bims-midbra 2022-03-20 papers

Issue of 2022‒03‒20
two papers selected by
Ana Paula Mendonça
University of Padova

Toxicol Mech Methods. 2022 Mar 17. 1-13

Defective mitophagy and induction of apoptosis by the depleted levels of PINK1 and parkin in Pb and β-amyloid peptide induced toxicity.

Lakshmi Jaya Madhuri B, Neelima Ayyalasomayajula, Lokesh Murumulla, Prasanna Kumar Dixit, Challa Suresh.

Exposure to lead (Pb), an environmental pollutant, is closely associated with the development of neurodegenerative disorders through oxidative stress induction and alterations in mitochondrial function. Damaged mitochondria could be one of the reasons for the progression of Alzheimer's Disease (AD). Mitophagy is vital in keeping the cell healthy. To know its role in Pb-induced AD, we investigated the PINK1/parkin dependent pathway by studying specific mitophagy marker proteins such as PINK1 and parkin in differentiated SH-SY5Y cells. Our data have indicated a significant reduction in the levels of PINK1 and parkin in cells exposed to Pb and β-amyloid peptides, both Aβ (25-35) and Aβ (1-40) individually and in different combinations, resulting in defective mitophagy. Also, the study unravels the status of mitochondrial permeability transition pore (MPTP), mitochondrial mass, mitochondrial membrane potential (MMP) and mitochondrial ROS production in cells treated with individual and different combination of Pb and Aβ peptides. An increase in mitochondrial ROS production, enhanced MPTP opening, depolarization of membrane potential and reduced mitochondrial mass in the exposed groups were observed. Also, in the present study, we found that Pb and β-amyloid peptides could trigger apoptosis by activating the Bak protein, which releases the cytochrome c from mitochondria through MPTP that further activates the AIF (apoptosis inducing factor) and caspase-3 proteins in the cytosol. The above findings reveal the potential role of mechanisms like PINK1/parkin mediated mitophagy and dysfunctional mitochondria mediated apoptosis in Pb induced neurotoxicity.

Keywords: Alzheimer’s disease; Lead toxicity; Mitophagy; PINK1/parkin; apoptosis; β-Amyloid peptide

DOI: https://doi.org/10.1080/15376516.2022.2054749

Prog Neurobiol. 2022 Mar 11. pii: S0301-0082(22)00050-8. [Epub ahead of print]213 102264

Ultrastructural view of astrocyte arborization, astrocyte-astrocyte and astrocyte-synapse contacts, intracellular vesicle-like structures, and mitochondrial network.

The complexity of astrocyte morphology and syncytial coupling through gap junctions are crucial for astrocyte function in the brain. However, the ultrastructural details of astrocyte arborization and interactions between neighboring astrocytes remain unknown. While a prevailing view is that synapses selectively contact peripheral astrocyte processes, the precise spatial-location selectivity of synapses abutting astrocytes is unresolved. Additionally, knowing the location and quantity of vesicles and mitochondria are prerequisites to answer two emerging questions - whether astrocytes have a signaling role within the brain and whether astrocytes are highly metabolically active. Here, we provided structural context for these questions by tracing and 3D reconstructing three neighboring astrocytes using serial block-face scanning electron microscopy. Our reconstructions reveal a spongiform astrocytic morphology resulting from the abundance of reflexive and leaflet processes. At the interfaces, varying sizes of astrocyte-astrocyte contacts were identified. Inside an astrocyte domain, synapses contact the entire astrocyte, and synapse-astrocyte contacts increase from soma to terminal leaflets. In contrast to densely packed vesicles at synaptic boutons, vesicle-like structures were scant within astrocytes. Lastly, astrocytes contain dense mitochondrial networks with a mitochondrial volume ratio similar to that of neurites. Together, these ultrastructural details should expand our understanding of functional astrocyte-astrocyte and astrocyte-neuron interactions.

Keywords: Aldh1l1-eGFP; Astrocyte network; Mitochondria; Serial blockface scanning electron microscopy (SBF-SEM); Synapses; Synaptic-like microvesicles; Three-dimensional reconstruction

DOI: https://doi.org/10.1016/j.pneurobio.2022.102264