scholarly journals NECAB2 orchestrates an endosomal pathway of mitochondrial quality control at striatal synapses

2021 ◽  
Author(s):  
Partha Narayan Dey ◽  
Diones Bueno ◽  
Teresa Schacht ◽  
Christina Wolf ◽  
Verena Wüllner ◽  
...  
Keyword(s):  
Quality Control ◽  
Calcium Binding ◽  
Synaptic Function ◽  
Mitochondrial Quality Control ◽  
Escrt Machinery ◽  
Early Endosomes ◽  
Mitochondrial Efficiency ◽  
Endosomal Pathway ◽  
Striatal Function ◽  
Deficient Mice

SummarySynaptic signaling depends on ATP generated by mitochondria. Due to extensive connectivity, the striatum is especially vulnerable to mitochondrial dysfunction and thus requires efficient mitochondrial quality control. We found that the neuronal calcium-binding protein NECAB2 ensures synaptic function in the striatum by increasing mitochondrial efficiency. NECAB2 associates with early endosomes and mitochondria at striatal synapses. Loss of NECAB2 dysregulates proteins of the endosomal ESCRT machinery and oxidative phosphorylation. Mitochondria from NECAB2-deficient mice are more abundant but less efficient. These mitochondria exhibit increased respiration and superoxide production but produce less ATP. This accumulation of faulty mitochondria is caused by a defective assembly of mitochondria with early endosomes in response to oxidative stress. Impairment of this mechanism causes loss of striatal synapses and behavioral dysfunctions such as reduced motivation and altered sensory gating. NECAB2 therefore orchestrates an endosomal pathway of mitochondrial quality control important for striatal function.

scholarly journals Epithelial Ablation of Miro1/Rhot1 GTPase Leads to Mitochondrial Dysfunction and Lung Inflammation by Cigarette Smoke

2021 ◽  
Author(s):  
Shikha Sharma ◽  
Qixin Wang ◽  
Thivanka Muthumalage ◽  
Irfan Rahman
Keyword(s):  
Quality Control ◽  
Mitochondrial Dysfunction ◽  
Cigarette Smoke ◽  
Calcium Binding ◽  
Lung Inflammation ◽  
Inflammatory Cells ◽  
Mouse Lung ◽  
Control Mechanisms ◽  
Histopathological Changes ◽  
Mitochondrial Quality Control

Cigarette smoke (CS) exposure results in lung damage and inflammation through mitochondrial dysfunction. Mitochondria quality control is sustained by Miro1 (Rhot1), a calcium-binding membrane-anchored GTPase by its interaction with PINK1/Parkin during mitophagy. However, the exact mechanism that operates this interaction of mitophagy machinery in Miro1 degradation and CS-induced mitochondrial dysfunction that results in lung inflammation remains unclear. We hypothesized that mitochondrial Miro1 plays an important role in regulating mitophagy machinery and resulting lung inflammation by CS in mouse lung. We showed a role of Miro1 in CS-induced mitochondrial dysfunction and quality control mechanisms. The Rhot1Fl/Fl (WT) and lung epithelial cell-specific Rhot1 KO were exposed to mainstream CS for 3 days (acute) and 4 months (chronic). The cellular infiltration, cytokines, and lung histopathology were studied for the inflammatory response in the lungs. Acute CS exposure showed a notable increase in the total inflammatory cells, macrophages, and neutrophils associated with inflammatory mediators and Miro1 associated mitochondrial quality control proteins Parkin and OPA1. Chronic exposure showed an increase infiltration of total inflammatory cells and neutrophils versus air controls. Histopathological changes, such as pulmonary macrophages and neutrophils were increased in CS exposed mice. The epithelial Miro1 ablation led to augmentation of inflammatory cell infiltration with alteration in the levels of pro-inflammatory cytokines and histopathological changes. Thus, CS induces disruption of mitochondrial quality control mechanisms, and Rhot1/Miro1 mediates the process of CS-induced mitochondrial dysfunction ensuing lung inflammatory responses.

scholarly journals Epithelial Ablation of Miro1/Rhot1 GTPase Augments Lung Inflammation by Cigarette Smoke

2021 ◽  
Vol 28 (4) ◽  
pp. 501-512
Author(s):  
Shikha Sharma ◽  
Qixin Wang ◽  
Thivanka Muthumalage ◽  
Irfan Rahman
Keyword(s):  
Quality Control ◽  
Cigarette Smoke ◽  
Inflammatory Mediators ◽  
Calcium Binding ◽  
Lung Inflammation ◽  
Inflammatory Responses ◽  
Inflammatory Cells ◽  
Mitochondrial Quality Control ◽  
Lung Epithelial ◽  
Notable Increase

