scholarly journals O‐GlcNAc controls mitochondrial quality control mechanisms and mitochondrial stress response proteins

2021 ◽  
Vol 35 (S1) ◽  
Author(s):  
Ibtihal Alghusen ◽  
Heather Wilkins ◽  
Chad Slawson
Keyword(s):  
Quality Control ◽  
Stress Response ◽  
Control Mechanisms ◽  
Mitochondrial Quality Control ◽  
Mitochondrial Stress ◽  
Stress Response Proteins

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.

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.

scholarly journals Evolving and Expanding the Roles of Mitophagy as a Homeostatic and Pathogenic Process

2019 ◽  
Vol 99 (1) ◽  
pp. 853-892 ◽  
Author(s):  
Åsa B. Gustafsson ◽  
Gerald W. Dorn
Keyword(s):  
Quality Control ◽  
Tissue Homeostasis ◽  
Metabolic Reprogramming ◽  
Control Mechanisms ◽  
Mitochondrial Quality Control ◽  
Comprehensive Overview ◽  
The Past ◽  
Cellular Autophagy ◽  
Quantity Control ◽  
Pathogenic Process

The central functions fulfilled by mitochondria as both energy generators essential for tissue homeostasis and gateways to programmed apoptotic and necrotic cell death mandate tight control over the quality and quantity of these ubiquitous endosymbiotic organelles. Mitophagy, the targeted engulfment and destruction of mitochondria by the cellular autophagy apparatus, has conventionally been considered as the mechanism primarily responsible for mitochondrial quality control. However, our understanding of how, why, and under what specific conditions mitophagy is activated has grown tremendously over the past decade. Evidence is accumulating that nonmitophagic mitochondrial quality control mechanisms are more important to maintaining normal tissue homeostasis whereas mitophagy is an acute tissue stress response. Moreover, previously unrecognized mitophagic regulation of mitochondrial quantity control, metabolic reprogramming, and cell differentiation suggests that the mechanisms linking genetic or acquired defects in mitophagy to neurodegenerative and cardiovascular diseases or cancer are more complex than simple failure of normal mitochondrial quality control. Here, we provide a comprehensive overview of mitophagy in cellular homeostasis and disease and examine the most revolutionary concepts in these areas. In this context, we discuss evidence that atypical mitophagy and nonmitophagic pathways play central roles in mitochondrial quality control, functioning that was previously considered to be the primary domain of mitophagy.

scholarly journals Multitiered and Cooperative Surveillance of Mitochondrial Phosphatidylserine Decarboxylase 1

2017 ◽  
Vol 37 (17) ◽  
Author(s):  
Oluwaseun B. Ogunbona ◽  
Ouma Onguka ◽  
Elizabeth Calzada ◽  
Steven M. Claypool
Keyword(s):  
Quality Control ◽  
Heat Exposure ◽  
Mitochondrial Pathway ◽  
Temperature Sensitive ◽  
Intermembrane Space ◽  
Control Mechanisms ◽  
Inner Mitochondrial Membrane ◽  
Mitochondrial Quality Control ◽  
Inner Membrane ◽  
Α Subunit

ABSTRACT Phosphatidylserine decarboxylase 1 (Psd1p), an ancient enzyme that converts phosphatidylserine to phosphatidylethanolamine in the inner mitochondrial membrane, must undergo an autocatalytic self-processing event to gain activity. Autocatalysis severs the protein into a large membrane-anchored β subunit that noncovalently associates with the small α subunit on the intermembrane space side of the inner membrane. Here, we determined that a temperature sensitive (ts) PSD1 allele is autocatalytically impaired and that its fidelity is closely monitored throughout its life cycle by multiple mitochondrial quality control proteases. Interestingly, the proteases involved in resolving misfolded Psd1ts vary depending on its autocatalytic status. Specifically, the degradation of a Psd1ts precursor unable to undergo autocatalysis requires the unprecedented cooperative and sequential actions of two inner membrane proteases, Oma1p and Yme1p. In contrast, upon heat exposure postautocatalysis, Psd1ts β subunits accumulate in protein aggregates that are resolved by Yme1p acting alone, while the released α subunit is degraded in parallel by an unidentified protease. Importantly, the stability of endogenous Psd1p is also influenced by Yme1p. We conclude that Psd1p, the key enzyme required for the mitochondrial pathway of phosphatidylethanolamine production, is closely monitored at several levels and by multiple mitochondrial quality control mechanisms present in the intermembrane space.

scholarly journals Alternative Mitophagy Protects the Heart Against Obesity-Associated Cardiomyopathy

2021 ◽  
Author(s):  
Mingming Tong ◽  
Toshiro Saito ◽  
Peiyong Zhai ◽  
Shin-ichi Oka ◽  
Wataru Mizushima ◽  
...  
Keyword(s):  
Quality Control ◽  
Transcriptional Activation ◽  
Cardiac Dysfunction ◽  
Systolic Dysfunction ◽  
Chronic Phase ◽  
Normal Diet ◽  
Autophagic Flux ◽  
Control Mechanisms ◽  
Mitochondrial Quality Control ◽  
Obesity Cardiomyopathy

