Title Promoter Affiliations Abstract "Small heat shock proteins (HSPBs) sequestration at the outer mitochondrial membrane abrogates oxidative stress induced intrinsic apoptosis by preventing the release of cytochrome c from the mitochondria." "Vincent Timmerman" "Peripheral Neuropathies Group" "Small heat shock proteins (HSPBs) are ATP-independent chaperones that are involved in maintaining the proteome integrity by preventing aberrant protein aggregation. They form highly dynamic, polydisperse oligomeric ensembles, and contain long intrinsically disordered regions. Experimental challenges posed by these aforementioned properties have greatly hindered our understanding of HSPBs. Unpublished work from our lab has shown that HSPBs execute an unexpected dual role in mitochondrial protein quality control. We found out that HSPBs are able to translocate to the mitochondrial intermembrane space (IMS) under basal condition where they prevent protein aggregation; however, after heat shock (42°C for 1 hour) to induce protein misfolding, they immediately translocate to the outer mitochondrial membrane (OMM) for a reason that is unknown. Remarkable is that a P182L mutant of HSPB1 (causing peripheral neuropathy) exhibits the enrichment of the HSPB1 protein on the OMM even under the basal condition, triggering mis-signaling of an unknown pathway that subsequently leads to mitochondrial dysfunctions. In this PhD proposal, I will systematically characterize the function of HSPBs on the OMM, identify their upstream regulators for immediate translocation to the OMM post heat shock and the turn of events following it, which is particularly relevant under different cellular states." "Mitochondria take centre stage: pathways to reduced oocyte quality and opportunities for curative strategies under maternal metabolic stress conditions." "Jo Leroy" "Veterinary physiology and biochemistry" "Infertility is a major socio-economic problem affecting millions worldwide and is specifically linked to maternal obesity and other (diet induced) metabolic disorders. Understanding the mechanisms by which altered metabolism affect fertility is crucial for successful interventions. Mitochondria are the power house within the oocyte. Reduced somatic cell mitochondrial function occurs early in the pathogenesis of metabolic diseases. This is mainly due to the lipotoxic effects of elevated free fatty acid concentrations in blood. For the oocyte to be developmentally competent, the number and function of mitochondria should reach a certain threshold. There are several thousands of mitochondria in the mature oocyte derived from about 20 mitochondria in the germ cell. In addition to their bio-energetic roles, mitochondria are also sensors of stress. Oxidative stress and associated cellular damage elicit stress signalling between the mitochondria and the nucleus to start a protective machinery. The effects of metabolic stress on mitochondrial replication and stress responses during oocyte growth and subsequent embryo development are not known. In this project we will use in vitro and in vivo animal models to study mitochondrial functions and stress responses under maternal metabolic stress conditions in growing oocytes. Defect-based protective and rescue interventions will also be tested to investigate opportunities for curative interventions." "Polyamine and iron interplay at the interface between mitochondria and lysosomes with its putative implications for Parkinson’s disease." "Peter Vangheluwe" "Laboratory of Cellular Transport Systems" "Parkinson's disease (PD) is a progressive neurodegenerative disease whose main symptoms are the consequence of the loss of dopaminergic neurons in the substantia nigra. Its pathological hallmarks include protein aggregation and lysosomal and mitochondrial dysfunction. In addition, excess iron accumulation in dopaminergic neurons and defects in the metabolism of polyamines have been implicated in the pathology of PD. Multiple studies suggest that polyamine and iron metabolism are intricately linked. However, a comprehensive study of the relationship between iron and polyamine homeostasis is still lacking, and the actors responsible for this interplay have yet to be identified at the molecular level. Consequently, the aim of this Ph.D. project is to establish the relationship between iron and polyamine and how it affects lysosomal and mitochondrial function in the context of PD. ATP13A2 loss-of-function mutations cause a spectrum of neurodegenerative diseases, including PD. Previous research from the hosting lab demonstrated that ATP13A2 transports polyamines from the lysosomal lumen to the cytosol and the mitochondrial matrix. This process is important to maintain lysosomal membrane integrity by preventing a toxic build-up of polyamine in lysosomes, and also to maintain mitochondrial redox homeostasis, since polyamines are potent anti-oxidants. Interestingly, ATP13A2 loss-of-function also causes iron accumulation in the cytosol, and some data suggest that polyamine transporters may promote iron internalization into mammalian