Biology subjects

Hanschmann, E.-M.

Publications and source records attributed to Hanschmann, E.-M..

3 recordsLinked to original sources

bioRxiv2021

GDAP1 loss of function inhibits the mitochondrial pyruvate dehydrogenase complex by altering the actin cytoskeleton

Charcot-Marie-Tooth (CMT) disease 4A is an autosomal-recessive polyneuropathy caused by mutations of ganglioside-induced differentiation-associated protein 1 (GDAP1), a putative glutathione transferase, which affects mitochondrial shape and alters cellular Ca2+ homeostasis. Here, we identify the underlying mechanism. We found that patient-derived motoneurons and GDAP1 knockdown SH-SY5Y cells display two phenotypes: more tubular mitochondria and a metabolism characterized by glutamine dependence and fewer cytosolic lipid droplets. GDAP1 interacts with the actin-depolymerizing protein Cofilin-1 in a redoxdependent manner, suggesting a role for actin signaling. Consistently, GDAP1 loss causes less F-actin close to mitochondria, which restricts mitochondrial localization of the fission factor dynamin-related protein 1, instigating tubularity. Changes in the actin cytoskeleton also disrupt mitochondria-ER contact sites. This results in lower mitochondrial Ca2+ levels and inhibition of the pyruvate dehydrogenase complex, explaining the metabolic changes upon GDAP1 loss of function. Together, these findings reconcile GDAP1-associated phenotypes and implicate disrupted actin signaling in CMT4A pathophysiology.

neuroscience↗

bioRxiv2020

Cofilin1 oxidation links oxidative distress to mitochondrial demise and neuronal cell death

Many cell death pathways, including apoptosis, regulated necrosis and ferroptosis are relevant for neuronal cell death and share common mechanisms such as the formation of reactive oxygen species (ROS). However, which molecular signaling pathways contribute to related pathologies and how they are interconnected remains elusive. Here, we present the role of cofilin1 in regulating mitochondrial functions and neuronal impairment. Cofilin1 deletion in neuronal HT22 cells exerted increased mitochondrial resilience, assessed by quantification of mitochondrial ROS production, mitochondrial membrane potential and ATP levels. HT22 cells deficient for cofilin1 exhibited a profound glycolytic shift to meet their energy demand in conditions of erastin and glutamate toxicity, whereas control cells were metabolically impaired and underwent ferroptosis and oxytosis, respectively. Further, cofilin1 was confirmed as a key player in glutamate-mediated excitotoxicity in primary cortical neurons isolated from cofilin1flx/flx, CaMKII-Cre knock-out mice. Mitochondrial respiration and cell viability were significantly preserved in cofilin1-/- primary neurons under conditions of excitotoxicity. Using isolated mitochondria and recombinant cofilin1, we provide a further link to toxicity-related mitochondrial impairment mediated by oxidized cofilin1. Wildtype cofilin1 directly affected the mitochondrial membrane potential, mitochondrial ROS accumulation and mitochondrial respiration. The detrimental impact of cofilin1 on mitochondria depends on oxidation of cysteine residues at positions 139 and 147. Our findings show that the actin-regulating protein cofilin1 acts as a redox sensor in oxidative cell death pathways of ferroptosis and oxytosis, and also promotes glutamate excitotoxicity. Oxidized cofilin1 links ROS accumulation to mitochondrial demise and neuronal cell death. Protective effects by cofilin1 inhibition are particularly attributed to preserved mitochondrial integrity and function. Thus, interfering with the oxidation and pathological activation of cofilin1 may offer an effective therapeutic strategy in neurodegenerative diseases.

neuroscience↗

bioRxiv2020

FeS-cluster coordination of vertebrate thioredoxins regulates suppression of hypoxia-induced factor 2α through iron regulatory protein 1

Iron-regulatory protein 1 (IRP1), a central regulator of iron metabolism in vertebrates, also affects cellular response to hypoxia. IRP1 binds to the iron-responsive element (IRE) in the mRNA encoding hypoxia-inducible factor (HIF) 2, thereby blocking the translation of the HIF2-mRNA, and allowing the transcriptional regulation of, e.g., erythropoiesis. Here, we characterize the oxidoreductase thioredoxin 1 (Trx1) as a new regulator of hypoxia signaling. Human and murine Trx1 complex iron-sulfur clusters using one of the active site cysteinyl residues and a vertebrate-specific additional cysteinyl residue outside the active site. FeS-Trx1 is inactive, activated apo-Trx1 reduces cysteinyl residues in the binding pocket of IRP1/apo-Aconitase 1, which allows IRP1 to bind IREs in regulated mRNAs. Therefore, translation of the HIF2 mRNA requires either sufficient iron supply or the lack of reducing power of the Trx system under iron-limiting conditions. FeS-Trx1 thus links both redox and iron homeostasis to hypoxia responses.

biochemistry↗