Targeting Mitochondrial Dysfunction: Role for PINK1 and Parkin in Mitochondrial Quality Control

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

10.20944/preprints202108.0220.v2 ◽

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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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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Trimetazidine and exercise provide comparable improvements to high fat diet-induced muscle dysfunction through enhancement of mitochondrial quality control

Scientific Reports ◽

10.1038/s41598-021-98771-6 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Wenliang Zhang ◽

Baiyang You ◽

Dake Qi ◽

Ling Qiu ◽

Jeffrey W. Ripley-Gonzalez ◽

...

Keyword(s):

Skeletal Muscle ◽

Quality Control ◽

Mitochondrial Dysfunction ◽

Muscle Atrophy ◽

High Fat Diet ◽

C2c12 Cells ◽

Muscle Dysfunction ◽

High Fat ◽

Mitochondrial Quality Control ◽

Mitochondrial Functions

AbstractObesity induces skeletal muscle dysfunction. The pathogenesis of which appears to substantially involve mitochondrial dysfunction, arising from impaired quality control. Exercise is a major therapeutic strategy against muscle dysfunction. Trimetazidine, a partial inhibitor of lipid oxidation, has been proposed as a metabolic modulator for several cardiovascular pathologies. However, the effects of Trimetazidine on regulating skeletal muscle function are largely unknown. Our present study used cell culture and obese mice models to test a novel hypothesis that Trimetazidine could improve muscle atrophy with similar results to exercise. In C2C12 cells, high palmitic acid-induced atrophy and mitochondrial dysfunction, which could be reversed by the treatment of Trimetazidine. In our animal models, with high-fat diet-induced obesity associated with skeletal muscle atrophy, Trimetazidine prevented muscle dysfunction, corrected metabolic abnormalities, and improved mitochondrial quality control and mitochondrial functions similarly to exercise. Thus, our study suggests that Trimetazidine successfully mimics exercise to enhance mitochondrial quality control leading to improved high-fat diet-induced muscle dysfunction.

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Disturbed mitochondrial quality control involved in hepatocytotoxicity induced by silica nanoparticles

Nanoscale ◽

10.1039/d0nr01893g ◽

2020 ◽

Vol 12 (24) ◽

pp. 13034-13045 ◽

Cited By ~ 2

Author(s):

Yi Qi ◽

Ru Ma ◽

Xueyan Li ◽

Songqing Lv ◽

Xiaoying Liu ◽

...

Keyword(s):

Quality Control ◽

Mitochondrial Dysfunction ◽

Silica Nanoparticles ◽

Cell Damage ◽

Mitochondrial Dynamics ◽

Control Process ◽

Mitochondrial Quality Control ◽

Quality Control Process

SiNPs triggered hepatocytotoxicity through interfering mitochondrial quality control process, including imbalanced mitochondrial dynamics, disturbed mitophagy and suppressed biogenesis, leading to mitochondrial dysfunction and ensuing cell damage.

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Current Progress of Mitochondrial Quality Control Pathways Underlying the Pathogenesis of Parkinson’s Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/4578462 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 6

Author(s):

Xue Jiang ◽

Tao Jin ◽

Haining Zhang ◽

Jing Miao ◽

Xiuzhen Zhao ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Quality Control ◽

Mitochondrial Dysfunction ◽

Neurodegenerative Disorder ◽

Mitochondrial Dynamics ◽

Alpha Synuclein ◽

Substantia Nigra Pars Compacta ◽

Toxic Metabolite ◽

Mitochondrial Quality Control

Parkinson’s disease (PD), clinically characterized by motor and nonmotor symptoms, is a common progressive and multisystem neurodegenerative disorder, which is caused by both genetic and environmental risk factors. The main pathological features of PD are the loss of dopaminergic (DA) neurons and the accumulation of alpha-synuclein (α-syn) in the residual DA neurons in the substantia nigra pars compacta (SNpc). In recent years, substantial progress has been made in discovering the genetic factors of PD. In particular, a total of 19 PD-causing genes have been unraveled, among which some members have been regarded to be related to mitochondrial dysfunction. Mitochondria are key regulators of cellular metabolic activity and are critical for many important cellular processes including energy metabolism and even cell death. Their normal function is basically maintained by the mitochondrial quality control (MQC) mechanism. Accordingly, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a kind of neurotoxin, exerts its neurotoxic effects at least partially by producing its toxic metabolite, namely, 1-methyl-4-phenylpyridine (MPP+), which in turn causes mitochondrial dysfunction by inhibiting complex I and mimicking the key features of PD pathogenesis. This review focused on three main aspects of the MQC signaling pathways, that is, mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial autophagy; hence, it demonstrates in detail how genetic and environmental factors result in PD pathogenesis by interfering with MQC pathways, thereby hopefully contributing to the discovery of novel potential therapeutic targets for PD.

