scholarly journals Culling sick mitochondria from the herd

2010 ◽  
Vol 191 (7) ◽  
pp. 1225-1227 ◽  
Author(s):  
Leo J. Pallanck
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Critical Role ◽  
Mitochondrial Fusion ◽  
Mitochondrial Quality Control ◽  
Endoplasmic Reticulum Associated Degradation ◽  
Cell Biol

The PINK1–Parkin pathway plays a critical role in mitochondrial quality control by selectively targeting damaged mitochondria for autophagy. In this issue, Tanaka et al. (2010. J. Cell Biol. doi: 10.1083/jcb.201007013) demonstrate that the AAA-type ATPase p97 acts downstream of PINK1 and Parkin to segregate fusion-incompetent mitochondria for turnover. p97 acts by targeting the mitochondrial fusion-promoting factor mitofusin for degradation through an endoplasmic reticulum–associated degradation (ERAD)-like mechanism.

scholarly journals Receptor-mediated mitophagy regulates EPO production and protects against renal anemia

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Guangfeng Geng ◽  
Jinhua Liu ◽  
Changlu Xu ◽  
Yandong yan Pei ◽  
Linbo Chen ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Quality Control ◽  
Therapeutic Strategy ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Renal Anemia ◽  
Inflammatory Factors ◽  
Oxygen Species ◽  
Mitochondrial Quality Control ◽  
Hematopoietic Disorders

Erythropoietin (EPO) drives erythropoiesis and is secreted mainly by the kidney upon hypoxic or anemic stress. The paucity of EPO production in renal EPO-producing cells (REPs) causes renal anemia, one of the most common complications of chronic nephropathies. Although mitochondrial dysfunction is commonly observed in several renal and hematopoietic disorders, the mechanism by which mitochondrial quality control impacts renal anemia remains elusive. In this study, we showed that FUNDC1, a mitophagy receptor, plays a critical role in EPO-driven erythropoiesis induced by stresses. Mechanistically, EPO production is impaired in REPs in Fundc1-/- mice upon stresses, and the impairment is caused by the accumulation of damaged mitochondria, which consequently leads to the elevation of the reactive oxygen species (ROS) level and triggers inflammatory responses by up-regulating proinflammatory cytokines. These inflammatory factors promote the myofibroblastic transformation of REPs, resulting in the reduction of EPO production. We therefore provide a link between aberrant mitophagy and deficient EPO generation in renal anemia. Our results also suggest that the mitochondrial quality control safeguards REPs under stresses, which may serve as a potential therapeutic strategy for the treatment of renal anemia.

scholarly journals Demonstration that endoplasmic reticulum-associated degradation of glycoproteins can occur downstream of processing by endomannosidase

2011 ◽  
Vol 438 (1) ◽  
pp. 133-142 ◽  
Author(s):  
Nikolay V. Kukushkin ◽  
Dominic S. Alonzi ◽  
Raymond A. Dwek ◽  
Terry D. Butters
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Chinese Hamster ◽  
Human Embryonic Kidney ◽  
Previous Evidence ◽  
Endoplasmic Reticulum Associated Degradation ◽  
Single Protein ◽  
Free Oligosaccharides ◽  
Intermediate Compartment ◽  
Functional Version

During quality control in the ER (endoplasmic reticulum), nascent glycoproteins are deglucosylated by ER glucosidases I and II. In the post-ER compartments, glycoprotein endo-α-mannosidase provides an alternative route for deglucosylation. Previous evidence suggests that endomannosidase non-selectively deglucosylates glycoproteins that escape quality control in the ER, facilitating secretion of aberrantly folded as well as normal glycoproteins. In the present study, we employed FOS (free oligosaccharides) released from degrading glycoproteins as biomarkers of ERAD (ER-associated degradation), allowing us to gain a global rather than single protein-centred view of ERAD. Glucosidase inhibition was used to discriminate between glucosidase- and endomannosidase-mediated ERAD pathways. Endomannosidase expression was manipulated in CHO (Chinese-hamster ovary)-K1 cells, naturally lacking a functional version of the enzyme, and HEK (human embryonic kidney)-293T cells. Endomannosidase was shown to decrease the levels of total FOS, suggesting decreased rates of ERAD. However, following pharmacological inhibition of ER glucosidases I and II, endomannosidase expression resulted in a partial switch between glucosylated FOS, released from ER-confined glycoproteins, to deglucosylated FOS, released from endomannosidase-processed glycoproteins transported from the Golgi/ERGIC (ER/Golgi intermediate compartment) to the ER. Using this approach, we have identified a previously unknown pathway of glycoprotein flow, undetectable by the commonly employed methods, in which secretory cargo is targeted back to the ER after being processed by endomannosidase.

scholarly journals Mieap forms membraneless organelles to compartmentalize and facilitate cardiolipin metabolism

2020 ◽  
Author(s):  
Naoki Ikari ◽  
Katsuko Honjo ◽  
Yoko Sagami ◽  
Yasuyuki Nakamura ◽  
Hirofumi Arakawa
Keyword(s):  
Quality Control ◽  
Critical Role ◽  
Enzymatic Reactions ◽  
Liquid Droplets ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Quality Control ◽  
Kidney Mitochondria ◽  
Intrinsically Disordered ◽  
Liver And Kidney ◽  
Inducible Protein

