scholarly journals Mitophagy Eliminates the Accumulation of SARM1 on the Mitochondria, Alleviating Programmed Axon Death in Acrylamide Neuropathy

2022 ◽  
Author(s):  
Shuai Wang ◽  
Hui Yong ◽  
Cuiqin Zhang ◽  
Kang Kang ◽  
Mingxue Song ◽  
...  
Keyword(s):  
Quality Control ◽  
Molecular Mechanisms ◽  
Interleukin 1 ◽  
Biological Significance ◽  
Control Mechanisms ◽  
Dependent Manner ◽  
Mitochondrial Network ◽  
Mitochondrial Localization ◽  
Mitochondrial Quality Control ◽  
Axon Loss

Abstract Sterile-α and toll/interleukin 1 receptor motif containing protein 1 (SARM1) is the central executioner of programmed axon death (Wallerian degeneration). Although it has been confirmed to have a mitochondrial targeting sequence and can bind to and stabilize PINK1 on mitochondria, the biological significance for mitochondrial localization of SARM1 is still unclear. The relationship between mitochondrial quality control mechanisms and programmed axon death also needs to be clarified. Chronic acrylamide (ACR) intoxication cause typical pathology of axon degeneration involving early axon loss. Here, we demonstrated that the SARM1 dependent Wallerian axon self-destruction pathway was activated following ACR intoxication. Moreover, increased SARM1 was observed on the mitochondria, which interfered with the mitochondrial quality control mechanisms. As a protective response to stress, mitochondrial components enriched in SARM1 were isolated from the mitochondrial network through an increased fission process and were degraded in an autophagy-dependent manner. Importantly, rapamycin (RAPA) administration eliminated mitochondrial accumulated SARM1 and inhibited axon loss. Thus, mitochondrial localization of SARM1 may be complement to the coordinated activity of NMNAT2 and SARM1, and may be part of the self-limiting molecular mechanisms of programmed axon death. In the early latent period, the mitochondrial localization of SARM1 will help it to be isolated by the mitochondrial network and to be degraded through mitophagy to maintain local axon homeostasis. When the mitochondrial quality control mechanisms are broken down, SARM1 will cause irreversible damage for axon death.

scholarly journals Mitophagy Eliminates the Accumulation of SARM1 on the Mitochondria, Alleviating Axon Degeneration in Acrylamide Neuropathy

2021 ◽  
Author(s):  
Shuai Wang ◽  
Hui Yong ◽  
Cuiqin Zhang ◽  
Kang Kang ◽  
Mingxue Song ◽  
...  
Keyword(s):  
Latent Period ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Interleukin 1 ◽  
Biological Significance ◽  
Axon Degeneration ◽  
Dependent Manner ◽  
Mitochondrial Localization ◽  
Irreversible Damage ◽  
Axon Damage

Abstract Background: Sterile-α and toll/interleukin 1 receptor motif containing protein 1 (SARM1) is the central executioner of axon degeneration. Although it has been confirmed to have a mitochondrial targeting sequence and can bind to and stabilize PINK1 on depolarized mitochondria, the biological significance for mitochondrial localization of SARM1 is still unclear. Chronic acrylamide (ACR) intoxication can cause typical pathology of axonal injury, owning the potential to explore the interaction between mitochondria and SARM1 during the latent period of axon destruction.Methods: The expression and the mitochondria distribution of SARM1 were evaluated in in vivo and in vitro ACR neuropathy models. Transmission electron microscopy, immunoblotting, and immunofluorescence were performed to evaluate mitochondrial dynamics and PINK1-dependent mitophagy. LC3 turnover experiment and live cell imaging were conducted to further assess the state of mitophagy flux. In order to verify the effect of mitophagy in SARM1-mediated axon degeneration, low-dose and low-frequency rapamycin was administered in ACR-exposed rats to increase basal autophagy.Results: In a time- and dose-dependent manner, ACR induced peripheral nerve injury in rats and truncated axons of differentiated N2a cell. Moreover, the severity of this axon damage was consistent with the up-regulation of SARM1. SARM1 prominently accumulated on mitochondria, and at the same time mitophagy was activated. Importantly, rapamycin (RAPA) administration eliminated mitochondrial accumulated SARM1 and alleviated SARM1 dependent axonal degeneration.Conclusions: Complementing to the coordinated activity of NMNAT2 and SARM1, mitochondrial localization of SARM1 may be part of the self-limiting molecular mechanisms of Wallerian axon destruction. In the early latent period of axon damage, the mitochondrial localization of SARM1 will help it to be isolated by the mitochondrial network and to be degraded through PINK1-dependent mitophagy to maintain local axon homeostasis. When the mitochondrial quality control mechanisms are broken down, SARM1 will cause irreversible damage for axon degeneration. Moderate autophagy activation can be invoked as potential strategies to alleviate axon degeneration in ACR neuropathy and even other axon degeneration diseases.