cells. We hypothesize that the transport of polyamines and iron from the lysosomes into the mitochondria are coupled via the polyamine transporter ATP13A2 and that ATP13A2 plays a crucial role in iron homeostasis and redistribution. The strong anti-oxidant and metal-chelating properties of polyamines may also act as a physiological buffer against the oxidative stress caused by the accumulation of iron. Therefore, we will examine whether ATP13A2 and the regulation of polyamine homeostasis may also affect ferroptosis, which is an iron-dependent cell death caused by lipid peroxidation." "Timed dendrite-axon routing of mitochondria enables successful repair in the injured central nervous system" "Lieve Moons" "Animal Physiology and Neurobiology" "Neural insults and neurodegenerative diseases typically result in permanent functional deficits and represent a growing social and economic problem in our aging society. As the central nervous system of adult mammals only has a limited regenerative capacity, identifying cellular and molecular mechanisms that enable neuronal regeneration forms a critical step towards designing future pro-regenerative therapies. Within this project we aim to validate our intriguing findings and innovative hypothesis that dendritic/synaptic remodeling upon neuronal injury is essential for axonal regeneration, and assess whether adequate intra-neuronal energy channeling could underlie the observed antagonistic interplay between dendrite and axon regrowth in the central nervous system. Thereto, this work will combine in vitro and in vivo approaches and include molecular, biochemical, morphological and functional tools in mice. Identification of underlying regulatory molecules via omics approaches, and confirmation and validation of our findings, will generate pivotal insights into how re-directing mitochondrial trafficking/functioning may promote neuronal repair in the mammalian central nervous system." "Molecular mechanisms of Parkin translocation to mitochondria" "Wim Vandenberghe" "Laboratory for Parkinson Research" "Parkinson’s disease (PD) is a devastating, currently incurable brain disorder. In PD, specific nerve cells gradually die, causing tremor, slowness of movement, falls, dementia and many other problems. Why these nerve cells die, is not well understood. However, in rare familial cases PD is caused by genetic mutations that disrupt the function of the protein Parkin. Recently, it was discovered that Parkin is crucial to maintain a healthy pool of mitochondria in the cell. Mitochondria are cellular organelles that are essential for energy production but, when damaged, can induce cell death. Dysfunctional mitochondria must therefore be promptly eliminated if the cell is to survive. When mitochondria are damaged, Parkin rapidly and selectively moves from its usual location in the cell to the sick mitochondria and targets them for destruction, thus protecting the cell. The molecular mechanisms underlying this rapid movement of Parkin to sick mitochondria are currently unknown. In this project we will use state-of-the-art proteomic methods to unravel the molecular machinery that regulates the translocation of Parkin to damaged mitochondria. Using cell culture and fly models of PD we will investigate how specific proteins interact with Parkin to modulate its mitochondrial translocation. This work may identify new molecular targets for disease-modifying therapy in PD." "Role of pink1, a Parkinson related gene, in mitochondria and synaptic activity." "Patrik Verstreken" "Laboratory of Neuronal Communication (VIB-KU Leuven)" "Mitochondria are dynamic organelles involved in ATP production, buffering of calcium and apoptosis. Genetic studies of neuromuscular junctions in Drosophila have demonstrated that synapses without mitochondria show defects in the mobilization of a reserve pool (RP) of vesicles. These defects are ATP dependent. Mutants of pink1, a gene involved in inherited Parkinsons disease (PD), also display an RP defect. This defect is probably caused by a depolarization of the mitochondrial membrane, caused by a decreased Complex I function, which leads to a reduction of the oxidative phosphorylation. With the proposed project we want to gain further insight in the role of pink1 in synaptic mitochondria, and better understand the etiology of PD. Two approaches will be used to do this: 1) understand how Pink1 interacts with Complex I. To check whether Complex I is the direct and most important target of Pink1, a functional rescue of pink1 with yeast Complex I will be performed. We will use RNAi against all the nuclear encoding subunits of Complex I in order to show which subunit is affected by Pink1. 2) We are performing a genetic screen to find novel genes that, on one hand, are dominant suppressors of pink1 mutant phenotypes and, on the other hand, play a role in neuronal communication." "The molecular hug between the ER and mitochondria in Charcot- Marie-Tooth disease type 1A" "Cardio & organ systems" "Protein misfolding is a hallmark of many neurodegenerative diseases. