Atherosclerosis as Mitochondriopathy: Repositioning the Disease to Help Finding New Therapies

Atherosclerosis is a complex pathology that involves both metabolic dysfunction and chronic inflammatory process. During the last decade, a considerable progress was achieved in describing the pathophysiological features of atherosclerosis and developing approaches that target the abnormal lipid metabolism and chronic inflammation. However, early events in the arterial wall that initiate the disease development still remain obscure. Finding effective therapeutic targets in these early processes would allow developing methods for disease prevention and, possibly, atherosclerotic plaque regression. Currently, these early events are being actively studied by several research groups. One of the processes that are being investigated is the development of mitochondrial dysfunction, which was demonstrated to be present in the affected areas of the arterial wall. Detection and characterization of mitochondrial dysfunction associated with several chronic human disorders was made possible by the improved methods of studying mitochondrial biology and detecting mitochondrial DNA (mtDNA) mutations. It was found to be involved in several key atherogenic processes, such as oxidative stress, chronic inflammation, and intracellular lipid accumulation. Mitochondrial dysfunction can occur in all types of cells involved in the pathogenesis of atherosclerosis: monocytes and macrophages, smooth muscle cells, lymphocytes, and the endothelial cells. However, therapies that would specifically target the mitochondria to correct mitochondrial dysfunction and neutralize the defective organelles are still remain to be developed and characterized. The aim of this review is to outline the prospects for mitochondrial therapy for atherosclerosis. We discuss mechanisms of mitochondria-mediated atherogenic processes, known mitochondria-targeting therapy strategies, and novel mitochondria-targeting drugs in the context of atherosclerosis.

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Targeting Mitochondria as Therapeutic Strategy for Metabolic Disorders

The Scientific World JOURNAL ◽

10.1155/2014/604685 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 25

Author(s):

Daniela Sorriento ◽

Antonietta Valeria Pascale ◽

Rosa Finelli ◽

Anna Lisa Carillo ◽

Roberto Annunziata ◽

...

Keyword(s):

Metabolic Syndrome ◽

Mitochondrial Dysfunction ◽

Small Molecules ◽

Metabolic Disorders ◽

Therapeutic Strategy ◽

Cell Metabolism ◽

Therapeutic Interventions ◽

Mtdna Mutations ◽

Pathological Conditions ◽

Mitochondria Targeting

Mitochondria are critical regulator of cell metabolism; thus, mitochondrial dysfunction is associated with many metabolic disorders. Defects in oxidative phosphorylation, ROS production, or mtDNA mutations are the main causes of mitochondrial dysfunction in many pathological conditions such as IR/diabetes, metabolic syndrome, cardiovascular diseases, and cancer. Thus, targeting mitochondria has been proposed as therapeutic approach for these conditions, leading to the development of small molecules to be tested in the clinical scenario. Here we discuss therapeutic interventions to treat mitochondrial dysfunction associated with two major metabolic disorders, metabolic syndrome, and cancer. Finally, novel mechanisms of regulation of mitochondrial function are discussed, which open new scenarios for mitochondria targeting.

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Mitochondrial Dysfunction in Vascular Wall Cells and Its Role in Atherosclerosis

International Journal of Molecular Sciences ◽

10.3390/ijms22168990 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8990

Author(s):

Diana Salnikova ◽

Varvara Orekhova ◽

Andrey Grechko ◽

Antonina Starodubova ◽

Evgeny Bezsonov ◽

...

Keyword(s):

Oxidative Stress ◽

Mitochondrial Dysfunction ◽

Arterial Wall ◽

Cell Types ◽

Vascular Wall ◽

Energy Status ◽

Mtdna Mutations ◽

Atherosclerosis Development ◽

Atherosclerosis Treatment ◽

The Impact

Altered mitochondrial function is currently recognized as an important factor in atherosclerosis initiation and progression. Mitochondrial dysfunction can be caused by mitochondrial DNA (mtDNA) mutations, which can be inherited or spontaneously acquired in various organs and tissues, having more or less profound effects depending on the tissue energy status. Arterial wall cells are among the most vulnerable to mitochondrial dysfunction due to their barrier and metabolic functions. In atherosclerosis, mitochondria cause alteration of cellular metabolism and respiration and are known to produce excessive amounts of reactive oxygen species (ROS) resulting in oxidative stress. These processes are involved in vascular disease and chronic inflammation associated with atherosclerosis. Currently, the list of known mtDNA mutations associated with human pathologies is growing, and many of the identified mtDNA variants are being tested as disease markers. Alleviation of oxidative stress and inflammation appears to be promising for atherosclerosis treatment. In this review, we discuss the role of mitochondrial dysfunction in atherosclerosis development, focusing on the key cell types of the arterial wall involved in the pathological processes. Accumulation of mtDNA mutations in isolated arterial wall cells, such as endothelial cells, may contribute to the development of local inflammatory process that helps explaining the focal distribution of atherosclerotic plaques on the arterial wall surface. We also discuss antioxidant and anti-inflammatory approaches that can potentially reduce the impact of mitochondrial dysfunction.

