Mitochondria as a Target for Future Diabetes Treatments

Diabetes mellitus is rapidly becoming the world’s most dangerous serial killer. Type 1 diabetes (T1D) is a currently incurable autoimmune disease marked by progressive, and eventually exhaustive, destruction of the insulin-producing pancreatic beta cells. Type 2 diabetes (T2D) describes the combination of insulin resistance in peripheral tissue, insufficient insulin secretion from the pancreatic beta cells, and excessive glucagon secretion from the pancreatic alpha cells. T1D as well as severe cases of T2D are treated with insulin replacement, which can merely be considered as life support for the acute phases of the disease. Islet replacement of insulin-producing pancreatic beta cells represents a potential treatment method for both insulin-depleted diabetes (T1D) and insulin-resistant diabetes (T2D) and may shift diabetes management from life saving measures to a cure. One of the key challenges in islet transplants is the generation of reactive oxygen species (ROS) and the associated oxidative stress, which restricts graft longevity. A major leak of ROS takes place during oxidative phosphorylation at mitochondrial electron transport chain (ETC). Additionally, hyperglycemia-induced superoxide (O2•-) production has been linked to the development and progression of diabetic complications, both macrovascular and microvascular. Decreasing ROS in diabetic patients may prevent the incidence of long term diabetes complications. This review provides an overview of the role of mitochondria in diabetes, introducing them as a possible target for future treatment of diabetes

Clinical characteristics of tinnitus annoyance and perception

Tinnitus, or the perception of sounds without an external source, affects up to 15% of the adult population worldwide. It relates to a number of psychological and psychiatric disorders such as psychological distress, insomnia and depression, and develops on a broad range of physical insults. To date, it is nearly impossible to obtain quantitative data on this symptom and thus complaints are often labelled as ‘only’ imaginary. Nevertheless, the sheer number of affected individuals makes it clear that tinnitus is everything but an orphan symptom. Variations in the clinical presentation may arise from the specific physical insult, the quality of first diagnosis and immediate medical aid as well as genetic predisposition. Thus, regional differences have to be considered when approaching tinnitus patients. The aim of this thesis was to study patient populations managed for tinnitus at the Department of Otorhinolaryngology - Head and Neck Surgery, Helsinki University Hospital (Helsinki, Finland). In the first study, we were able to show that music exposure even at low volume can pose a noise trauma and tinnitus occurs long before tone-audiometric hearing disabilities become evident. The alarming finding of the second study was its confirmation of pediatric tinnitus as a largely ignored symptom and that tinnitus in the childhood is under-diagnosed and this may have severe consequences for development of the individual. The third study could demonstrate that pupillometry can be considered as a viable option for studying autonomic activation in tinnitus subjects and emphasized the close link between tinnitus and depression. From our fourth study, a systematic literature review, we cannot clearly conclude if tinnitus and suicide are interrelated entities. The results of the last study indicate that tinnitus patients describe their own perceived tinnitus sound as well as external given sounds very divergent and therefore subjective tinnitus descriptions should be interpreted with great caution. Taken together, an early recognition of tinnitus symptoms may increase not only the overall quality of life of the affected patients, more importantly, it may decrease the risk of psychological and psychiatric co-morbidities and suicidal behavior. A major limitation still is that tinnitus lacks both, clear-cut biomarkers that are specific enough to be allocated solely to the symptom and methods that are sensitive enough to detect them

Clinical Characteristics of Troublesome Pediatric Tinnitus

Objectives:The frequency of tinnitus in children and adults is practically the same. However, although adults reveal their symptoms and seek for medical aid, the suffering often remains unrecognized in the young. This is due to both the inability of children to properly describe their symptoms and the lack of recognition.Materials and methods:Among 5768 patients entering our department with complaints of tinnitus between 2010 and 2015, there were only 112 children. A full clinical history and medical status had been determined at the time of presentation and were analyzed retrospectively.Results:The average duration from first complain to clinical presentation was approximately 12 months. A normal hearing capability of less than 25 dB was measured in 80% of the cases. Only 23 patients presented with a hearing impairment. The causes ranged from hearing loss, previous orthodontic treatment, noise trauma, middle ear aeration, muscular neck tension, and skull base fracture. Typical co-morbidities such as sleeping disorders, concentration disorders, and hyperacusis were observed.Conclusions:This retrospective study shows that recognition of tinnitus in the childhood is generally delayed. A better characterization of complaints and triggers, however, is a prerequisite to sensitize medical personnel and caretakers for the suffering and to avoid developmental impairments.Peer reviewe