Mitochondrial quality control is sustained by Miro1 (Rhot1), a calcium-binding membrane-anchored GTPase during mitophagy. The exact mechanism that operates the interaction of Miro1 with mitophagy machinery and their role in cigarette smoke (CS)-induced mitochondrial dysfunction that often results in lung inflammation is unclear. We hypothesized that Miro1 plays an important role in regulating mitophagy machinery and the resulting lung inflammation by CS exposure to mice. The lung epithelial Rhot1fl/fl (WT) and Rhot1CreCC10 mice were exposed to mainstream CS for 3 days (acute) and 4 months (chronic). Acute CS exposure showed a notable increase in the total inflammatory cells, macrophages, and neutrophils that are associated with inflammatory mediators. Chronic exposure showed increased infiltration of neutrophils versus air controls. The effects of acute and chronic CS exposure were augmented in the Rhot1CreCC10 group, indicating that epithelial Miro1 ablation led to the augmentation of inflammatory cell infiltration with alteration in the inflammatory mediators. Thus, Rhot1/Miro1 plays an important role in regulating CS-induced lung inflammatory responses with implications in mitochondrial quality control.

scholarly journals Epithelial Ablation of Miro1/Rhot1 GTPase Leads to Mitochondrial Dysfunction and Lung Inflammation by Cigarette Smoke

2021 ◽  
Author(s):  
Shikha Sharma ◽  
Qixin Wang ◽  
Thivanka Muthumalage ◽  
Irfan Rahman
Keyword(s):  
Quality Control ◽  
Mitochondrial Dysfunction ◽  
Cigarette Smoke ◽  
Calcium Binding ◽  
Lung Inflammation ◽  
Inflammatory Cells ◽  
Mouse Lung ◽  
Control Mechanisms ◽  
Histopathological Changes ◽  
Mitochondrial Quality Control

Cigarette smoke (CS) exposure results in lung damage and inflammation through mitochondrial dysfunction. Mitochondria quality control is sustained by Miro1 (Rhot1), a calcium-binding membrane-anchored GTPase by its interaction with PINK1/Parkin during mitophagy. However, the exact mechanism that operates this interaction of mitophagy machinery in Miro1 degradation and CS-induced mitochondrial dysfunction that results in lung inflammation remains unclear. We hypothesized that mitochondrial Miro1 plays an important role in regulating mitophagy machinery and resulting lung inflammation by CS in mouse lung. We showed a role of Miro1 in CS-induced mitochondrial dysfunction and quality control mechanisms. The Rhot1Fl/Fl (WT) and lung epithelial cell-specific Rhot1 KO were exposed to mainstream CS for 3 days (acute) and 4 months (chronic). The cellular infiltration, cytokines, and lung histopathology were studied for the inflammatory response in the lungs. Acute CS exposure showed a notable increase in the total inflammatory cells, macrophages, and neutrophils associated with inflammatory mediators and Miro1 associated mitochondrial quality control proteins Parkin and OPA1. Chronic exposure showed an increase infiltration of total inflammatory cells and neutrophils versus air controls. Histopathological changes, such as pulmonary macrophages and neutrophils were increased in CS exposed mice. The epithelial Miro1 ablation led to augmentation of inflammatory cell infiltration with alteration in the levels of pro-inflammatory cytokines and histopathological changes. Thus, CS induces disruption of mitochondrial quality control mechanisms, and Rhot1/Miro1 mediates the process of CS-induced mitochondrial dysfunction ensuing lung inflammatory responses.

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

2021 ◽  
Author(s):  
Naoki Ikari ◽  
Katsuko Honjo ◽  
Yoko Sagami ◽  
Yasuyuki Nakamura ◽  
Hirofumi Arakawa
Keyword(s):  
Quality Control ◽  
Enzymatic Reactions ◽  
Liquid Droplets ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Quality Control ◽  
Intrinsically Disordered ◽  
Intrinsically Disordered Regions ◽  
Inducible Protein ◽  
Deficient Mice ◽  
Liquid Liquid Phase Separation

