A5055915480- Mitochondrial Function and Pathology
- ATP Synthase and ATPases Research
- Autophagy in Disease and Therapy
- RNA Research and Splicing
- Endoplasmic Reticulum Stress and Disease
- Cancer, Hypoxia, and Metabolism
- Parkinson's Disease Mechanisms and Treatments
- RNA regulation and disease
- RNA modifications and cancer
- Adipose Tissue and Metabolism
- Nuclear Receptors and Signaling
- Biotin and Related Studies
- Redox biology and oxidative stress
- Neurological diseases and metabolism
- Cell death mechanisms and regulation
- Metalloenzymes and iron-sulfur proteins
- Ocular and Laser Science Research
- Dysphagia Assessment and Management
- Amyotrophic Lateral Sclerosis Research
- Protein Tyrosine Phosphatases
- Esophageal and GI Pathology
- Biomedical Text Mining and Ontologies
- Advanced Proteomics Techniques and Applications
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Trace Elements in Health
University of Pittsburgh
2019-2025
National Hospital Organization Takasaki Medical Center
2021
The University of Tokyo
2012-2020
National Institute of Neurological Disorders and Stroke
2017-2019
National Institutes of Health
2017-2018
Toxicologie, Pharmacologie et Signalisation Cellulaire
2015
Within the mitochondrial matrix, protein aggregation activates unfolded response and PINK1–Parkin-mediated mitophagy to mitigate proteotoxicity. We explore how autophagy eliminates aggregates from within mitochondria role of fission in mitophagy. show that PINK1 recruits Parkin onto subdomains after actinonin-induced proteotoxicity proximal focal misfolded mitochondrial-localized mutant ornithine transcarbamylase (ΔOTC). colocalizes on polarized harboring proteins foci with ubiquitin,...
Regulated intramembrane proteolysis is a widely conserved mechanism for controlling diverse biological processes. Considering that irreversible, it must be precisely regulated in context-dependent manner. Here, we show phosphoglycerate mutase 5 (PGAM5), mitochondrial Ser/Thr protein phosphatase, cleaved its N-terminal transmembrane domain response to membrane potential (ΔΨm) loss. This ΔΨm loss-dependent cleavage of PGAM5 was mediated by presenilin-associated rhomboid-like (PARL). PARL...
Abstract Dominant mutations in the mitochondrial paralogs coiled-helix-coiled-helix (CHCHD) domain 2 (C2) and CHCHD10 (C10) were recently identified as causing Parkinson’s disease amyotrophic lateral sclerosis/frontotemporal dementia/myopathy, respectively. The mechanism by which they disrupt cristae, however, has been uncertain. Using first C2/C10 double knockout (DKO) mice, we report that C10 pathogenesis normal function of are intimately linked. Similar to patients with mutations, found...
PINK1 is activated by autophosphorylation and forms a high-molecular-weight complex, thereby initiating the selective removal of damaged mitochondria autophagy. Other than translocase outer mitochondrial membrane complexes, members PINK1-containing protein complexes remain obscure. By mass spectrometric analysis co-immunoprecipitates, we identify inner TIM23 as component complex. downregulation decreases levels significantly delays autophosphorylation, indicating that promotes accumulation...
p38 mitogen-activated protein kinases (MAPKs) play important roles in various cellular stress responses, including cell death, which is roughly categorized into apoptosis and necrosis. Although signaling has been extensively studied, the molecular mechanisms of p38-mediated death are unclear. ASK1 a stress-responsive MAP3K that acts as an upstream kinase activated by stresses, such oxidative stress. Here, we show NR4A2, member NR4A nuclear receptor family, necrosis promoter downstream...
Summary Damaged mitochondria can be cleared from the cell by mitophagy, using a pathway formed recessive Parkinson’s disease genes PINK1 and Parkin. How mitochondrial damage is sensed PINK1-Parkin pathway, however, remains uncertain. Here, Parkin substrate-based reporter in genome-wide screens, we identified that diverse forms of converge on loss membrane potential (MMP) to activate PINK1. Consistently, MMP but not presequence translocase-associated motor (PAM) import provided essential...
To maintain cellular homeostasis, cells are equipped with precise systems that trigger the appropriate stress responses. Mitochondria not only provide energy but also integrate response signaling pathways, including those regulating cell death. Several lines of evidence suggest mitochondrial proteins function in this process, such as Bcl-2 family apoptosis and phosphoglycerate mutase member 5 (PGAM5) necroptosis, regulated by several kinases. It has been suggested phosphorylation-dependent...