AbstractLiquid droplets function as membraneless organelles that compartmentalize and facilitate efficient biological reactions in cells. They are formed by proteins with an intrinsically disordered region(s) (IDR) via liquid–liquid phase separation. Mieap/SPATA18, a p53-inducible protein, plays a critical role in the suppression of human and murine colorectal tumors via mitochondrial quality control. However, the regulatory mechanism underlying this process remains unclear. Here, we report that Mieap is an IDR-containing protein that drives the formation of liquid droplets in the mitochondria. Mieap liquid droplets (MLDs) specifically phase separate the mitochondrial phospholipid cardiolipin. Lipidomic analysis of cardiolipin suggested that Mieap promotes enzymatic reactions involved in cardiolipin metabolism, including biosynthesis and remodeling. Accordingly, four cardiolipin biosynthesis enzymes, TAMM41, PGS1, PTPMT1, and CRLS1, and two remodeling enzymes, PLA2G6 and TAZ, are phase separated by MLDs. Mieap-deficient mice exhibited altered cristae structure in the liver and kidney mitochondria and a trend of obesity. These results suggest that Mieap drives the formation of membraneless organelles to compartmentalize and promotes cardiolipin metabolism at the inner mitochondrial membrane, thus playing a possible role in mitochondrial quality control.

scholarly journals Modulation of Mitochondrial Quality Control Processes by BGP-15 in Oxidative Stress Scenarios: From Cell Culture to Heart Failure

2021 ◽  
Vol 2021 ◽  
pp. 1-22
Author(s):  
Orsolya Horvath ◽  
Katalin Ordog ◽  
Kitti Bruszt ◽  
Nikoletta Kalman ◽  
Dominika Kovacs ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heart Failure ◽  
Hydrogen Peroxide ◽  
Quality Control ◽  
Mitochondrial Fusion ◽  
Neonatal Rat ◽  
Failure Model ◽  
Mitochondrial Quality Control ◽  
Insulin Sensitizer ◽  
Heart Failure Model

Heart failure (HF) is a complex chronic clinical disease characterized by among others the damage of the mitochondrial network. The disruption of the mitochondrial quality control and the imbalance in fusion-fission processes lead to a lack of energy supply and, finally, to cell death. BGP-15 (O-[3-piperidino-2-hydroxy-1-propyl]-nicotinic acid amidoxime dihydrochloride) is an insulin sensitizer molecule and has a cytoprotective effect in a wide variety of experimental models. In our recent work, we aimed to clarify the mitochondrial protective effects of BGP-15 in a hypertension-induced heart failure model and “in vitro.” Spontaneously hypertensive rats (SHRs) received BGP-15 or placebo for 18 weeks. BGP-15 treatment preserved the normal mitochondrial ultrastructure and enhanced the mitochondrial fusion. Neonatal rat cardiomyocytes (NRCMs) were stressed by hydrogen-peroxide. BGP-15 treatment inhibited the mitochondrial fission processes, promoted mitochondrial fusion, maintained the integrity of the mitochondrial genome, and moreover enhanced the de novo biogenesis of the mitochondria. As a result of these effects, BGP-15 treatment also supports the maintenance of mitochondrial function through the preservation of the mitochondrial structure during hydrogen peroxide-induced oxidative stress as well as in an “in vivo” heart failure model. It offers the possibility, which pharmacological modulation of mitochondrial quality control under oxidative stress could be a novel therapeutic approach in heart failure.

The roles of mitochondria-associated membranes in mitochondrial quality control under endoplasmic reticulum stress

Life Sciences ◽  
2019 ◽  
Vol 231 ◽  
pp. 116587 ◽  
Author(s):  
Beiwu Lan ◽  
Yichun He ◽  
Hongyu Sun ◽  
Xinzi Zheng ◽  
Yufei Gao ◽  
...  
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Endoplasmic Reticulum Stress ◽  
Mitochondrial Quality Control

scholarly journals Mitochondria-Associated Endoplasmic Reticulum Membranes (MAMs) and Their Prospective Roles in Kidney Disease

2020 ◽  
Vol 2020 ◽  
pp. 1-21
Author(s):  
Peng Gao ◽  
Wenxia Yang ◽  
Lin Sun
Keyword(s):  
Quality Control ◽  
Endoplasmic Reticulum ◽  
Kidney Disease ◽  
Er Stress ◽  
Future Research ◽  
Inflammasome Activation ◽  
Mitochondrial Quality Control ◽  
Downstream Signaling ◽  
Contact Sites ◽  
Progression Of Kidney Disease

Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) serve as essential hubs for interorganelle communication in eukaryotic cells and play multifunctional roles in various biological pathways. A defect in ER-mitochondria signaling or MAMs dysfunction has pleiotropic effects on a variety of intracellular events, which results in disturbances of the mitochondrial quality control system, Ca2+ dyshomeostasis, apoptosis, ER stress, and inflammasome activation, which all contribute to the onset and progression of kidney disease. Here, we review the structure and molecular compositions of MAMs as well as the experimental methods used to study these interorganellar contact sites. We will specifically summarize the downstream signaling pathways regulated by MAMs, mainly focusing on mitochondrial quality control, oxidative stress, ER-mitochondria Ca2+ crosstalk, apoptosis, inflammasome activation, and ER stress. Finally, we will discuss how alterations in MAMs integrity contribute to the pathogenesis of kidney disease and offer directions for future research.

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