-A and ET-B receptors. The protein levels of both ET-1 receptors and hypoxia-inducible factor 1 (HIF-1) in the retinal tissues were also determined by western blot analysis. RESULTS: One of the retinal veins became exceptionally constricted and was nearly occluded, and the chorioretinal blood flow significantly decreased in the retinas of SHRs following the injection of ET-1. Immunoreactivity to ET-A receptor was higher in SHR retinas than in WKY retinas. The protein levels of ET-A receptor and HIF-1 were also significantly higher in SHR retinas than in WKY retinas. CONCLUSIONS: An increase of ET-1 in circulating blood leads to the local constriction of retinal veins and this effect is accentuated in hypertensive rats by an upregulation of ET-A receptor. It is plausible that such a constriction of retinal veins increases retinal venous pressure, and may even contribute to the pathogenesis of RVO.

Cornea Thermography: Optimal Evaluation of the Outcome and the Resulting Reproducibility.

PURPOSE: The aim of the study was to establish a standardized quantitative evaluation of corneal temperature (CT) that includes anchoring reference points in the topography and minimization of artifacts. We further investigated the distribution and the short- and long-term reproducibility of the CT values, as well as the influence of the core temperatures. METHODS: The CT values in both eyes of 40 healthy subjects were measured through thermography. These examinations took place over the course of four visits within 2 consecutive weeks. At each visit, the CTs were measured twice in both eyes with intervals of 15 minutes between measurements. RESULTS: CT values were not significantly different between the right and left eyes and their distribution was nearly normal. The CTs increased slightly when measured twice over the 15-minute intervals (short-term reproducibility) but remained stable over a period of 2 weeks (long-term reproducibility). In addition, the CT values depended on the core temperatures. CONCLUSIONS: Ocular surface thermography is a fast and noninvasive examination. The methods of optimized and standardized evaluation of the CT values facilitate comparisons and follow-ups. TRANSLATIONAL RELEVANCE: Thermography can be used clinically and scientifically only if both the measurement and its evaluation are efficient and standardized and if the outcomes are highly reproducible.

Individualised patient profile: clinical utility of Flammer syndrome phenotype and general lessons for predictive, preventive and personalised medicine.

This case report introduces a female patient, who since her teenager age evidently suffers from Flammer syndrome (FS) as the clearly defined sub-optimal health condition. Further, the patient has experienced collateral pathological conditions which primarily might be linked to the family (genetic) predisposition, but the development of which could be synergistically promoted by the FS-phenotype. The facts are thoroughly analysed and consequent hypotheses are presented, which are indicative for highly desirable predictive diagnostics and targeted preventive measures to be created based on the accurate interpretation of the individualised patient profile. The authors emphasise the great clinical relevance of the FS and field-related research.

The discovery of the Flammer syndrome: a historical and personal perspective.

This review describes the clinical and basic research that led to the description of Flammer syndrome. It is narrated from a personal perspective. This research was initiated by the observation of an increased long-term fluctuation of visual fields in a subgroup of glaucoma patients. As these patients had strikingly cold hands, peripheral blood flow was tested with a capillary microscopy, and vasospastic syndrome (VS) was diagnosed. Further studies on these patients revealed frequently weakened autoregulation of ocular blood flow and increased flow resistivity in retroocular vessels. Their retinal vessels were more rigid and irregular and responded less to flickering light. Holistic investigation demonstrated low blood pressure, silent myocardial ischaemia, altered beat-to-beat variation, altered gene expression in the lymphocytes, slightly increased plasma endothelin level and increased systemic oxidative stress. This combination of signs and symptoms was better described by the term primary vascular dysregulation (PVD) than by VS. Subsequent studies showed additional symptoms frequently related to PVD, such as low body mass index, cold extremities combined with slightly increased core temperature, prolonged sleep onset time, reduced feelings of thirst, increased sensitivity to smell and also for certain drugs and increased retinal venous pressure. To better characterise this entire syndrome, the term Flammer syndrome (FS) was introduced. Most subjects with FS were healthy. Nevertheless, FS seemed to increase the risk for certain eye diseases, particularly in younger patients. This included normal-tension glaucoma, anterior ischaemic optic neuropathy, retinal vein occlusions, Susac syndrome and central serous chorioretinopathy. Hereditary diseases, such as Leber's optic neuropathy or retinitis pigmentosa, were also associated with FS, and FS symptoms and sings occurred more frequent in patients with multiple sclerosis or with acute hearing loss. Further research should lead to a more concise definition of FS, a precise diagnosis and tools for recognizing people at risk for associated diseases. This may ultimately lead to more efficient and more personalised treatment.

Suppressed endothelin-1 by anti-VEGF therapy is important for patients with BRVO-related macular edema to improve their vision.

