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

10.20944/preprints202108.0220.v1 ◽

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.

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

Pathophysiology ◽

10.3390/pathophysiology28040033 ◽

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.

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

International Journal of Molecular Sciences ◽

10.3390/ijms22062881 ◽

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.

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

The FASEB Journal ◽

10.1096/fasebj.2021.35.s1.03479 ◽

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

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Mitochondrial quality control and neurological disease: an emerging connection

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399410001456 ◽

2010 ◽

Vol 12 ◽

Cited By ~ 57

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.

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Inter-Organelle Membrane Contact Sites and Mitochondrial Quality Control during Aging: A Geroscience View

Cells ◽

10.3390/cells9030598 ◽

2020 ◽

Vol 9 (3) ◽

pp. 598 ◽

Cited By ~ 9

Author(s):

Anna Picca ◽

Riccardo Calvani ◽

Hélio José Coelho-Junior ◽

Francesco Landi ◽

Roberto Bernabei ◽

...

Keyword(s):

Quality Control ◽

Mitochondrial Dysfunction ◽

Mitochondrial Dynamics ◽

Mitochondrial Quality Control ◽

Membrane Contact Sites ◽

Contact Sites ◽

Age Related ◽

Bidirectional Communication ◽

Membrane Contact ◽

Organelle Membrane

Mitochondrial dysfunction and failing mitochondrial quality control (MQC) are major determinants of aging. Far from being standalone organelles, mitochondria are intricately related with cellular other compartments, including lysosomes. The intimate relationship between mitochondria and lysosomes is reflected by the fact that lysosomal degradation of dysfunctional mitochondria is the final step of mitophagy. Inter-organelle membrane contact sites also allow bidirectional communication between mitochondria and lysosomes as part of nondegradative pathways. This interaction establishes a functional unit that regulates metabolic signaling, mitochondrial dynamics, and, hence, MQC. Contacts of mitochondria with the endoplasmic reticulum (ER) have also been described. ER-mitochondrial interactions are relevant to Ca2+ homeostasis, transfer of phospholipid precursors to mitochondria, and integration of apoptotic signaling. Many proteins involved in mitochondrial contact sites with other organelles also participate to degradative MQC pathways. Hence, a comprehensive assessment of mitochondrial dysfunction during aging requires a thorough evaluation of degradative and nondegradative inter-organelle pathways. Here, we present a geroscience overview on (1) degradative MQC pathways, (2) nondegradative processes involving inter-organelle tethering, (3) age-related changes in inter-organelle degradative and nondegradative pathways, and (4) relevance of MQC failure to inflammaging and age-related conditions, with a focus on Parkinson’s disease as a prototypical geroscience condition.

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Mitochondrial quality control in acute ischemic stroke

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211046992 ◽

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

Physiological Reviews ◽

10.1152/physrev.00005.2018 ◽

2019 ◽

Vol 99 (1) ◽

pp. 853-892 ◽

Cited By ~ 37

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.

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