Mitochondria in health, disease, and aging

Physiological Reviews, Год журнала: 2023, Номер 103(4), С. 2349 - 2422

Опубликована: Апрель 6, 2023

Mitochondria are well known as organelles responsible for the maintenance of cellular bioenergetics through production ATP. Although oxidative phosphorylation may be their most important function, mitochondria also integral synthesis metabolic precursors, calcium regulation, reactive oxygen species, immune signaling, and apoptosis. Considering breadth responsibilities, fundamental metabolism homeostasis. Appreciating this significance, translational medicine has begun to investigate how mitochondrial dysfunction can represent a harbinger disease. In review, we provide detailed overview metabolism, bioenergetics, dynamics, autophagy, damage-associated molecular patterns, mitochondria-mediated cell death pathways, at any these levels is associated with disease pathogenesis. Mitochondria-dependent pathways thereby an attractive therapeutic target ameliorating human

Язык: Английский

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Empagliflozin attenuates cardiac microvascular ischemia/reperfusion injury through improving mitochondrial homeostasis

Cardiovascular Diabetology, Год журнала: 2022, Номер 21(1)

Опубликована: Июнь 15, 2022

Abstract Background Empagliflozin has been reported to protect endothelial cell function, regardless of diabetes status. However, the role empagliflozin in microvascular protection during myocardial ischemia reperfusion injury (I/R) not fully understood. Methods Electron microscopy, western blots, immunofluorescence, qPCR, mutant plasmid transfection, co-immunoprecipitation were employed explore whether could alleviate damage and cardiac I/R injury. Results In mice, attenuated injury-induced occlusion microthrombus formation. human coronary artery cells, led adhesive factor upregulation, nitric oxide synthase inactivation, focal adhesion kinase downregulation, barrier dysfunction, cytoskeletal degradation cellular apoptosis; however, treatment diminished these effects. improved mitochondrial oxidative stress, respiration adenosine triphosphate metabolism I/R-treated cells by preventing phosphorylation dynamin-related protein 1 (Drp1) fission (Fis1), thus repressing fission. The protective effects on homeostasis function abrogated re-introduction phosphorylated Fis1, but Drp1, suggesting that Fis1 dephosphorylation is predominant mechanism whereby inhibits Besides, induced primarily activating DNA-dependent catalytic subunit (DNA-PKcs) pathway, while inactivated this pathway exerting anti-oxidative Conclusions These results demonstrated can microvasculature inhibiting DNA-PKcs/Fis1/mitochondrial

Язык: Английский

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The Drp1-Mediated Mitochondrial Fission Protein Interactome as an Emerging Core Player in Mitochondrial Dynamics and Cardiovascular Disease Therapy

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5785 - 5785

Опубликована: Март 17, 2023

Mitochondria, the membrane-bound cell organelles that supply most of energy needed for function, are highly regulated, dynamic bearing ability to alter both form and functionality rapidly maintain normal physiological events challenge stress cell. This amazingly vibrant movement distribution mitochondria within cells is controlled by coordinated interplay between mitochondrial processes fission fusion events, as well quality-control processes, mainly autophagy (also known mitophagy). Fusion connects unites neighboring depolarized derive a healthy distinct mitochondrion. In contrast, segregates damaged from intact counterparts followed selective clearance via specific autophagy, i.e., mitophagy. Hence, encompass all fusion, fission, mitophagy, biogenesis sustaining homeostasis. Accumulated evidence strongly suggests impairment has already emerged core player in pathogenesis, progression, development various human diseases, including cardiovascular ailments, leading causes death globally, which take an estimated 17.9 million lives each year. The crucial factor governing process recruitment dynamin-related protein 1 (Drp1), GTPase regulates cytosol outer membrane guanosine triphosphate (GTP)-dependent manner, where it oligomerized self-assembles into spiral structures. this review, we first aim describe structural elements, functionality, regulatory mechanisms key protein, Drp1, other adaptor proteins, (Fis1), (Mff), dynamics 49 (Mid49), 51 (Mid51). area review focuses on recent advances understanding role Drp1-mediated interactome unravel missing links events. Lastly, discuss promising mitochondria-targeted therapeutic approaches involve current interactions their critical roles pathogeneses diseases (CVDs).

Язык: Английский

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New insights into the role of mitochondrial dynamics in oxidative stress-induced diseases

Biomedicine & Pharmacotherapy, Год журнала: 2024, Номер 178, С. 117084 - 117084

Опубликована: Авг. 1, 2024

The accumulation of excess reactive oxygen species (ROS) can lead to oxidative stress (OS), which induce gene mutations, protein denaturation, and lipid peroxidation directly or indirectly. expression is reduced ATP level in cells, increased cytoplasmic Ca

Язык: Английский

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Cellular Senescence, Mitochondrial Dysfunction, and Their Link to Cardiovascular Disease

Cells, Год журнала: 2024, Номер 13(4), С. 353 - 353

Опубликована: Фев. 17, 2024

Cardiovascular diseases (CVDs), a group of disorders affecting the heart or blood vessels, are primary cause death worldwide, with an immense impact on patient quality life and disability. According to World Health Organization, CVD takes estimated 17.9 million lives each year, where more than four out five deaths due attacks strokes. In decades come, increased prevalence age-related CVD, such as atherosclerosis, coronary artery stenosis, myocardial infarction (MI), valvular disease, failure (HF) will contribute even greater health economic burden global average expectancy increases consequently world’s population continues age. Considering this, it is important focus our research efforts understanding fundamental mechanisms underlying CVD. this review, we cellular senescence mitochondrial dysfunction, which have long been established We also assess recent advances in targeting dysfunction including energy starvation oxidative stress, mitochondria dynamics imbalance, cell apoptosis, mitophagy, therapies that influence both therefore perhaps represent strategies most clinical potential, range, utility.

