A Mitochondria-Cluster At The Proximal Axon Initial Segment Controls Axodendritic TAU Trafficking In Rodent Primary And Human iPSCderived Neurons

Loss of neuronal polarity and missorting of the axonal microtubule-associated protein TAU are hallmarks of Alzheimer’s disease (AD) and related tauopathies. Impairment of mitochondrial function is causative for various neurogenetic mitochondriopathies, but the role of mitochondria in tauopathies and in axonal TAU-sorting is still unclear. The axon initial segment (AIS) is vital for maintaining neuronal polarity and proper sorting of TAU. Here, we aimed to investigate the role of mitochondria in the AIS regarding the maintenance of TAU polarity. Using global mitochondria impairment, but also live-cell-imaging and photoactivation methods, we specifically tracked and selectively impaired mitochondria in the AIS in primary mouse and human iPSC-derived neurons, and measured the subsequent missorting of TAU. We observed that global application of mitochondrial toxins efficiently induced tauopathy-like missorting, indicating involvement of mitochondria in TAU polarity. Mitochondria show a biased distribution within the AIS, with a proximal cluster and relative absence in the central AIS. The mitochondria of this cluster are largely immobile and only sparsely participate in axonal mitochondria-trafficking. Locally constricted impairment of only the AIS-mitochondria-cluster leads to detectable increases of somatic TAU, reminiscent of AD-like TAU-missorting. Here, we provide first evidence that the mitochondrial distribution within the proximal axon is biased towards the proximal AIS and that proper function of this newly described mitochondrial cluster may be essential for the maintenance of TAU neuronal polarity. This strengthens the role of mitochondrial impairment as an upstream event and therapeutic target in the pathological cascade leading to TAU missorting and consequent neuronal dysfunction.

Mitochondria and Parkinson’s Disease: Clinical, Molecular, and Translational Aspects

Mitochondrial dysfunction represents a well-established player in the pathogenesis of both monogenic and idiopathic Parkinson’s disease (PD). Initially originating from the observation that mitochondrial toxins cause PD, findings from genetic PD supported a contribution of mitochondrial dysfunction to the disease. Here, proteins encoded by the autosomal recessively inherited PD genes Parkin, PTEN-induced kinase 1 (PINK1), and DJ-1 are involved in mitochondrial pathways. Additional evidence for mitochondrial dysfunction stems from models of autosomal-dominant PD due to mutations in alpha-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2). Moreover, patients harboring alterations in mitochondrial polymerase gamma (POLG) often exhibit signs of parkinsonism. While some molecular studies suggest that mitochondrial dysfunction is a primary event in PD, others speculate that it is the result of impaired mitochondrial clearance. Most recent research even implicated damage-associated molecular patterns released from non-degraded mitochondria in neuroinflammatory processes in PD. Here, we summarize the manifold literature dealing with mitochondria in the context of PD. Moreover, in light of recent advances in the field of personalized medicine, patient stratification according to the degree of mitochondrial impairment followed by mitochondrial enhancement therapy may hold potential for at least a subset of genetic and idiopathic PD cases. Thus, in the second part of this review, we discuss therapeutic approaches targeting mitochondrial dysfunction with the aim to prevent or delay neurodegeneration in PD.

Mitochondrial DNA Manipulations Affect Tau Oligomerization

Background: Mitochondrial dysfunction and tau aggregation occur in Alzheimer’s disease (AD), and exposing cells or rodents to mitochondrial toxins alters their tau. Objective: To further explore how mitochondria influence tau, we measured tau oligomer levels in human neuronal SH-SY5Y cells with different mitochondrial DNA (mtDNA) manipulations. Methods: Specifically, we analyzed cells undergoing ethidium bromide-induced acute mtDNA depletion, ρ0 cells with chronic mtDNA depletion, and cytoplasmic hybrid (cybrid) cell lines containing mtDNA from AD subjects. Results: We found cytochrome oxidase activity was particularly sensitive to acute mtDNA depletion, evidence of metabolic re-programming in the ρ0 cells, and a relatively reduced mtDNA content in cybrids generated through AD subject mitochondrial transfer. In each case tau oligomer levels increased, and acutely depleted and AD cybrid cells also showed a monomer to oligomer shift. Conclusion: We conclude a cell’s mtDNA affects tau oligomerization. Overlapping tau changes across three mtDNA-manipulated models establishes the reproducibility of the phenomenon, and its presence in AD cybrids supports its AD-relevance.

Mitochondrial dysfunction and energy deprivation in the mechanism of neurodegeneration

Energy-producing organelles mitochondria are involved in a number of cellular functions. Deregulation of mitochondrial function due to mutations or effects of mitochondrial toxins is proven to be a trigger for diverse pathologies, including neurodegenerative disorders. Despite the extensive research done in the last decades, the mechanisms by which mitochondrial dysfunction leads to neuronal deregulation and cell death have not yet been fully elucidated. Brain cells are specifically dependent on mitochondria due to their high energy demands to maintain neuronal ion gradients and signal transduction, and also, to mediate neuronal health through the processes of mitochondrial calcium homeostasis, mitophagy, mitochondrial reactive oxygen species production and mitochondrial dynamics. Some of these processes have been independently implicated in the mechanism of neuronal loss in neurodegeneration. Moreover, it is increasingly recognised that these processes are interdependent and interact within the mitochondria to ensure proper neuronal function and survival.

Mitophagy contributes to alpha-tocopheryl succinate toxicity in GSNOR-deficient hepatocellular carcinoma

The denitrosylating enzyme S-nitrosoglutathione reductase (GSNOR), has been reported to control the selective degradation of mitochondria through mitophagy, by modulating the extent of nitric oxide-modified proteins (S-nitrosylation). The accumulation of S-nitrosylated proteins due to GSNOR downregulation is a feature of hepatocellular carcinoma, causing mitochondrial defects that sensitize these tumors to mitochondrial toxins, in particular to mitochondrial complex II inhibitor alpha-tocopheryl succinate (αTOS). However, it is not known if mitophagy defects contribute to GSNOR-deficient cancer cells sensitivity to αTOS, nor if mitophagy inhibition could be used as a common mechanism to sensitize liver cancers to this toxin. Here, we provide evidence that GSNOR-deficient cancer cells show defective mitophagy. Furthermore, we show that αTOS is a mitophagy inducer and that mitophagy defects of GSNOR-deficient liver cancer cells contribute to its toxicity. We finally prove that the inhibition of mitophagy by depletion of Parkin, a pivotal ubiquitin ligase targeting mitochondria for degradation, enhances αTOS toxicity, thus suggesting that this drug could be effective in treating mitophagy-defective tumors.