Biology subjects

Ignatenko, O.

Publications and source records attributed to Ignatenko, O..

3 recordsLinked to original sources

bioRxiv2023

Parkinson's genes orchestrate pyroptosis through selective trafficking of mtDNA to leaky lysosomes

Inflammation is an age-related factor that underlies numerous human disorders. A key driver of inflammation is the release of mitochondrial DNA (mtDNA), which binds and activates cytosolic sensors. This induces transcriptional responses and, ultimately, pyroptotic cell death. The main challenge has been to understand how mtDNA can cross the two mitochondrial membranes to access the cytosol. Through a genome-wide CRISPR knockout screen we identified a new pyroptotic pathway defined by mtDNA exit within mitochondrial-derived vesicles that are delivered to lysosomes. Critically, breach of lysosomes allows mtDNA to access cytosol, requiring multiple Parkinsons Disease-related proteins and Gasdermin pores, identified in the screen. These data place mitochondria-to-lysosome transport as a driver of pyroptosis and link multiple PD proteins along a common pathway. One sentence summaryParkinsons disease-related proteins regulate pyroptosis

cell biology↗

bioRxiv2023

Depletion of LONP2 unmasks differential requirements for peroxisomal function between cell types and in cholesterol metabolism.

Peroxisomes play a central role in tuning metabolic and signaling programs in a tissue- and cell type-specific manner. However, the mechanisms by which the status of peroxisomes is communicated and integrated into cellular signaling pathways is not yet understood. Herein, we report the cellular responses to acute peroxisomal proteotoxic stress upon silencing the peroxisomal protease/chaperone LONP2. Depletion of LONP2 triggered accumulation of its substrates, alterations in peroxisome size and numbers, and luminal protein import failure. Gene expression changes and lipidomic analysis revealed striking cell specific differences in the response to siLONP2. Specific to COS-7 cells was a strong activation of the integrated stress response (ISR) and upregulation of ribosomal biogenesis gene expression levels. Common changes between COS-7 and U2OS cell lines included repression of the retinoic acid signaling pathway, and upregulation of sphingolipids. Cholesterol accumulated in the endomembrane compartments in both cell lines, consistent with evidence that peroxisomes are required for cholesterol flux out of late endosomes. These unexpected consequences of peroxisomal stress provide an important insight for our understanding of the tissue-specific responses seen in peroxisomal disorders.

cell biology↗

bioRxiv2021

Mitochondrial dysfunction compromises ciliary homeostasis in astrocytes

Astrocytes, often considered as secondary responders to neurodegenerative processes, are emerging as primary drivers of brain disease. The underlying pathogenic mechanisms are, however, insufficiently understood. Here we show that pathogenesis of mitochondrial spongiotic encephalopathy, a severe manifestation of mitochondrial brain diseases, involves abnormal maintenance of the astrocytic primary cilium, a major signaling organelle of a cell. We show that progressive respiratory chain deficiency in astrocytes activates FOXJ1 and RFX transcription factors and master regulators of motile ciliogenesis. Consequently, a wide aberrant nuclear expression program with FOXJ1 and RFX target genes, encoding motile cilia components, is induced in astrocytes. While the affected astrocytes still retain a single cilium, these organelles elongate and become remarkably distorted. Multiciliated ventricle-lining ependymal cells show no overt cilia morphology defects despite similar mitochondrial dysfunction. We propose that the chronic activation of the integrated mitochondrial stress response (ISRmt), specifically induced in astrocytes, drives anabolic metabolism and promotes ciliary growth. Collectively, our evidence indicate that 1) an active signaling axis exists between astrocyte mitochondria and primary cilia; 2) ciliary signaling is part of ISRmt in astrocytes; 3) metabolic ciliopathy is a novel pathomechanism for mitochondria-related neurodegenerative diseases.

neuroscience↗