Vitko, D. | bioRxiv Science

bioRxiv2023

Integrated omics analysis unveils a DNA damage response to neurogenic injury

Spinal cord injury (SCI) evokes profound bladder dysfunction. Current treatments are limited by a lack of molecular data to inform novel therapeutic avenues. Previously, we showed systemic inosine treatment improved bladder function following SCI in rats. Here, we applied multi-omics analysis to explore molecular alterations in the bladder and their sensitivity to inosine following SCI. Canonical pathways regulated by SCI included those associated with protein synthesis, neuroplasticity, wound healing, and neurotransmitter degradation. Upstream regulator analysis identified MYC as a key regulator, whereas causal network analysis predicted multiple regulators of DNA damage response signaling following injury, including PARP-1. Staining for both DNA damage ({gamma}H2AX) and PARP activity (poly-ADP-ribose) markers in the bladder was increased following SCI, and attenuated in inosine-treated tissues. Proteomics analysis suggested that SCI induced changes in protein synthesis-, neuroplasticity-, and oxidative stress-associated pathways, a subset of which were shown in transcriptomics data to be inosine-sensitive. These findings provide novel insights into the molecular landscape of the bladder following SCI, and highlight a potential role for PARP inhibition to treat neurogenic bladder dysfunction. Synopsis O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=100 SRC="FIGDIR/small/571015v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@7c3e79org.highwire.dtl.DTLVardef@e998f5org.highwire.dtl.DTLVardef@38fd4aorg.highwire.dtl.DTLVardef@17d3aba_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIEmployed a multi-omics approach, integrating both transcriptomic and proteomic analyses, to investigate the molecular response in a rat model of spinal cord injury (SCI) and the therapeutic effect of inosine. C_LIO_LIDiscovered multiple regulators of the DNA damage response, including PARP-1, using causal network analysis. C_LIO_LIObserved decreased markers of DNA damage and PARP activity in inosine-treated tissues, indicating the therapeutic potential of inosine in neurogenic dysfunction. C_LIO_LIIdentified significant alterations in molecular pathways associated with protein synthesis, neuroplasticity, wound healing, and neurotransmitter degradation after SCI, and their modulation by inosine, highlighting its neuroprotective effects beyond DNA damage repair. C_LI

cell biology↗

bioRxiv2021

MICS1 is the Ca2+ /H+ antiporter of mammalian mitochondria

Mitochondrial Ca2+ ions are crucial regulators of bioenergetics, cell death pathways and cytosolic Ca2+ homeostasis. Mitochondrial Ca2+ content strictly depends on Ca2+ transporters. In recent decades, the major players responsible for mitochondrial Ca2+ uptake and release have been identified, except the mitochondrial Ca2+/H+ exchanger (CHE). Originally identified as the mitochondrial K+/H+ exchanger, LETM1 was also considered as a candidate for the mitochondrial CHE. Defining the mitochondrial interactome of LETM1, we identified MICS1, the only mitochondrial member of the TMBIM family. Applying cell-based and cell-free biochemical assays, here we demonstrate that MICS1 is responsible for the Na+- and permeability transition pore-independent mitochondrial Ca2+ release and identify MICS1 as the long-sought mitochondrial CHE. This finding provides the final piece of the puzzle of mitochondrial Ca2+ transporters and opens the door to exploring its importance in health and disease, and to developing drugs modulating Ca2+ exchange.

biochemistry↗

bioRxiv2019

Ifnar1 signaling breaks the hepatic urea cycle to regulate adaptive immunity

Infections induce complex host responses linked to antiviral defense, inflammation and tissue damage and repair. These processes are increasingly understood to involve systemic metabolic reprogramming. We hypothesized that the liver as a central metabolic hub may orchestrate many of these changes during infection. Thus, we investigated the systemic interplay between inflammation and metabolism in a mouse model of chronic viral infection and hepatitis. Here we show that virus-induced type I interferon (IFN-I) modulates wide-spread metabolic alterations of the liver in a hepatocyte-intrinsic Ifnar1-dependent way. Specifically, IFN-I repressed the transcription of numerous genes with metabolic function including Otc and Ass1, which encode enzymes of the urea cycle. This led to decreased arginine and increased ornithine concentrations in the circulation, resulting in suppressed virus-specific CD8 T cell responses and ameliorated liver pathology. These findings establish IFN-I-induced modulation of hepatic metabolism and the urea cycle as an endogenous mechanism of immunoregulation.

immunology↗