Biology subjects

Nazarko, T. Y.

Publications and source records attributed to Nazarko, T. Y..

3 recordsLinked to original sources

bioRxiv2025

Mdm38/LETM1 couples ion homeostasis and proteostatic mechanisms in the inner mitochondrial membrane

The mitochondrial inner membrane is among the most protein-dense cellular membranes. Its functional integrity is maintained through a concerted action of several conserved mechanisms that are far from clear. Here, using the bakers yeast model, we functionally characterize Mdm38/LETM1, a disease-related protein implicated in mitochondrial translation and ion homeostasis, although the molecular basis of these connections remains elusive. Our findings reveal a novel role for Mdm38 in maintaining protein homeostasis within the inner membrane. Specifically, we demonstrate that Mdm38 is required for mitochondrial iron homeostasis and for signaling iron bioavailability from mitochondria to vacuoles. These processes are linked to the m- AAA quality control protease, whose unrestrained activity disrupts the assembly and stability of respiratory chain complexes in Mdm38-deficient cells. Our study highlights the central role of Mdm38 in mitochondrial biology and reveals how it couples proteostatic mechanisms to ion homeostasis across subcellular compartments.

biochemistry↗

bioRxiv2022

A differential effect for tau isoforms and mutants in decreasing the stability of Arc

Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates of the microtubule associated protein tau, a main component of neurofibrillary tangles. Alzheimers disease (AD) is the most common type of tauopathy and dementia, with amyloid-beta pathology as an additional hallmark feature of the disease. Besides the role of tau in stabilizing microtubules, it is localized at postsynaptic sites and can disrupt synaptic plasticity when knocked out or overexpressed. The activity-regulated cytoskeleton-associated protein (Arc), is an immediate early gene that plays a key role in synaptic plasticity, learning and memory. Arc has been implicated in AD pathogenesis, where it was found to regulate activity-dependent release of amyloid-beta (A{beta}). Here we show that Arc protein is upregulated in the hippocampus of tau knockout (Tau KO) mice and in dendrites of Tau KO primary hippocampal neurons. Conversely, overexpression of tau decreased Arc stability exclusively in neuronal dendrites and was coupled to an increase in the expression of dendritic and somatic surface GluA1-containing -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. The Tau-dependent decrease in Arc was proteasome sensitive, yet independent of Arc ubiquitination and required the endophilin-binding domain of Arc, which is essential for promoting the endocytosis of AMPA receptors. Importantly, these effects on Arc stability and GluA1 localization were not observed in the commonly studied tau mutant, P301L. Our findings show a physiological role for tau in regulating Arc and implicate specific variants of tau in regulating Arc stability and AMPA receptor targeting, which may in part explain observed deficits in synaptic plasticity in select types of tauopathies.

neuroscience↗

bioRxiv2020

Nitrogen starvation and stationary phase lipophagy have distinct molecular mechanisms

In yeast, the selective autophagy of intracellular lipid droplets (LDs) or lipophagy can be induced by either nitrogen (N) starvation or carbon limitation (e.g. in the stationary (S) phase). We developed the yeast, Komagataella phaffii (formerly Pichia pastoris), as a new lipophagy model and compared the N-starvation and S-phase lipophagy in over 30 autophagy-related mutants using the Erg6-GFP processing assay. Surprisingly, two lipophagy pathways had hardly overlapping stringent molecular requirements. While the N-starvation lipophagy strictly depended on the core autophagic machinery (Atg1-Atg9, Atg18 and Vps15), vacuole fusion machinery (Vam7 and Ypt7) and vacuolar proteolysis (proteinases A and B), only Atg6 and proteinases A and B were essential for the S-phase lipophagy. The rest of the proteins were only partially required in the S-phase. Moreover, we isolated the prl1 (for positive regulator of lipophagy 1) mutant affected in the S-phase lipophagy but not N-starvation lipophagy. The prl1 defect was at a stage of delivery of the LDs from the cytoplasm to the vacuole further supporting mechanistically different nature of the two lipophagy pathways. Taken together, our results suggest that N-starvation and S-phase lipophagy have distinct molecular mechanisms.

cell biology↗