Abstract Liquid droplets function as membraneless organelles that compartmentalize and facilitate efficient biological reactions. They are formed by proteins with intrinsically disordered regions (IDRs) via liquid–liquid phase separation. Mieap/SPATA18, a p53-inducible protein, participates in suppression of colorectal tumors by promoting mitochondrial quality control. However, the regulatory mechanism involved remains unclear. Here, we report that Mieap is an IDR-containing protein that drives formation of liquid droplets in mitochondria. Mieap liquid droplets specifically phase separate the mitochondrial phospholipid, cardiolipin. Lipidomic analysis of cardiolipin suggests that Mieap promotes enzymatic reactions involved in cardiolipin metabolism, including biosynthesis and remodeling. Accordingly, four cardiolipin biosynthetic enzymes, TAMM41, PGS1, PTPMT1, and CRLS1, and two remodeling enzymes, PLA2G6 and TAZ, are phase-separated by Mieap liquid droplets. Mieap-deficient mice exhibit altered crista structure in mitochondria of various tissues, including brown fat, and tend to become obese. These results suggest that Mieap drives formation of membraneless organelles to compartmentalize and promote cardiolipin metabolism at the inner mitochondrial membrane, thus potentially contributing to mitochondrial quality control.

scholarly journals PI3K/Akt pathway-mediated HO-1 induction regulates mitochondrial quality control and attenuates endotoxin-induced acute lung injury

2019 ◽  
Vol 99 (12) ◽  
pp. 1795-1809 ◽  
Author(s):  
Jia Shi ◽  
Jianbo Yu ◽  
Yuan Zhang ◽  
Lili Wu ◽  
Shuan Dong ◽  
...  
Keyword(s):  
Quality Control ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Akt Pathway ◽  
Mitochondrial Quality Control

scholarly journals PINK1: A Bridge between Mitochondria and Parkinson’s Disease

Life ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 371
Author(s):  
Filipa Barroso Gonçalves ◽  
Vanessa Alexandra Morais
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Quality Control ◽  
High Energy ◽  
Common Denominator ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Homeostasis ◽  
Cellular Environment ◽  
Familial Form ◽  
Mitochondrial Functions

Mitochondria are known as highly dynamic organelles essential for energy production. Intriguingly, in the recent years, mitochondria have revealed the ability to maintain cell homeostasis and ultimately regulate cell fate. This regulation is achieved by evoking mitochondrial quality control pathways that are capable of sensing the overall status of the cellular environment. In a first instance, actions to maintain a robust pool of mitochondria take place; however, if unsuccessful, measures that lead to overall cell death occur. One of the central key players of these mitochondrial quality control pathways is PINK1 (PTEN-induce putative kinase), a mitochondrial targeted kinase. PINK1 is known to interact with several substrates to regulate mitochondrial functions, and not only is responsible for triggering mitochondrial clearance via mitophagy, but also participates in maintenance of mitochondrial functions and homeostasis, under healthy conditions. Moreover, PINK1 has been associated with the familial form of Parkinson’s disease (PD). Growing evidence has strongly linked mitochondrial homeostasis to the central nervous system (CNS), a system that is replenished with high energy demanding long-lasting neuronal cells. Moreover, sporadic cases of PD have also revealed mitochondrial impairments. Thus, one could speculate that mitochondrial homeostasis is the common denominator in these two forms of the disease, and PINK1 may play a central role in maintaining mitochondrial homeostasis. In this review, we will discuss the role of PINK1 in the mitochondrial physiology and scrutinize its role in the cascade of PD pathology.

Mitocytosis, a migrasome-mediated mitochondrial quality-control process

Cell ◽  
2021 ◽  
Vol 184 (11) ◽  
pp. 2896-2910.e13
Author(s):  
Haifeng Jiao ◽  
Dong Jiang ◽  
Xiaoyu Hu ◽  
Wanqing Du ◽  
Liangliang Ji ◽  
...  
Keyword(s):  
Quality Control ◽  
Control Process ◽  
Mitochondrial Quality Control ◽  
Quality Control Process

scholarly journals At the heart of mitochondrial quality control: many roads to the top

2021 ◽  
Author(s):  
Roberta A. Gottlieb ◽  
Honit Piplani ◽  
Jon Sin ◽  
Savannah Sawaged ◽  
Syed M. Hamid ◽  
...  
Keyword(s):  
Quality Control ◽  
Unfolded Protein Response ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Quality Control ◽  
Unfolded Protein ◽  
Selective Elimination ◽  
Protein Response ◽  
Mitochondrial Unfolded Protein Response

AbstractMitochondrial quality control depends upon selective elimination of damaged mitochondria, replacement by mitochondrial biogenesis, redistribution of mitochondrial components across the network by fusion, and segregation of damaged mitochondria by fission prior to mitophagy. In this review, we focus on mitochondrial dynamics (fusion/fission), mitophagy, and other mechanisms supporting mitochondrial quality control including maintenance of mtDNA and the mitochondrial unfolded protein response, particularly in the context of the heart.

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