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) induces ER stress, activating the unfolded protein response (UPR). The ER connects to mitochondria at mitochondria associated membranes (MAM), a specialized platform with an important role in cell homeostasis, including the regulation of calcium signalling, mitochondrial function, the UPR and ER stress. Although their exact role is largely unknown, defective MAM have been demonstrated in several neurodegenerative disorders. Charcot-Marie-Tooth disease type 1A (CMT1A) is a demyelinating disease of the peripheral nervous system and is caused by a duplication of the peripheral myelin protein 22 (PMP22) gene for which no cure exists to date. PMP22 is an aggregation-prone protein situated in myelin produced by Schwann cells. It is not known how the overexpression of PMP22 leads to an abnormal myelin sheath structure and dysfunction in CMT1A. This project aims to explore the effect of PMP22 overproduction and aggregation in the ER on the UPR response and on MAM-mediated cell signalling and function in CMT1A Schwann cells. I hypothesize that PMP22 protein misfolding in CMT1A induces ER stress, leading to the activation of the UPR and Ca2+ signaling pathways, in which MAM play a major role. The outcome of this study, conducted with animal and human models, can reveal important therapeutic targets in CMT1A and other PMP22-related diseases." "The molecular hug between the ER and mitochondria in Charcot- Marie-Tooth disease type 1A" "Esther WOLFS" "Cardio & organ systems" "Protein misfolding is a hallmark of many neurodegenerative diseases. Accumulation of misfolded proteins in the endoplasmic reticulum (ER) induces ER stress, activating the unfolded protein response (UPR). The ER connects to mitochondria at mitochondria associated membranes (MAM), a specialized platform with an important role in cell homeostasis, including the regulation of calcium signalling, mitochondrial function, the UPR and ER stress. Although their exact role is largely unknown, defective MAM have been demonstrated in several neurodegenerative disorders. Charcot-Marie-Tooth disease type 1A (CMT1A) is a demyelinating disease of the peripheral nervous system and is caused by a duplication of the peripheral myelin protein 22 (PMP22) gene for which no cure exists to date. PMP22 is an aggregation-prone protein situated in myelin produced by Schwann cells. It is not known how the overexpression of PMP22 leads to an abnormal myelin sheath structure and dysfunction in CMT1A. This project aims to explore the effect of PMP22 overproduction and aggregation in the ER on the UPR response and on MAM-mediated cell signalling and function in CMT1A Schwann cells. I hypothesize that PMP22 protein misfolding in CMT1A induces ER stress, leading to the activation of the UPR and Ca2+ signaling pathways, in which MAM play a major role. The outcome of this study, conducted with animal and human models, can reveal important therapeutic targets in CMT1A and other PMP22-related diseases." "Mitochondria as effectors and targets of cardiac remodeling in heart failure." "Cardiovascular Imaging and Dynamics" "Metabolic changes can contribute to the contractile dysfunction of the heart directly by reducing energetic efficiency and indirectly by affecting signaling pathways, e.g. through increased production of reactive oxygen species. A major question is whether in ischemic cardiomyopathy metabolic and mitochondrial changes are related to ischemic stress or to an increased mechanical loading, and consequently whether there is more than one functional phenotype underlying the observed morphology of hibernating myocytes. Therefore we intend to investigate and compare in conditions of ischemic stress and mechanical stress the changes in mitochondria and metabolism." "Role of the endoplasmic reticulum and of mitochondria in the Ca2+ metabolism of motor neurons." "Ludo Van Den Bosch" "Laboratory for Neurobiology (VIB-KU Leuven)" "Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective death of motor neurons in the motor cortex, brain stem and spinal cord. Excitotoxicity is one of the mechanisms underlying this selective motor neuron death. Excitotoxicity is the pathological process that results from the overstimulation of the postsynaptic glutamate receptors, which leads ultimately to neuronal death. In this research project, we will investigate the intracellular systems that increase or diminish the calcium concentration in motor neurons. We will focus on the role of the endoplasmic reticulum and of mitochondria in the calcium metabolism as there are indications that these systems are compromised during the disease process and/or could predispose patients to ALS. In addition, we will search for strategies that counteract the disturbances in the calcium metabolism and that protect motor neurons. Using these strategies, we want to get a better understanding of the underlying mechanisms that cause the selective motor neuron death during ALS and we hope that we can contribute to the treatment of this dramatic and fatal neurodegenerative disorder."