scholarly journals The Role of Mitochondrial Quality Control in Cardiac Ischemia/Reperfusion Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Jia Huang ◽  
Ruibing Li ◽  
Chengbin Wang
Keyword(s):  
Quality Control ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Heart Diseases ◽  
Ischemia Reperfusion ◽  
Cardiac Ischemia ◽  
Mitochondrial Morphology ◽  
Mitochondrial Network ◽  
Mitochondrial Quality Control

A healthy mitochondrial network produces a large amount of ATP and biosynthetic intermediates to provide sufficient energy for myocardium and maintain normal cell metabolism. Mitochondria form a dynamic and interconnected network involved in various cellular metabolic signaling pathways. As mitochondria are damaged, controlling mitochondrial quantity and quality is activated by changing their morphology and tube network structure, mitophagy, and biogenesis to replenish a healthy mitochondrial network to preserve cell function. There is no doubt that mitochondrial dysfunction has become a key factor in many diseases. Ischemia/reperfusion (IR) injury is a pathological manifestation of various heart diseases. Cardiac ischemia causes temporary tissue and organelle damage. Although reperfusion is essential to compensate for nutrient deficiency, blood flow restoration inconsequently further kills the previously ischemic cardiomyocytes. To date, dysfunctional mitochondria and disturbed mitochondrial quality control have been identified as critical IR injury mechanisms. Many researchers have detected abnormal mitochondrial morphology and mitophagy, as well as aberrant levels and activity of mitochondrial biogenesis factors in the IR injury model. Although mitochondrial damage is well-known in myocardial IR injury, the causal relationship between abnormal mitochondrial quality control and IR injury has not been established. This review briefly describes the molecular mechanisms of mitochondrial quality control, summarizes our current understanding of the complex role of mitochondrial quality control in IR injury, and finally speculates on the possibility of targeted control of mitochondria and the methods available to mitigate IR injury.

scholarly journals Adipocyte-Mineralocorticoid Receptor Alters Mitochondrial Quality Control Leading to Mitochondrial Dysfunction and Senescence of Visceral Adipose Tissue

2021 ◽  
Vol 22 (6) ◽  
pp. 2881
Author(s):  
Clara Lefranc ◽  
Malou Friederich-Persson ◽  
Fabienne Foufelle ◽  
Aurélie Nguyen Dinh Cat ◽  
Frédéric Jaisser
Keyword(s):  
Quality Control ◽  
Adipose Tissue ◽  
Mitochondrial Dysfunction ◽  
Cellular Senescence ◽  
Mineralocorticoid Receptor ◽  
Molecular Mechanisms ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Oxidative Stress ◽  
Specific Effects

Mineralocorticoid receptor (MR) expression is increased in the adipose tissue (AT) of obese patients and animals. We previously demonstrated that adipocyte-MR overexpression in mice (Adipo-MROE mice) is associated with metabolic alterations. Moreover, we showed that MR regulates mitochondrial dysfunction and cellular senescence in the visceral AT of obese db/db mice. Our hypothesis is that adipocyte-MR overactivation triggers mitochondrial dysfunction and cellular senescence, through increased mitochondrial oxidative stress (OS). Using the Adipo-MROE mice with conditional adipocyte-MR expression, we evaluated the specific effects of adipocyte-MR on global and mitochondrial OS, as well as on OS-induced damage. Mitochondrial function was assessed by high throughput respirometry. Molecular mechanisms were probed in AT focusing on mitochondrial quality control and senescence markers. Adipo-MROE mice exhibited increased mitochondrial OS and altered mitochondrial respiration, associated with reduced biogenesis and increased fission. This was associated with OS-induced DNA-damage and AT premature senescence. In conclusion, targeted adipocyte-MR overexpression leads to an imbalance in mitochondrial dynamics and regeneration, to mitochondrial dysfunction and to ageing in visceral AT. These data bring new insights into the MR-dependent AT dysfunction in obesity.