BACKGROUND: Branch retinal vein occlusion (BRVO) commonly occurs at the arteriovenous crossing in the unilateral eye, and cardiovascular diseases can be risk factors of BRVO. However, the pathomechanism leading to BRVO is not yet clear. In addition to mechanical compression, the vein might locally constrict due to an altered biochemical environment, such as an increase in the concentration of endothelin-1 (ET-1). We evaluated changes in ET-1 following injection of intravitreal bevacizumab (IVB), which is the anti-vascular endothelial growth factor (VEGF) agent with the longest serum half-life, to determine the effect on BRVO-related macular edema. METHODS: Twenty consecutive patients with BRVO-related macular edema (10 males, 10 females; age range 56-83 years) who visited our hospital were included in this prospective study. Visual acuity (VA); central retinal thickness (CRT), determined by macular optical coherence tomography (OCT); and plasma ET-1 levels were obtained before IVB treatment and 1 month later. RESULTS: Patients had hypertension (80 %), dyslipidemia (50 %), diabetes mellitus (35 %), or collagen disease (5 %). Mean CRT was significantly decreased from 673.0 ± 327.8 to 388.2 ± 155.0 µm (P = 0.0007), and mean VA was significantly improved after IVB (P = 0.0239). Mean plasma ET-1 was significantly decreased from 1.272 ± 0.451 to 1.095 ± 0.316 pg/mL (P = 0.0238); however, the plasma ET-1 level was increased in all five patients who did not show improved VA after IVB. CONCLUSIONS: In patients with BRVO-related macular edema, anti-VEGF therapy leads to an expected reduction in ET-1 levels; however, the ET-1 level was found to increase in some patients; this is clearly related to less improvement of VA after anti-VEGF therapy. TRIAL REGISTRATION: University hospital Medical Information Network (UMIN) Center UMIN000013236. Registered 10 October, 2012.

Retinal venous pressure: the role of endothelin.

The retinal venous pressure (RVP) can be measured non-invasively. While RVP is equal to or slightly above intraocular pressure (IOP) in healthy people, it is often markedly increased in patients with eye or systemic diseases. Beside a mechanical obstruction, the main cause of such an elevation is a local dysregulation of a retinal vein, particularly a constriction induced by endothelin-1 (ET-1). A local increase of ET-1 can result from a high plasma level, as ET-1 can diffuse from the fenestrated capillaries of the choroid into the optic nerve head (ONH), bypassing the blood retinal barrier. A local increase can also result from increased local production either by a sick neighboring artery or retinal tissue. Generally, the main factors increasing ET-1 are inflammations and hypoxia, either locally or in a remote organ. RVP is known to be increased in patients with glaucoma, retinal vein occlusion (RVO), diabetic retinopathy, high mountain disease, and primary vascular dysregulation (PVD). PVD is the major vascular component of Flammer syndrome (FS). An increase of RVP decreases perfusion pressure, which heightens the risk for hypoxia. An increase of RVP also elevates transmural pressure, which in turn heightens the risk for retinal edema. In patients with RVO, a high level of RVP may not only be a consequence but also a potential cause of the occlusion; therefore, it risks causing a vicious circle. Narrow retinal arteries and particularly dilated retinal veins are known risk indicators for future cardiovascular events. As the major cause for such a retinal venous dilatation is an increased RVP, RVP may likely turn out to be an even stronger predictor.

Comet assay as an indirect measure of systemic oxidative stress.

Higher eukaryotic organisms cannot live without oxygen; yet, paradoxically, oxygen can be harmful to them. The oxygen molecule is chemically relatively inert because it has two unpaired electrons located in different pi * anti-bonding orbitals. These two electrons have parallel spins, meaning they rotate in the same direction about their own axes. This is why the oxygen molecule is not very reactive. Activation of oxygen may occur by two different mechanisms; either through reduction via one electron at a time (monovalent reduction), or through the absorption of sufficient energy to reverse the spin of one of the unpaired electrons. This results in the production of reactive oxidative species (ROS). There are a number of ways in which the human body eliminates ROS in its physiological state. If ROS production exceeds the repair capacity, oxidative stress results and damages different molecules. There are many different methods by which oxidative stress can be measured. This manuscript focuses on one of the methods named cell gel electrophoresis, also known as "comet assay" which allows measurement of DNA breaks. If all factors known to cause DNA damage, other than oxidative stress are kept constant, the amount of DNA damage measured by comet assay is a good parameter of oxidative stress. The principle is simple and relies upon the fact that DNA molecules are negatively charged. An intact DNA molecule has such a large size that it does not migrate during electrophoresis. DNA breaks, however, if present result in smaller fragments which move in the electrical field towards the anode. Smaller fragments migrate faster. As the fragments have different sizes the final result of the electrophoresis is not a distinct line but rather a continuum with the shape of a comet. The system allows a quantification of the resulting "comet" and thus of the DNA breaks in the cell.

Central retinal venous pressure in eyes of normal-tension glaucoma patients with optic disc hemorrhage.