Spatial adjustment of bioenergetics, a possible determinant of contractile adaptation and development of contractile failure

Cardiomyocytes depend on mitochondrial oxidative phosphorylation (OXPHOS) for energy metabolism, which is facilitated by the mitochondrial electron transfer system (ETS). In a series of thermogenic redox reactions, electrons are shuttled through the ETS to oxygen as the final electron acceptor. This electron transfer is coupled to proton translocation across the inner mitochondrial membrane, which itself is the main driving force for ATP production. Oxygen availability is thus a prerequisite for ATP production and consequently contractility. Notably, cardiomyocytes are exceptionally large cells and densely packed with contractile structures, which constrains intracellular oxygen distribution. Moreover, oxygen must pass through layers of actively respiring mitochondria to reach the ones located in the innermost contractile compartment. Indeed, uneven oxygen distribution was observed in cardiomyocytes, suggesting that local ATP supply may also vary according to oxygen availability. Here, we discuss how spatial adjustment of bioenergetics to intracellular oxygen fluctuations may underlie cardiac contractile adaptation and how this adaptation may pose a risk for the development of contractile failure

NOA1, a Novel ClpXP Substrate, Takes an Unexpected Nuclear Detour Prior to Mitochondrial Import

The mitochondrial matrix GTPase NOA1 is a nuclear encoded protein, essential for mitochondrial protein synthesis, oxidative phosphorylation and ATP production. Here, we demonstrate that newly translated NOA1 protein is imported into the nucleus, where it localizes to the nucleolus and interacts with UBF1 before nuclear export and import into mitochondria. Mutation of the nuclear localization signal (NLS) prevented both nuclear and mitochondrial import while deletion of the N-terminal mitochondrial targeting sequence (MTS) or the C-terminal RNA binding domain of NOA1 impaired mitochondrial import. Absence of the MTS resulted in accumulation of NOA1 in the nucleus and increased caspase-dependent apoptosis. We also found that export of NOA1 from the nucleus requires a leptomycin-B sensitive, Crm1-dependent nuclear export signal (NES). Finally, we show that NOA1 is a new substrate of the mitochondrial matrix protease complex ClpXP. Our results uncovered an unexpected, mandatory detour of NOA1 through the nucleolus before uptake into mitochondria. We propose that nucleo-mitochondrial translocation of proteins is more widespread than previously anticipated providing additional means to control protein bioavailability as well as cellular communication between both compartments.Max Planck Society for the Advancement of Scienc

Hearing disorder from music; a neglected dysfunction

Conclusion: Music-induced acute acoustic trauma is not inevitably linked to hearing dysfunction as validated by conventional pure tone audiometry. Tinnitus is often in combination with hyperacusis. Our results point at 'silent hearing loss' as the underlying pathology, having afferent nerve terminal damage rather than hair cell loss as the structural correlate. Objectives: Exposure to loud music is one of the most common causes of acute acoustic trauma, which adolescents and teenagers experience by voluntary exposure to loud music of sound levels up to 110 dB(A). Methods: The clinical and psychophysical data of 104 consecutive patients with music-induced hearing disorder (MIHD) were analyzed to construct individual hearing and tinnitus profiles. In all cases, tinnitus was the presenting symptom. Results: Hearing abilities were normal in about two-thirds of the tinnitus patients. Tinnitus was experienced most often as a high-frequency tone (83%). The Tinnitus Handicap Inventory (THI) scores ranged from 0 to 94 with an average score of 43.1. Visual analog scales (VAS) were used to assess tinnitus loudness (average 42.4) and annoyance (average 54.2), and tinnitus awareness was estimated (average 60.3). All VAS values correlated strongly with the THI. Hyperacusis was present in 65% and 71% of the patients reported sleeping disorders.Peer reviewe

S-Nitrosylation of mitochondrial caspases

Caspase-3 is a cysteine protease located in both the cytoplasm and mitochondrial intermembrane space that is a central effector of many apoptotic pathways. In resting cells, a subset of caspase-3 zymogens is S-nitrosylated at the active site cysteine, inhibiting enzyme activity. During Fas-induced apoptosis, caspases are denitrosylated, allowing the catalytic site to function. In the current studies, we sought to identify the subpopulation of caspases that is regulated by S-nitrosylation. We report that the majority of mitochondrial, but not cytoplasmic, caspase-3 zymogens contain this inhibitory modification. In addition, the majority of mitochondrial caspase-9 is S-nitrosylated. These studies suggest that S-nitrosylation plays an important role in regulating mitochondrial caspase function and that the S-nitrosylation state of a given protein depends on its subcellular localization

