Mitochondria–Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in <scp><i>PINK1</i>‐PD</scp> or <scp><i>PRKN</i>‐PD</scp> Neurons

Grossmann, Dajana; Malburg, Nina; Glaß, Hannes; Weeren, Veronika; Sondermann, Verena; Pfeiffer, Julia F.; Petters, Janine; Lukas, Jan; Seibler, Philip; Klein, Christine; Grünewald, Anne; Hermann, Andreas

doi:10.1002/mds.29525

Cited by 15 publications

(8 citation statements)

References 51 publications

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“…The differentiation protocol that we used in this study yielded a high percentage of motoneurons [ 20 , 22 , 23 ]. Since motoneurons are in the close vicinity of skeletal muscles and joints, by using an MN specific protocol we hoped to mimic a realistic scenario.…”

Section: Discussionmentioning

confidence: 99%

“…The human cell line used in this publication was published previously [ 20 ]. Fibroblasts originated from a healthy human female donor aged 48 at biopsy and were reprogrammed with standard Yamanaka factors (OCT4, KLF4, SOX2, and MYCC) delivered with the Sendai virus, as published [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

“…Fibroblasts originated from a healthy human female donor aged 48 at biopsy and were reprogrammed with standard Yamanaka factors (OCT4, KLF4, SOX2, and MYCC) delivered with the Sendai virus, as published [ 21 ]. Induced pluripotent stem cells (iPSC) were proliferated in mTESR1 (#85850, STEMCELL Technologies; Vancouver, BC, Canada) and characterized for pluripotency, trilineage differentiation, silencing of transgenes, and mycoplasm contamination [ 20 ]. The fully established iPSC lines were then converted to small molecule neuronal progenitor cells (smNPCs) using a previously published dual SMAD inhibition protocol [ 22 ].…”

Section: Methodsmentioning

confidence: 99%

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Corrosion Products from Metallic Implants Induce ROS and Cell Death in Human Motoneurons In Vitro

Glaß

Jonitz‐Heincke

Petters

et al. 2023

JFB

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Due to advances in surgical procedures and the biocompatibility of materials used in total joint replacement, more and younger patients are undergoing these procedures. Although state-of-the-art joint replacements can last 20 years or longer, wear and corrosion is still a major risk for implant failure, and patients with these implants are exposed for longer to these corrosive products. It is therefore important to investigate the potential effects on the whole organism. Released nanoparticles and ions derived from commonly used metal implants consist, among others, of cobalt, nickel, and chromium. The effect of these metallic products in the process of osteolysis and aseptic implant loosening has already been studied; however, the systemic effect on other cell types, including neurons, remains elusive. To this end, we used human iPSC-derived motoneurons to investigate the effects of metal ions on human neurons. We treated human motoneurons with ion concentrations regularly found in patients, stained them with MitoSOX and propidium iodide, and analyzed them with fluorescence-assisted cell sorting (FACS). We found that upon treatment human motoneurons suffered from the formation of ROS and subsequently died. These effects were most prominent in motoneurons treated with 500 μM of cobalt or nickel, in which we observed significant cell death, whereas chromium showed fewer ROS and no apparent impairment of motoneurons. Our results show that the wear and corrosive products of metal implants at concentrations readily available in peri-implant tissues induced ROS and subsequently cell death in an iPSC-derived motoneuron cell model. We therefore conclude that monitoring of neuronal impairment is important in patients undergoing total joint replacement.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Corrosion Products from Metallic Implants Induce ROS and Cell Death in Human Motoneurons In Vitro

Glaß

Jonitz‐Heincke

Petters

et al. 2023

JFB

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“…These changes encompass mitochondrial fragmentation, disruption of the mitochondrial membrane potential (∆Ψ m ), elevated levels of mitochondrial calcium ([Ca 2+ ] m ), and increased production of mitochondrial ROS [13,[16][17][18]. Calcium ions are essential for many cellular functions, such as regulating signaling pathways and initiating cell-death processes [19]. Alteration in cytosolic Ca 2+ levels can impact cell function and trigger cellular responses, such as ferroptosis induction [18,20].…”

Section: Introductionmentioning

confidence: 99%

“…The mitochondrial calcium uniporter (MCU) serves as the main entry point of Ca 2+ into the mitochondrial matrix. This important function makes MCU crucial for regulating the mitochondrial calcium level in cells [19,21]. Inhibition of the MCU with, e.g., Ru265, a modified ruthenium compound, is known to exhibit potential neuroprotective effects against hypoxic/ischemic (HI) brain injury.…”

Section: Introductionmentioning

confidence: 99%

Increased Vulnerability to Ferroptosis in FUS-ALS

Ismail,

Großmann,

Hermann

2024

Biology

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Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxide accumulation, plays a pivotal role in various pathological conditions, including neurodegenerative diseases. While reasonable evidence for ferroptosis exists, e.g., in Parkinson’s disease or Alzheimer’s disease, there are only a few reports on amyotrophic lateral sclerosis (ALS), a fast progressive and incurable neurodegenerative disease characterized by progressive motor neuron degeneration. Interestingly, initial studies have suggested that ferroptosis might be significantly involved in ALS. Key features of ferroptosis include oxidative stress, glutathione depletion, and alterations in mitochondrial morphology and function, mediated by proteins such as GPX4, xCT, ACSL4 FSP1, Nrf2, and TfR1. Induction of ferroptosis involves small molecule compounds like erastin and RSL3, which disrupt system Xc− and GPX4 activity, respectively, resulting in lipid peroxidation and cellular demise. Mutations in fused in sarcoma (FUS) are associated with familial ALS. Pathophysiological hallmarks of FUS-ALS involve mitochondrial dysfunction and oxidative damage, implicating ferroptosis as a putative cell-death pathway in motor neuron demise. However, a mechanistic understanding of ferroptosis in ALS, particularly FUS-ALS, remains limited. Here, we investigated the vulnerability to ferroptosis in FUS-ALS cell models, revealing mitochondrial disturbances and increased susceptibility to ferroptosis in cells harboring ALS-causing FUS mutations. This was accompanied by an altered expression of ferroptosis-associated proteins, particularly by a reduction in xCT expression, leading to cellular imbalance in the redox system and increased lipid peroxidation. Iron chelation with deferoxamine, as well as inhibition of the mitochondrial calcium uniporter (MCU), significantly alleviated ferroptotic cell death and lipid peroxidation. These findings suggest a link between ferroptosis and FUS-ALS, offering potential new therapeutic targets.

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Analysis of dopaminergic neuron-specific mitochondrial morphology and function using tyrosine hydroxylase reporter iPSC lines

Yokota

2024

Anat Sci Int

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Mitochondria–Endoplasmic Reticulum Contact Sites Dynamics and Calcium Homeostasis Are Differentially Disrupted in PINK1‐PD or PRKN‐PD Neurons

Cited by 15 publications

References 51 publications

Corrosion Products from Metallic Implants Induce ROS and Cell Death in Human Motoneurons In Vitro

Corrosion Products from Metallic Implants Induce ROS and Cell Death in Human Motoneurons In Vitro

Increased Vulnerability to Ferroptosis in FUS-ALS

Analysis of dopaminergic neuron-specific mitochondrial morphology and function using tyrosine hydroxylase reporter iPSC lines

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