The metabolite acetyl-coenzyme A (acetyl-CoA) serves as an essential element for a wide range of cellular functions including adenosine triphosphate (ATP) production, lipid synthesis, and protein acetylation. Intracellular acetyl-CoA concentrations are associated with nutrient availability, but the mechanisms by which cell responds to fluctuations in levels remain elusive. Here, we generate system selectively manipulate nucleo-cytoplasmic using clustered regularly interspaced short...
Phosphoglycerate mutase family member 5 (PGAM5) is a mitochondrial protein phosphatase that has been reported to be involved in various stress responses from quality control cell death. However, its roles vivo are largely unknown. Here, we show Pgam5-deficient mice resistant several metabolic insults. Under cold combined with fasting, better maintained body temperature than wild-type and showed an extended survival rate. Serum triglycerides lipid content brown adipose tissue (BAT), center of...
Protein biotinylation via chemical or enzymatic reactions is often coupled with streptavidin-based enrichment and on-bead digestion in numerous biological applications. However, the popular method faces major challenges of streptavidin contamination, overwhelming signals from endogenous biotinylated proteins, lost information on sites, limited sequence coverage enriched proteins. Here, we explored thiol-cleavable biotin as an alternative approach to elute proteins streptavidin-coated beads...
Accumulating evidence suggests that brown adipose tissue (BAT) is a potential therapeutic target for managing obesity and related diseases. PGAM family member 5, mitochondrial serine/threonine protein phosphatase (PGAM5), resides in the mitochondria regulates many biological processes, including cell death, mitophagy, immune responses. Because BAT mitochondria-rich tissue, we have hypothesized PGAM5 has physiological function BAT. We previously reported PGAM5-knockout (KO) mice are resistant...
Mitochondria evolved from endosymbiotic bacteria to become essential organelles of eukaryotic cells. The unique lipid composition and structure mitochondrial membranes are critical for the proper functioning mitochondria. However, stress responses that help maintain membrane integrity not well understood. One reason this lack insight is absence efficient tools specifically damage membranes. Here, through a compound screen, we found two bis-biguanide compounds, chlorhexidine alexidine,...
Background and Objectives: It is important to evaluate the swallowing function of patients with acute cerebral infarction. The effects nutritional intervention after an early assessment by a flexible endoscopic evaluation (FEES) were evaluated. Methods Study Design: This retrospective study included 274 who hospitalized for infarction underwent FEES between 2016 2018. within 48 h from admission divided into shorter hospital stay group (＜30 days) longer (≥30 days). A multivariate analysis was...
Systemic inflammatory response syndrome (SIRS) is a form of fatal acute inflammation for which there no effective treatment. Here, we revealed that the ablation Kelch domain containing 10 (KLHDC10), had originally identified as an activator Apoptosis Signal-regulating Kinase 1 (ASK1), protects mice against TNFα-induced SIRS. The disease development SIRS mainly divided into two stages. early stage characterized by systemic necroptosis, regulated necrosis mediated Receptor-interacting protein...
Summary The metabolite acetyl-CoA serves as an essential element for a wide range of cellular functions including ATP production, lipid synthesis and protein acetylation. Intracellular concentrations are associated with nutrient availability, but the mechanisms by which cell responds to fluctuations in levels remain elusive. Here, we generate system selectively manipulate nucleo-cytoplasmic using CRISPR-mediated gene editing acetate supplementation culture media. Using this quantitative...
Abstract Dominant mutations in the mitochondrial paralogs CHCHD2 (C2) and CHCHD10 (C10) were recently identified as causing Parkinson’s disease ALS/FTD/myopathy, respectively. Disruption of cristae has been observed mutant C10 patient tissues animal models, but mechanism for this disruption remains controversial. Additionally, knock-in (KI) mice reported to activate a integrated stress response (mt-ISR) develop cardiomyopathy not seen knockout (KO) mice, calling into question whether...
Summary The heme-regulated kinase HRI is activated under heme/iron deficient conditions; however, the underlying molecular mechanism incompletely understood. Here, we show that iron deficiency-induced activation involves a heme-independent requires mitochondrial protein DELE1. Notably, import of DELE1 and its subsequent stability are regulated by availability. Under steady state conditions, degraded matrix-resident protease LONP1 soon after import. Upon chelation, arrested, thereby...