OBJECTIVE: To compare central retinal venous pressure (CRVP) among eyes with and without optic disc hemorrhage (ODH) in bilateral normal-tension glaucoma (NTG) patients and NTG eyes without an episode of ODH. METHODS: In this prospective study, 22 bilateral NTG patients showing a unilateral ODH and 29 bilateral NTG patients without an episode of ODH were included. Eyes were categorized into group A (n = 22, eyes with ODH), group B (n = 22, fellow eyes without ODH), and group C (n = 29, NTG eyes without an episode of ODH). A contact lens ophthalmodynamometer was used to measure CRVP and central retinal arterial pressure (CRAP). RESULTS: Intraocular pressure (IOP) measured on the day of contact lens ophthalmodynamometry showed no difference among groups. However, the mean baseline IOP in group A was significantly lower than that in group C (P = .008). The CRVP in group A (29.1 ± 10.8 mmHg) was significantly lower than that in group C (40.1 ± 8.8 mmHg, P = .001), but similar to that in group B (30.5 ± 8.7 mmHg, P = .409). A similar relationship was noted for CRAP. No significant eye-associated variable for ODH was found in group A and B by conditional logistic regression analysis (all P > 0.05). However, multivariate logistic regression analysis in groups A and C revealed that low mean baseline IOP (odds ratio [OR] = 0.69, 95% confidence interval [CI] 0.49-0.98, P = 0.043) and low CRVP (OR = 0.88, 95% CI 0.80-0.95, P = 0.003) were associated with ODH. CONCLUSIONS: CRVP was lower in NTG eyes with ODH than in eyes without an episode of ODH, but similar to that of fellow eyes without ODH. These imply less likelihood of association between increased central retinal venous resistance and ODH.

Patients with diabetic retinopathy have high retinal venous pressure.

BACKGROUND: The introduction of ophthalmodynamometric measurement of retinal venous pressure (RVP) now permits the quantification, or at least an approximation, of the real pressure in the retinal veins. METHODS: We measured the RVP of healthy control subjects, patients with diabetes without diabetic retinopathy (nonDR) and patients with diabetes and diabetic retinopathy (DR). RESULTS: The mean ± SD RVP for the control, nonDR and DR groups were 23.4 ± 7.33, 22.5 ± 5.78 and 37.7 ± 10.1 mmHg, respectively. In the diabetes patients with DR, the RVP was markedly and significantly increased, and this result was significantly age dependent. RVP was not increased in the group of diabetes patients without DR. In our tested population, diabetes had a minor influence on intraocular pressure. CONCLUSION: Regardless of the cause, a marked increase in RVP in diabetes patients with DR is clinically relevant, as it reduces perfusion pressure and increases transmural pressure. The reduced perfusion pressure contributes to hypoxia, and the increased transmural pressure can facilitate retinal edema. Diabetes is an increasing burden, and DR is one of its most severe complications. Strategies to recognize the risk for DR and to develop personalized prevention and therapy therefore have major implications. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01771835.

Mitochondrial function in neuronal cells depends on p97/VCP/Cdc48-mediated quality control.

Maintaining mitochondrial function is essential for neuronal survival and offers protection against neurodegeneration. Ubiquitin-mediated, proteasome-dependent protein degradation in the form of outer mitochondrial membrane associated degradation (OMMAD) was shown to play roles in maintenance of mitochondria on the level of proteostasis, but also mitophagy and cell death. Recently, the AAA-ATPase p97/VCP/Cdc48 was recognized as part of OMMAD acting as retrotranslocase of ubiquitinated mitochondrial proteins for proteasomal degradation. Thus, p97 likely plays a major role in mitochondrial maintenance. Support for this notion comes from mitochondrial dysfunction associated with amyotrophic lateral sclerosis and hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD) caused by p97 mutation. Using SH-SY5Y cells stably expressing p97 or dominant-negative p97(QQ) treated with mitochondrial toxins rotenone, 6-OHDA, or Aß-peptide as model for neuronal cells suffering from mitochondrial dysfunction, we found mitochondrial fragmentation under normal and stress conditions was significantly increased upon inactivation of p97. Furthermore, inactivation of p97 resulted in loss of mitochondrial membrane potential and increased production of reactive oxygen species (ROS). Under additional stress conditions, loss of mitochondrial membrane potential and increased ROS production was even more pronounced. Loss of mitochondrial fidelity upon inactivation of p97 was likely due to disturbed maintenance of mitochondrial proteostasis as the employed treatments neither induced mitophagy nor cell death. This was supported by the accumulation of oxidatively-damaged proteins on mitochondria in response to p97 inactivation. Dysfunction of p97 under normal and stress conditions in neuron-like cells severely impacts mitochondrial function, thus supporting for the first time a role for p97 as a major component of mitochondrial proteostasis.

Quality control of oxidatively damaged mitochondrial proteins is mediated by p97 and the proteasome.

Protein quality control is essential for maintaining mitochondrial fidelity. Proteins damaged by reactive oxygen species necessitate quality control to prevent mitochondrial dysfunction connected to aging and neurodegeneration. Here we report a role for the AAA ATPase p97/VCP and the proteasome in the quality control of oxidized mitochondrial proteins under low oxidative stress as well as normal conditions. Proteasomal inhibition and blocking p97-dependent protein retrotranslocation interfered with degradation of oxidized mitochondrial proteins. Thus, ubiquitin-dependent, p97-, and proteasome-mediated degradation of oxidatively damaged proteins plays a key role in maintaining mitochondrial fidelity and is likely an important defense mechanism against aging and neurodegeneration.