Язык: Английский

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Energetic dysfunction in sepsis: a narrative review

Annals of Intensive Care, Год журнала: 2021, Номер 11(1)

Опубликована: Июль 3, 2021

Growing evidence associates organ dysfunction(s) with impaired metabolism in sepsis. Recent research has increased our understanding of the role substrate utilization and mitochondrial dysfunction pathophysiology sepsis-related dysfunction. The purpose this review is to present as a coherent whole highlight future directions.Sepsis characterized by systemic organ-specific changes metabolism. Alterations oxygen consumption, levels circulating substrates, glucose lipid oxidation, are all associated poor outcomes both animal models patients. pathophysiological relevance bioenergetics specific examples immunodeficiency, cerebral dysfunction, cardiomyopathy, acute kidney injury diaphragmatic failure also described.Recent understandings may pave way for new diagnostic therapeutic approaches. These findings could help physicians identify distinct subgroups sepsis develop personalized treatment strategies. Implications their use bioenergetic targets metabolism- mitochondria-targeted treatments need be evaluated studies.

Язык: Английский

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The Mitochondrial Permeability Transition: Nexus of Aging, Disease and Longevity

Cells, Год журнала: 2021, Номер 10(1), С. 79 - 79

Опубликована: Янв. 6, 2021

The activity of the mitochondrial permeability transition pore, mPTP, a highly regulated multi-component mega-channel, is enhanced in aging and aging-driven degenerative diseases. mPTP accelerates by releasing large amounts cell-damaging reactive oxygen species, Ca2+ NAD+. various pathways that control channel activity, directly or indirectly, can therefore either inhibit accelerate retard enhance progression diseases determine lifespan healthspan. Autophagy, catabolic process removes digests damaged proteins organelles, protects cell against disease. However, protective effect autophagy depends on mTORC2/SKG1 inhibition mPTP. Autophagy inhibited cells. Mitophagy, specialized form autophagy, which retards removing fragments with activated also cells, this leads to increased activation, major contributor neurodegenerative diseases, such as Alzheimer's Parkinson's turns autophagy/mitophagy into destructive leading death. Several drugs lifestyle modifications healthspan activation Therefore, elucidating intricate connections between activate context could discovery new slow

Язык: Английский

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Light-activated mitochondrial fission through optogenetic control of mitochondria-lysosome contacts

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Июль 25, 2022

Abstract Mitochondria are highly dynamic organelles whose fragmentation by fission is critical to their functional integrity and cellular homeostasis. Here, we develop a method via optogenetic control of mitochondria–lysosome contacts (MLCs) induce mitochondrial with spatiotemporal accuracy. MLCs can be achieved blue-light-induced association mitochondria lysosomes through various photoactivatable dimerizers. Real-time induction tracked in living cells measure the rate. The partially restores functions SLC25A46 −/− cells, which display defects hyperfused mitochondria. system thus provides platform for studying treating diseases.

Язык: Английский

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Targeting an allosteric site in dynamin-related protein 1 to inhibit Fis1-mediated mitochondrial dysfunction

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 19, 2023

The large cytosolic GTPase, dynamin-related protein 1 (Drp1), mediates both physiological and pathological mitochondrial fission. Cell stress triggers Drp1 binding to Fis1 subsequently, fragmentation, ROS production, metabolic collapse, cell death. Because also fission by Mff, therapeutics that inhibit should spare P110, a peptide inhibitor of Drp1-Fis1 interaction, reduces pathology in numerous models neurodegeneration, ischemia, sepsis without blocking the functions Drp1. Since peptides have pharmacokinetic limitations, we set out identify small molecules mimic P110's benefit. We map P110-binding site switch I-adjacent grove (SWAG) on Screening for SWAG-binding identifies SC9, which mimics benefits cells mouse model endotoxemia. suggest discovered this study may reduce burden Drp1-mediated pathologies potentially associated with other members GTPase family.

Язык: Английский

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Mitophagy and clear cell renal cell carcinoma: insights from single-cell and spatial transcriptomics analysis

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Июнь 27, 2024

Background Clear Cell Renal Carcinoma (ccRCC) is the most common type of kidney cancer, characterized by high heterogeneity and complexity. Recent studies have identified mitochondrial defects autophagy as key players in development ccRCC. This study aims to delve into changes mitophagic activity within ccRCC its impact on tumor microenvironment, revealing role cell metabolism, development, survival strategies. Methods Comprehensive analysis tissues using single sequencing spatial transcriptomics reveal mitophagy Mitophagy was determined be altered among renal clear cells gene set scoring. Key populations prognostic genes were NMF approaches. The UBB also demonstrated vitro experiments. Results Compared normal tissue, various types exhibited significantly increased levels mitophagy, especially cells. associated with levels, such UBC, UBA52, TOMM7, UBB, MAP1LC3B, CSNK2B, identified, their expression closely linked poor patient prognosis. Particularly, ubiquitination process involving found crucial for quality control. Conclusion highlights central regulatory factors ccRCC, significance disease progression.

Язык: Английский

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