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Jiuzhuan Huangjing Pills relieve mitochondrial dysfunction and attenuate high-fat diet-induced metabolic dysfunction-associated fatty liver disease

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2021.112092 ◽

2021 ◽

Vol 142 ◽

pp. 112092

Author(s):

Jian-Kang Mu ◽

Lei Zi ◽

Yan-Qin Li ◽

Li-Ping Yu ◽

Zheng-Guo Cui ◽

...

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Mitochondrial Dysfunction ◽

High Fat Diet ◽

Fatty Liver Disease ◽

Metabolic Dysfunction ◽

High Fat

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ROS as a Novel Indicator to Predict Anticancer Drug Efficacy

10.21203/rs.2.11911/v2 ◽

2019 ◽

Author(s):

Tarek Zaidieh ◽

James Smith ◽

Karen Ball ◽

Qian An

Keyword(s):

Cancer Cells ◽

Copy Number ◽

Drug Sensitivity ◽

Drug Efficacy ◽

Ros Generation ◽

Targeting Therapy ◽

Mitochondrial Dna Copy Number ◽

Conventional Drug ◽

Apoptosis Pathways ◽

Mitochondria Targeting

Abstract Background Mitochondria are considered a primary intracellular site of reactive oxygen species (ROS) generation. Generally, cancer cells with mitochondrial genetic abnormalities (copy number change and mutations) have escalated ROS levels compared to normal cells. Since high levels of ROS can trigger apoptosis, treating cancer cells with low doses of mitochondria-targeting / ROS-stimulating agents may offer cancer-specific therapy. This study aimed to investigate how baseline ROS levels might influence cancer cells’ response to ROS-stimulating therapy. Methods Four cancer and one normal cell lines were treated with a conventional drug (cisplatin) and a mitochondria-targeting agent (dequalinium chloride hydrate) separately and jointly. Cell viability was assessed and drug combination synergisms were indicated by the combination index (CI). Mitochondrial DNA copy number (MtDNAcn), ROS and mitochondrial membrane potential (MMP) were measured, and the relative expression levels of the genes and proteins involved in ROS-mediated apoptosis pathways were also investigated. Results Our data showed a correlation between the baseline ROS level, mtDNAcn and drug sensitivity in the tested cells. Synergistic effect of both drugs was also observed with ROS being the key contributor in cell death. Conclusions Our findings suggest that mitochondria-targeting therapy could be more effective compared to conventional treatments. In addition, cancer cells with low levels of ROS may be more sensitive to the treatment, while cells with high levels of ROS may be more resistant. This study provides an insight into understanding the influence of intracellular ROS on drug sensitivity, and may lead to the development of new therapeutic strategies to improve efficacy of anticancer therapy.

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Type I interferon potentiates metabolic dysfunction, inflammation, and accelerated aging in mtDNA mutator mice

10.1101/2020.09.22.308171 ◽

2020 ◽

Author(s):

Yuanjiu Lei ◽

Camila Guerra Martinez ◽

Sylvia Torres-Odio ◽

Samantha L. Bell ◽

Christine E. Birdwell ◽

...

Keyword(s):

Mitochondrial Dysfunction ◽

Inflammatory Responses ◽

Type I Interferon ◽

Aerobic Glycolysis ◽

Accelerated Aging ◽

Innate Immune ◽

Related Factor ◽

Type I ◽

Metabolic Dysfunction ◽

Polymerase Gamma

AbstractMitochondrial dysfunction is a key driver of inflammatory responses in human disease. However, it remains unclear whether alterations in mitochondria-innate immune crosstalk contribute to the pathobiology of mitochondrial disorders and aging. Using the polymerase gamma (POLG) mutator model of mitochondrial DNA (mtDNA) instability, we report that aberrant activation of the type I interferon (IFN-I) innate immune axis potentiates immunometabolic dysfunction, reduces healthspan, and accelerates aging in mutator mice. Mechanistically, elevated IFN-I signaling suppresses activation of nuclear factor erythroid 2-related factor 2 (Nrf2), which increases oxidative stress, enhances pro-inflammatory cytokine responses, and accelerates metabolic dysfunction. Ablation of IFN-I signaling attenuates hyper-inflammatory phenotypes by restoring Nrf2 activity and reducing aerobic glycolysis, which combine to lessen cardiovascular and myeloid dysfunction in aged mutator mice. These findings further advance our knowledge of how mitochondrial dysfunction shapes innate immune responses and provide a framework for understanding mitochondria-driven immunopathology in POLG-related diseases and aging.

