Palikaras, Konstantinos et al. (2019) International Worm Meeting "Neuronal mitophagy in C. elegans models of Alzheimer's disease."

Tavernarakis, Nektarios, Palikaras, Konstantinos

[International Worm Meeting, 2019]

Mitochondria, the indispensable and highly dynamic, energy-generating organelles in all eukaryotic cells, play essential roles in fundamental cellular processes. Neuronal cells depend, perhaps more than any other cell type, on proper mitochondrial function. Mitochondrial impairment is a major hallmark of several age-related neurodegenerative pathologies, including Alzheimer's disease. Interestingly, accumulation of damaged mitochondria has been observed in post-mortem brain of Alzheimer's disease patients. Although disease-associated tau and amyloid ? are known to deregulate mitochondrial function, it remains elusive whether they also directly influence the efficiency of mitophagy. Mitophagy is a selective type of autophagy mediating elimination of damaged mitochondria, and the major degradation pathway, by which cells regulate mitochondrial number in response to their metabolic state. However, little is known about the role of mitophagy in the pathogenesis of Alzheimer's disease. To address this question, we developed an in vivoimaging system to monitor mitophagy in neurons. We demonstrated that neuronal mitophagy is impaired in C. elegans models of Alzheimer's disease. Urolithin A- and nicotinamide mononucleotide-induced mitophagy ameliorates several pathological features of Alzheimer's disease, including cognitive defects. Mitophagy stimulation restores memory impairment through PINK-1-, PDR-1 or DCT-1-dependent pathways. Our findings suggest that impaired removal of damaged mitochondria is a pivotal event in Alzheimer's diseasepathogenesis highlighting mitophagy as a potential therapeutic intervention.

Palikaras, Konstantinos et al. (2015) International Worm Meeting "Coordination of mitophagy and mitochondrial biogenesis during ageing in C. elegans."

Palikaras, Konstantinos, Tavernarakis, Nektarios

[International Worm Meeting, 2015]

Mitochondria are highly dynamic, energy-generating organelles in eukaryotic cells and play an essential role in fundamental cellular processes. Mitochondrial function impinges on several signalling pathways modulating cellular metabolism, cell survival and organismal healthspan. Excessive mitochondrial dysfunction and aberrant accumulation of mitochondria in various cell types are shared hallmarks of many pathological conditions and ageing. Thus, maintenance of cellular homeostasis necessitates a tight regulation of mitochondrial biogenesis, as well as, the elimination of dysfunctional or superfluous mitochondria. Mitophagy is a selective type of autophagy mediating removal of damaged mitochondria, and the major degradation pathway, by which cells regulate mitochondrial number in response to metabolic state. However, little is known about the role and regulation of mitophagy during ageing. To address this question, we developed two composite systems for monitoring mitophagy in vivo, and identified conditions that either induce or suppress mitophagy. We used this systems to investigate the involvement of mitophagy in C. elegans ageing. Inhibition of mitophagy does not affect the lifespan of otherwise wild type animals. By contrast, mitophagy depletion markedly shortens the lifespan of long-lived diapause mutants, animals grown under dietary restriction and long-lived mutants with compromised mitochondrial function. We found that mitophagy-deficient animals display impaired mitochondrial function characterized by decreased ATP levels, elevated mitochondrial ROS generation, mitochondrial membrane depolarization, increased oxygen consumption and cytoplasmic Ca2+ elevation. Impairment of mitophagy compromises stress resistance and triggers mitochondrial retrograde signalling through the SKN-1 transcription factor that regulates both mitochondrial biogenesis genes and mitophagy by enhancing the expression of DCT-1 mitophagy receptor. Our results indicate that mitophagy and the retrograde response signalling are tightly coupled and coordinately contribute to promote mitochondrial homeostasis and longevity.

Palikaras, Konstantinos et al. (2013) International Worm Meeting "Coordination of mitophagy and the mitochondrial retrograde response during ageing in C. elegans."

Palikaras, Konstantinos, Tavernarakis, Nektarios

[International Worm Meeting, 2013]

Mitochondria are essential for energy production and have vital roles in calcium signalling and storage, metabolite synthesis and apoptosis in eukaryotic cells. Thus, maintenance of cellular homeostasis necessitates a tight regulation of mitochondrial biogenesis, as well as, the elimination of damaged or superfluous mitochondria. Mitophagy is a selective type of autophagy mediating elimination of damaged mitochondria, and the major degradative pathway, by which cells regulate mitochondrial number in response to metabolic state. However, little is known about the role and regulation of mitophagy during ageing. To address this question, we developed an imaging system to monitor mitophagy in vivo, and identified conditions that either induce or suppress mitophagy. We used this system to investigate the involvement of mitophagy in C.elegans ageing. Inhibition of mitophagy does not affect the lifespan of otherwise wild type animals. By contrast, inhibition of mitophagy markedly shortens the lifespan of long-lived diapause mutants, germline defective animals, or animals grown under dietary restriction. Similarly, impairment of mitophagy shortens the lifespan of long-lived mutants with compromised mitochondrial function. These findings indicate that mitophagy contributes a large part of lifespan extension under conditions of low insulin signalling, germline removal or mitochondrial dysfunction. Mitophagy-deficient mutants are less resistant under conditions of stress, such as heat or oxidative stress and UV-radiation. Mitophagy deficiency precipitates marked alterations of mitochondrial network morphology, mitochondrial mass, ROS levels, mitochondrial membrane potential and cytoplasmic calcium. Importantly, inhibition of mitophagy activates the retrograde response pathway that links mitochondrial function with nuclear gene expression to maintain mitochondrial homeostasis. Our results indicate that mitophagy and the retrograde response are tightly coupled and coordinately contribute to promote mitochondrial homeostasis and longevity.

Palikaras, Konstantinos et al. (2021) International Worm Meeting "Mitochondrial defects manifest an early pathogenic event undermining organismal fitness in a Tauopathy model"

Akbari, Mansour, Achanta, Kavya, Bohr, Vilhelm, Palikaras, Konstantinos

[International Worm Meeting, 2021]

Battling age-associated neurodegenerative pathologies and their pervasive societal impact, is a global enterprise. Alzheimer's disease (AD) is the most common dementia affecting elderly population and there is not any efficient therapeutic strategy until now. Age-dependent impairment of mitochondrial homeostasis is a common feature in evolutionary divergent organisms and is associated with neuronal loss and cognitive decline in AD. However, whether mitochondrial dysfunction is a culprit or bystander of AD pathology remain still elusive. Here, we utilized transgenic nematodes expressing the full length of wild type Tau (Tauwt-lo) in neuronal cells and monitored several aspects of mitochondrial morphology. Although Tauwt-lo expressing nematodes do not present Tau aggregates during larval stages, they display increased mitochondrial damaged and locomotion defects. Interestingly, calcium chelating agents restores mitochondrial activity and motility in Tauwt-lo expressing larvae suggesting that cytoplasmic calcium elevation mediates neuronal impairment. Our findings in their totality suggest that mitochondrial damage is an early pathogenic event of AD that is taking place before Tau aggregation undermining neuronal homeostasis and organismal fitness during aging.