Rationale: Obesity-associated cardiomyopathy characterized by hypertrophy and mitochondrial dysfunction. Mitochondrial quality control mechanisms, including mitophagy, are essential for the maintenance of cardiac function in obesity-associated cardiomyopathy. However, autophagic flux peaks at around 6 weeks of high fat diet (HFD) consumption and declines thereafter. Objective: We investigated whether mitophagy is activated during the chronic phase of cardiomyopathy associated with obesity (obesity cardiomyopathy) after general autophagy is downregulated and, if so, what the underlying mechanism and the functional significance are. Methods and Results: Mice were fed either a normal diet (ND) or a HFD (60 kcal % fat). Mitophagy, evaluated using Mito-Keima, was increased after 3 weeks of HFD consumption and continued to increase after conventional mechanisms of autophagy were inactivated, at least until 24 weeks. HFD consumption time-dependently up-regulated both Ser555-phosphorylated Ulk1 and Rab9 in the mitochondrial fraction. Mitochondria were sequestrated by Rab9-positive ring-like structures in cardiomyocytes isolated from mice after 20 weeks of HFD consumption, consistent with the activation of alternative mitophagy. Increases in mitophagy induced by HFD consumption for 20 weeks were abolished in cardiac-specific ulk1 knockout mouse hearts, in which both diastolic and systolic dysfunction were exacerbated. Rab9 S179A knock-in mice, in which alternative mitophagy is selectively suppressed, exhibited impaired mitophagy and more severe cardiac dysfunction than control mice following HFD consumption for 20 weeks. Overexpression of Rab9 in the heart increased mitophagy and protected against cardiac dysfunction during HFD consumption. HFD-induced activation of Rab9-dependent mitophagy was accompanied by upregulation of TFE3, which plays an essential role in transcriptional activation of mitophagy. Conclusions: Ulk1-Rab9-dependent alternative mitophagy is activated during the chronic phase of HFD consumption and serves as an essential mitochondrial quality control mechanism, thereby protecting the heart against obesity cardiomyopathy.

Mitophagy, mitochondrial dynamics and the general stress response in yeast

2011 ◽  
Vol 39 (5) ◽  
pp. 1514-1519 ◽  
Author(s):  
Matthias Müller ◽  
Andreas S. Reichert
Keyword(s):  
Quality Control ◽  
Stress Response ◽  
Neurodegenerative Disorders ◽  
Mitochondrial Dynamics ◽  
Mitochondrial Fission ◽  
Nutrient Sensing ◽  
Control Mechanisms ◽  
General Stress Response ◽  
General Stress

Autophagy is a fundamental cellular process promoting survival under various environmental stress conditions. Selective types of autophagy have gained much interest recently as they are involved in specific quality control mechanisms removing, for example, aggregated proteins or dysfunctional mitochondria. This is considered to counteract the development of a number of neurodegenerative disorders and aging. Here we review the role of mitophagy and mitochondrial dynamics in ensuring quality control of mitochondria. In particular, we provide possible explanations why mitophagy in yeast, in contrast with the situation in mammals, was found to be independent of mitochondrial fission. We further discuss recent findings linking these processes to nutrient sensing pathways and the general stress response in yeast. In particular, we propose a model for how the stress response protein Whi2 and the Ras/PKA (protein kinase A) signalling pathway are possibly linked and thereby regulate mitophagy.

scholarly journals Mitochondrial Mechanisms Underlying Tolerance to Fluctuating Oxygen Conditions: Lessons from Hypoxia-Tolerant Organisms

2019 ◽  
Vol 59 (4) ◽  
pp. 938-952 ◽  
Author(s):  
Inna M Sokolova ◽  
Eugene P Sokolov ◽  
Fouzia Haider
Keyword(s):  
Quality Control ◽  
Metabolic Regulation ◽  
Hypoxia Inducible Factor ◽  
Hypoxia Tolerance ◽  
Control Mechanisms ◽  
Mitochondrial Quality Control ◽  
Severe Problem ◽  
Terrestrial Vertebrates ◽  
Tolerant Species ◽  
Tolerance To Hypoxia

Abstract Oxygen (O2) is essential for most metazoan life due to its central role in mitochondrial oxidative phosphorylation (OXPHOS), which generates >90% of the cellular adenosine triphosphate. O2 fluctuations are an ultimate mitochondrial stressor resulting in mitochondrial damage, energy deficiency, and cell death. This work provides an overview of the known and putative mechanisms involved in mitochondrial tolerance to fluctuating O2 conditions in hypoxia-tolerant organisms including aquatic and terrestrial vertebrates and invertebrates. Mechanisms of regulation of the mitochondrial OXPHOS and electron transport system (ETS) (including alternative oxidases), sulphide tolerance, regulation of redox status and mitochondrial quality control, and the potential role of hypoxia-inducible factor (HIF) in mitochondrial tolerance to hypoxia are discussed. Mitochondrial phenotypes of distantly related animal species reveal common features including conservation and/or anticipatory upregulation of ETS capacity, suppression of reactive oxygen species (ROS)-producing electron flux through ubiquinone, reversible suppression of OXPHOS activity, and investment into the mitochondrial quality control mechanisms. Despite the putative importance of oxidative stress in adaptations to hypoxia, establishing the link between hypoxia tolerance and mitochondrial redox mechanisms is complicated by the difficulties of establishing the species-specific concentration thresholds above which the damaging effects of ROS outweigh their potentially adaptive signaling function. The key gaps in our knowledge about the potential mechanisms of mitochondrial tolerance to hypoxia include regulation of mitochondrial biogenesis and fusion/fission dynamics, and HIF-dependent metabolic regulation that require further investigation in hypoxia-tolerant species. Future physiological, molecular and genetic studies of mitochondrial responses to hypoxia, and reoxygenation in phylogenetically diverse hypoxia-tolerant species could reveal novel solutions to the ubiquitous and metabolically severe problem of O2 deficiency and would have important implications for understanding the evolution of hypoxia tolerance and the potential mitigation of pathological states caused by O2 fluctuations.

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