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Abstract 2630: Evidence of Early Heart Mitochondrial Dysfunction after Resuscitation from Cardiac Arrest

Circulation ◽

10.1161/circ.116.suppl_16.ii_583 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Natalia A Riobo ◽

Fei Han ◽

Tong Da ◽

Lance B Becker

Keyword(s):

Cardiac Arrest ◽

Cytochrome C ◽

Mitochondrial Dysfunction ◽

Complex I ◽

Atp Synthesis ◽

Spontaneous Circulation ◽

Metabolic Dysfunction ◽

Amplex Red ◽

Production Of Hydrogen ◽

Complex I Activity

Background: Reperfusion injury post-resuscitation is associated with metabolic dysfunction and free radicals production. It has been hypothesized that mitochondrial permeability changes induced by calcium overload underlies this uncoupling of respiration from ATP synthesis and initiates cytochrome c-dependent apoptotic cascades. Our goal is to evaluate the intrinsic status of the mitochondrial electron transfer chain, i.e. irreversible modifications, in resuscitated animals independently of transient changes in calcium and permeability. Methods: Female mice were subjected to 8 min cardiac arrest by KCl injection followed by mechanical ventilation and CPR until return of spontaneous circulation (resuscitation rate: 86%, 24 h survival: 40%) under continuous blood pressure and temperature monitoring. Animals were divided in 4 groups: SHAM (instrumented, no cardiac arrest), CA (8 min cardiac arrest), R30 (30 min post-resuscitation), and R60 (60 min post-resuscitation). Heart mitochondria were immediately isolated and physically disrupted to dissipate ionic gradients in the presence of a calcium chelator. Production of hydrogen peroxide (H 2 O 2 ) by Complex I and III was determined fluorometrically with the Amplex Red-HRP system and the activities of Complex I, II, and the Complex I-III and II-III segments by spectrophotometric techniques using appropriate substrates and inhibitors. Cytochrome c content and the COX IV subunit (as a loading control) were analyzed by western blot and densitometry. Results: A 40% increase in H 2 O 2 production by Complex I and III was evident after just 8 min of cardiac arrest (ECA group, p<0.05), which was followed by a progressive reduction in Complex I activity (ECA>R30>R60), resulting in a relative doubling of electron leak. In contrast, Complex II and II-III activities and cytochrome c content remained unaffected at all times evaluated. Conclusions: Using an animal model that closely mimics resuscitation in humans, we have found signs of early mitochondrial dysfunction independently of transient changes in permeability and calcium. These changes are consistent with increased ROS production at expense of impaired oxidative phosphorylation.

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A Slc25a46-/- mouse model simulating motor deficit, imbalance of redox system and mitochondria dysfunction during aging

The Journals of Gerontology Series A ◽

10.1093/gerona/glaa306 ◽

2020 ◽

Author(s):

Li Gao ◽

Min Wang ◽

Linfeng Liao ◽

Na Gou ◽

Piao Xu ◽

...

Keyword(s):

Mouse Model ◽

Mitochondrial Dysfunction ◽

Nuclear Gene ◽

Redox System ◽

Premature Aging ◽

Motor Deficit ◽

Mitochondria Dysfunction ◽

Respiratory Chain Enzyme ◽

Knock Out ◽

Mtdna Mutations

Abstract The mitochondrial theory of aging postulates that accumulation of mtDNA mutations and mitochondrial dysfunction are responsible for producing aging phenotypes. To more comprehensively explore the complex relationship between aging and mitochondria dysfunction, we have developed a mouse model with Slc25a46 knock out, a nuclear gene described as encoding mitochondrial carriers, by CRISPR/Cas9 gene editing to mimic some typical aging phenotypes in human. Slc25a46-/- mice present segmental premature aging phenotypes characterized by shortened lifespan of no more than two months, obviously defective motor ability, gastrocnemius muscle atrophy and imbalance of redox level in brain and liver. The underlying mechanism for multiple organ disorder may attribute to the mitochondrial dysfunction, which is mainly manifested on the damaged mitochondrial structure (e.g., vacuolar structure, irregular swelling and disorganized cristae) and an age-associated decrease in respiratory chain enzyme (mainly complex I and IV) activity. In summary, our study suggests that the Slc25a46-/- mouse is a valid animal model for segmental aging-related pathologies studies based on mitochondrial theory, generating a new platform to both understand mechanisms between aging and mitochondria dysfunction as well as to design mitochondria based therapeutic strategies to improve mitochondrial quality, and thereby the overall healthspan.