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 Mitochondrial quality control and neurological disease: an emerging connection

2010 ◽  
Vol 12 ◽  
Author(s):  
Inês Pimenta de Castro ◽  
L. Miguel Martins ◽  
Roberta Tufi
Keyword(s):  
Quality Control ◽  
Total Body Weight ◽  
High Rate ◽  
Control Mechanisms ◽  
Mitochondrial Quality Control ◽  
Stress Control ◽  
Energy Demands ◽  
Total Body ◽  
The Brain ◽  
Complex Organ

The human brain is a highly complex organ with remarkable energy demands. Although it represents only 2% of the total body weight, it accounts for 20% of all oxygen consumption, reflecting its high rate of metabolic activity. Mitochondria have a crucial role in the supply of energy to the brain. Consequently, their deterioration can have important detrimental consequences on the function and plasticity of neurons, and is thought to have a pivotal role in ageing and in the pathogenesis of several neurological disorders. Owing to their inherent physiological functions, mitochondria are subjected to particularly high levels of stress and have evolved specific molecular quality-control mechanisms to maintain the mitochondrial components. Here, we review some of the most recent advances in the understanding of mitochondrial stress-control pathways, with a particular focus on how defects in such pathways might contribute to neurodegenerative disease.

scholarly journals Mitophagy in Diabetic Cardiomyopathy: Roles and Mechanisms

2021 ◽  
Vol 9 ◽  
Author(s):  
Haoxiao Zheng ◽  
Hailan Zhu ◽  
Xinyue Liu ◽  
Xiaohui Huang ◽  
Anqing Huang ◽  
...  
Keyword(s):  
Quality Control ◽  
Diabetic Cardiomyopathy ◽  
Molecular Mechanisms ◽  
Myocardial Damage ◽  
Diabetic Heart ◽  
Substantial Contribution ◽  
Diabetic Patients ◽  
Mitochondrial Quality Control ◽  
Comprehensive Overview ◽  
Myocardial Insulin Resistance

Cardiovascular disease is the leading complication of diabetes mellitus (DM), and diabetic cardiomyopathy (DCM) is a major cause of mortality in diabetic patients. Multiple pathophysiologic mechanisms, including myocardial insulin resistance, oxidative stress and inflammation, are involved in the development of DCM. Recent studies have shown that mitochondrial dysfunction makes a substantial contribution to the development of DCM. Mitophagy is a type of autophagy that takes place in dysfunctional mitochondria, and it plays a key role in mitochondrial quality control. Although the precise molecular mechanisms of mitophagy in DCM have yet to be fully clarified, recent findings imply that mitophagy improves cardiac function in the diabetic heart. However, excessive mitophagy may exacerbate myocardial damage in patients with DCM. In this review, we aim to provide a comprehensive overview of mitochondrial quality control and the dual roles of mitophagy in DCM. We also propose that a balance between mitochondrial biogenesis and mitophagy is essential for the maintenance of cellular metabolism in the diabetic heart.

scholarly journals Polyamines as Quality Control Metabolites Operating at the Post-Transcriptional Level

Plants ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 109 ◽  
Author(s):  
Laetitia Poidevin ◽  
Dilek Unal ◽  
Borja Belda-Palazón ◽  
Alejandro Ferrando
Keyword(s):  
Quality Control ◽  
Molecular Mechanisms ◽  
Transcriptional Level ◽  
Control Mechanisms ◽  
Physiological Functions ◽  
Nonsense Mediated Decay ◽  
Stop Codons ◽  
Ribosome Stalling ◽  
Molecular Functions