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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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Mitochondrial Dysfunction and Aging: Insights from the Analysis of Extracellular Vesicles

International Journal of Molecular Sciences ◽

10.3390/ijms20040805 ◽

2019 ◽

Vol 20 (4) ◽

pp. 805 ◽

Cited By ~ 26

Author(s):

Anna Picca ◽

Flora Guerra ◽

Riccardo Calvani ◽

Cecilia Bucci ◽

Maria Lo Monaco ◽

...

Keyword(s):

Quality Control ◽

Mitochondrial Dysfunction ◽

Extracellular Vesicles ◽

Cell Function ◽

Nutrient Sensing ◽

Adverse Outcomes ◽

Biological Aging ◽

Low Grade ◽

Mitochondrial Quality Control ◽

Age Related

The progressive decline of cell function and integrity, manifesting clinically as increased vulnerability to adverse outcomes and death, is core to biological aging. Mitochondrial dysfunction, oxidative stress, altered intercellular communication (including chronic low-grade inflammation), genomic instability, telomere attrition, loss of proteostasis, altered nutrient sensing, epigenetic alterations, and stem cell exhaustion have been proposed as hallmarks of aging. These “aging pillars” are not mutually exclusive, making the matter intricate and leaving numerous unanswered questions. The characterization of circulating extracellular vesicles (EVs) has recently allowed specific secretory phenotypes associated with aging to be identified. As such, EVs may serve as novel biomarkers for capturing the complexity of aging. Besides the mitochondrial–lysosomal axis, EV trafficking has been proposed as an additional layer in mitochondrial quality control. Indeed, disruption of the mitochondrial–lysosomal axis coupled with abnormal EV secretion may play a role in the pathogenesis of aging and several disease conditions. Here, we discuss (1) the mechanisms of EV generation; (2) the relationship between the mitochondrial–lysosomal axis and EV trafficking in the setting of mitochondrial quality control; and (3) the prospect of using EVs as aging biomarkers and as delivery systems for therapeutics against age-related conditions.

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Dietary Antioxidants and the Mitochondrial Quality Control: Their Potential Roles in Parkinson’s Disease Treatment

Antioxidants ◽

10.3390/antiox9111056 ◽

2020 ◽

Vol 9 (11) ◽

pp. 1056 ◽

Cited By ~ 1

Author(s):

Davin Lee ◽

Min Gu Jo ◽

Seung Yeon Kim ◽

Chang Geon Chung ◽

Sung Bae Lee

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Quality Control ◽

Life Expectancy ◽

Mitochondrial Dysfunction ◽

Healthy Aging ◽

Human Life ◽

Dietary Antioxidants ◽

Mitochondrial Quality Control ◽

Age Related

Advances in medicine and dietary standards over recent decades have remarkably increased human life expectancy. Unfortunately, the chance of developing age-related diseases, including neurodegenerative diseases (NDDs), increases with increased life expectancy. High metabolic demands of neurons are met by mitochondria, damage of which is thought to contribute to the development of many NDDs including Parkinson’s disease (PD). Mitochondrial damage is closely associated with the abnormal production of reactive oxygen species (ROS), which are widely known to be toxic in various cellular environments, including NDD contexts. Thus, ways to prevent or slow mitochondrial dysfunction are needed for the treatment of these NDDs. In this review, we first detail how ROS are associated with mitochondrial dysfunction and review the cellular mechanisms, such as the mitochondrial quality control (MQC) system, by which neurons defend against both abnormal production of ROS and the subsequent accumulation of damaged mitochondria. We next highlight previous studies that link mitochondrial dysfunction with PD and how dietary antioxidants might provide reinforcement of the MQC system. Finally, we discuss how aging plays a role in mitochondrial dysfunction and PD before considering how healthy aging through proper diet and exercise may be salutary.

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Neurons Putting Out the Trash: A Novel Facet of Proteostasis and Mitochondrial Quality Control

Innovation in Aging ◽

10.1093/geroni/igaa057.2633 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

pp. 738-738

Author(s):

Monica Driscoll

Keyword(s):

Quality Control ◽

Mitochondrial Dysfunction ◽

Neurodegenerative Disease ◽

Human Disease ◽

Current Understanding ◽

Misfolded Proteins ◽

Mitochondrial Quality Control ◽

Considerable Evidence ◽

C Elegans ◽

Human Neurodegenerative Disease

Abstract Toxicity of misfolded proteins and mitochondrial dysfunction are pivotal factors that promote age-associated functional neuronal decline and neurodegenerative disease across species. Although these neurotoxic challenges have long been considered to be cell-intrinsic, considerable evidence now supports that misfolded human disease proteins originating in one neuron can appear in neighboring cells, a phenomenon proposed to promote pathology spread in human neurodegenerative disease. We have found that C. elegans adult neurons that express aggregating proteins can extrude large (~5µM) membrane-surrounded vesicles that can include the aggregated proteins and damaged mitochondria. We speculate that throwing out the trash may correspond to a conserved mechanism that constitutes a fundamental, but formerly unrecognized, branch of neuronal proteostasis and mitochondrial quality control. I will discuss our current understanding of the mechanisms of neuronal trash elimination.

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