Tinnitus and suicide : An unresolved relation

Tinnitus is an auditory phantom sensation which can be a devastating condition for the affected person causing annoyance and discomfort. It may be associated with psychiatric conditions. Patients with highly annoying tinnitus and different comorbidities may have a higher risk of expressing suicidal behaviour and ideation. We aimed to review available reports on the prevalence of suicide and suicidal behaviour with tinnitus patients in order to collate current concepts and to identify possible alarming signs and risk factors. A comprehensive search for appropriate studies listed in PubMed, Ovid and Cochrane databases was conducted using appropriate keyword combinations. We identified 22 publications including original articles, case reports and reviews of which 10 fit our stringent search criteria. Most importantly, from the present studies it appears not feasible to univocally conclude on the co-incidence of tinnitus and suicide. This is due to methodological differences in these approaches, complex interrelations between tinnitus and other psychiatric comorbidities and confounding factors such as the inclusion of patients suffering from post-traumatic stress disorder. More concerted actions involving different medical disciplines are needed to reflect the ethiological heterogeneity of tinnitus and suicide or suicidal behaviour to test for a relationship.Peer reviewe

Xenotopic expression of alternative oxidase (AOX) to study mechanisms of mitochondrial disease

The mitochondrial respiratory chain or electron transport chain (ETC) facilitates redox reactions which ultimately lead to the reduction of oxygen to water (respiration). Energy released by this process is used to establish a proton electrochemical gradient which drives ATP formation (oxidative phosphorylation, OXPHOS). It also plays an important role in vital processes beyond ATP formation and cellular metabolism, such as heat production, redox and ion homeostasis. Dysfunction of the ETC can thus impair cellular and organismal viability and is thought to be the underlying cause of a heterogeneous group of so-called mitochondrial diseases. Plants, yeasts, and many lower organisms, but not insects and vertebrates, possess an enzymatic mechanism that confers resistance to respiratory stress conditions, i.e., the alternative oxidase (AOX). Even in cells that naturally lack AOX, it is autonomously imported into the mitochondrial compartment upon xenotopic expression, where it refolds and becomes catalytically engaged when the cytochrome segment of the ETC is blocked. AOX was therefore proposed as a tool to study disease etiologies. To this end, AOX has been xenotopically expressed in mammalian cells and disease models of the fruit fly and mouse. Surprisingly, AOX showed remarkable rescue effects in some cases, whilst in others it had no effect or even exacerbated a condition. Here we summarize what has been learnt from the use of AOX in various disease models and discuss issues which still need to be addressed in order to understand the role of the ETC in health and disease.publishedVersionPeer reviewe

Control of mitochondrial superoxide production by reverse electron transport at complex I.

The generation of mitochondrial superoxide (O2̇̄) by reverse electron transport (RET) at complex I causes oxidative damage in pathologies such as ischemia reperfusion injury, but also provides the precursor to H2O2 production in physiological mitochondrial redox signaling. Here, we quantified the factors that determine mitochondrial O2̇̄ production by RET in isolated heart mitochondria. Measuring mitochondrial H2O2 production at a range of proton-motive force (Δp) values and for several coenzyme Q (CoQ) and NADH pool redox states obtained with the uncoupler p-trifluoromethoxyphenylhydrazone, we show that O2̇̄ production by RET responds to changes in O2 concentration, the magnitude of Δp, and the redox states of the CoQ and NADH pools. Moreover, we determined how expressing the alternative oxidase from the tunicate Ciona intestinalis to oxidize the CoQ pool affected RET-mediated O2̇̄ production at complex I, underscoring the importance of the CoQ pool for mitochondrial O2̇̄ production by RET. An analysis of O2̇̄ production at complex I as a function of the thermodynamic forces driving RET at complex I revealed that many molecules that affect mitochondrial reactive oxygen species production do so by altering the overall thermodynamic driving forces of RET, rather than by directly acting on complex I. These findings clarify the factors controlling RET-mediated mitochondrial O2̇̄ production in both pathological and physiological conditions. We conclude that O2̇̄ production by RET is highly responsive to small changes in Δp and the CoQ redox state, indicating that complex I RET represents a major mode of mitochondrial redox signaling