Plant polyamines (PAs) have been assigned a large number of physiological functions with unknown molecular mechanisms in many cases. Among the most abundant and studied polyamines, two of them, namely spermidine (Spd) and thermospermine (Tspm), share some molecular functions related to quality control pathways for tightly regulated mRNAs at the level of translation. In this review, we focus on the roles of Tspm and Spd to facilitate the translation of mRNAs containing upstream ORFs (uORFs), premature stop codons, and ribosome stalling sequences that may block translation, thus preventing their degradation by quality control mechanisms such as the nonsense-mediated decay pathway and possible interactions with other mRNA quality surveillance pathways.

scholarly journals PGC-1α regulates mitochondrial properties beyond biogenesis with aging and exercise training

2019 ◽  
Vol 317 (3) ◽  
pp. E513-E525 ◽  
Author(s):  
Jens Frey Halling ◽  
Henrik Jessen ◽  
Jacob Nøhr-Meldgaard ◽  
Bjørg Thiellesen Buch ◽  
Natascha Masselkhi Christensen ◽  
...  
Keyword(s):  
Exercise Training ◽  
Network Structure ◽  
Molecular Mechanisms ◽  
Metabolic Diseases ◽  
Adenine Nucleotide ◽  
Dependent Manner ◽  
Mitochondrial Network ◽  
Inner Mitochondrial Membrane ◽  
Respiratory Capacity ◽  
Age Related

Impaired mitochondrial function has been implicated in the pathogenesis of age-associated metabolic diseases through regulation of cellular redox balance. Exercise training is known to promote mitochondrial biogenesis in part through induction of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). Recently, mitochondrial ADP sensitivity has been linked to reactive oxygen species (ROS) emission with potential impact on age-associated physiological outcomes, but the underlying molecular mechanisms remain unclear. Therefore, the present study investigated the effects of aging and exercise training on mitochondrial properties beyond biogenesis, including respiratory capacity, ADP sensitivity, ROS emission, and mitochondrial network structure, in myofibers from inducible muscle-specific PGC-1α-knockout mice and control mice. Aged mice displayed lower running endurance and mitochondrial respiratory capacity than young mice. This was associated with intermyofibrillar mitochondrial network fragmentation, diminished submaximal ADP-stimulated respiration, increased mitochondrial ROS emission, and oxidative stress. Exercise training reversed the decline in maximal respiratory capacity independent of PGC-1α, whereas exercise training rescued the age-related mitochondrial network fragmentation and the impaired submaximal ADP-stimulated respiration in a PGC-1α-dependent manner. Furthermore, lack of PGC-1α was associated with altered phosphorylation and carbonylation of the inner mitochondrial membrane ADP/ATP exchanger adenine nucleotide translocase 1. In conclusion, the present study provides evidence that PGC-1α regulates submaximal ADP-stimulated respiration, ROS emission, and mitochondrial network structure in mouse skeletal muscle during aging and exercise training.

Mitochondrial quality control in acute ischemic stroke

2021 ◽  
pp. 0271678X2110469
Author(s):  
Hong An ◽  
Bing Zhou ◽  
Xunming Ji
Keyword(s):  
Quality Control ◽  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Mitochondrial Fission ◽  
Neurovascular Unit ◽  
Control Mechanisms ◽  
Mitochondrial Quality Control ◽  
Regulatory Pathways ◽  
Mitochondrial Transfer ◽  
And Function

Mitochondria play a central role in the pathophysiological processes of acute ischemic stroke. Disruption of the cerebral blood flow during acute ischemic stroke interrupts oxygen and glucose delivery, leading to the dysfunction of mitochondrial oxidative phosphorylation and cellular bioenergetic stress. Cells can respond to such stress by activating mitochondrial quality control mechanisms, including the mitochondrial unfolded protein response, mitochondrial fission and fusion, mitophagy, mitochondrial biogenesis, and intercellular mitochondrial transfer. Collectively, these adaptive response strategies contribute to retaining the integrity and function of the mitochondrial network, thereby helping to recover the homeostasis of the neurovascular unit. In this review, we focus on mitochondrial quality control mechanisms occurring in acute ischemic stroke. A better understanding of how these regulatory pathways work in maintaining mitochondrial homeostasis will provide a rationale for developing innovative neuroprotectants when these mechanisms fail in acute ischemic stroke.

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