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ROS as a novel indicator to predict anticancer drug efficacy

BMC Cancer ◽

10.1186/s12885-019-6438-y ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 6

Author(s):

Tarek Zaidieh ◽

James R. Smith ◽

Karen E. Ball ◽

Qian An

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Copy Number ◽

Drug Sensitivity ◽

Drug Efficacy ◽

Ros Generation ◽

Targeting Therapy ◽

Mitochondrial Dna Copy Number ◽

Mitochondria Targeting

Abstract Background Mitochondria are considered a primary intracellular site of reactive oxygen species (ROS) generation. Generally, cancer cells with mitochondrial genetic abnormalities (copy number change and mutations) have escalated ROS levels compared to normal cells. Since high levels of ROS can trigger apoptosis, treating cancer cells with low doses of mitochondria-targeting / ROS-stimulating agents may offer cancer-specific therapy. This study aimed to investigate how baseline ROS levels might influence cancer cells’ response to ROS-stimulating therapy. Methods Four cancer and one normal cell lines were treated with a conventional drug (cisplatin) and a mitochondria-targeting agent (dequalinium chloride hydrate) separately and jointly. Cell viability was assessed and drug combination synergisms were indicated by the combination index (CI). Mitochondrial DNA copy number (mtDNAcn), ROS and mitochondrial membrane potential (MMP) were measured, and the relative expression levels of the genes and proteins involved in ROS-mediated apoptosis pathways were also investigated. Results Our data showed a correlation between the baseline ROS level, mtDNAcn and drug sensitivity in the tested cells. Synergistic effect of both drugs was also observed with ROS being the key contributor in cell death. Conclusions Our findings suggest that mitochondria-targeting therapy could be more effective compared to conventional treatments. In addition, cancer cells with low levels of ROS may be more sensitive to the treatment, while cells with high levels of ROS may be more resistant. Doubtlessly, further studies employing a wider range of cell lines and in vivo experiments are needed to validate our results. However, this study provides an insight into understanding the influence of intracellular ROS on drug sensitivity, and may lead to the development of new therapeutic strategies to improve efficacy of anticancer therapy.

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Mitochondrial Dysfunction in Parkinson’s Disease: Focus on Mitochondrial DNA

Biomedicines ◽

10.3390/biomedicines8120591 ◽

2020 ◽

Vol 8 (12) ◽

pp. 591

Author(s):

Olga Buneeva ◽

Valerii Fedchenko ◽

Arthur Kopylov ◽

Alexei Medvedev

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Mitochondrial Dna ◽

Mitochondrial Dysfunction ◽

Nuclear Dna ◽

Good Evidence ◽

Inner Mitochondrial Membrane ◽

Mtdna Mutations ◽

Increased Risk ◽

Mtdna Replication

Mitochondria, the energy stations of the cell, are the only extranuclear organelles, containing their own (mitochondrial) DNA (mtDNA) and the protein synthesizing machinery. The location of mtDNA in close proximity to the oxidative phosphorylation system of the inner mitochondrial membrane, the main source of reactive oxygen species (ROS), is an important factor responsible for its much higher mutation rate than nuclear DNA. Being more vulnerable to damage than nuclear DNA, mtDNA accumulates mutations, crucial for the development of mitochondrial dysfunction playing a key role in the pathogenesis of various diseases. Good evidence exists that some mtDNA mutations are associated with increased risk of Parkinson’s disease (PD), the movement disorder resulted from the degenerative loss of dopaminergic neurons of substantia nigra. Although their direct impact on mitochondrial function/dysfunction needs further investigation, results of various studies performed using cells isolated from PD patients or their mitochondria (cybrids) suggest their functional importance. Studies involving mtDNA mutator mice also demonstrated the importance of mtDNA deletions, which could also originate from abnormalities induced by mutations in nuclear encoded proteins needed for mtDNA replication (e.g., polymerase γ). However, proteomic studies revealed only a few mitochondrial proteins encoded by mtDNA which were downregulated in various PD models. This suggests nuclear suppression of the mitochondrial defects, which obviously involve cross-talk between nuclear and mitochondrial genomes for maintenance of mitochondrial functioning.

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