TBC1D15 deficiency protects against doxorubicin cardiotoxicity via inhibiting DNA-PKcs cytosolic retention and DNA damage DOI Creative Commons
Wenjun Yu, Haixia Xu, Zhe Sun

et al.

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 13(12), P. 4823 - 4839

Published: Sept. 17, 2023

Clinical application of doxorubicin (DOX) is heavily hindered by DOX cardiotoxicity. Several theories were postulated for cardiotoxicity including DNA damage and response (DDR), although the mechanism(s) involved remains to be elucidated. This study evaluated potential role TBC domain family member 15 (TBC1D15) in Tamoxifen-induced cardiac-specific Tbc1d15 knockout (Tbc1d15CKO) or knockin (Tbc1d15CKI) male mice challenged with a single dose prior cardiac assessment 1 week 4 weeks following challenge. Adenoviruses encoding TBC1D15 containing shRNA targeting used overexpression knockdown isolated primary mouse cardiomyocytes. Our results revealed that evoked upregulation compromised myocardial function overt mortality, effects which ameliorated accentuated deletion overexpression, respectively. overtly apoptotic cell death, effect was alleviated exacerbated Meanwhile, provoked mitochondrial membrane collapse, oxidative stress damage, mitigated Further scrutiny fostered cytosolic accumulation cardinal DDR element DNA-dependent protein kinase catalytic subunit (DNA-PKcs). Liquid chromatography-tandem mass spectrometry co-immunoprecipitation denoted an interaction between DNA-PKcs at segment 594-624 TBC1D15. Moreover, mutant (∆594-624, 594-624) failed elicit accentuation DOX-induced retention DNA-PKcs, cardiomyocyte apoptosis wild type. However, contractile anomalies, apoptosis, accumulation, canceled off inhibition ATM activation. Taken together, our findings pivotal injury, possibly through binding thus gate-keeping its retention, route dysfunction

Language: Английский

Mitochondria are secreted in extracellular vesicles when lysosomal function is impaired DOI Creative Commons
Wenjing Liang, Shakti Sagar, Rishith Ravindran

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Aug. 18, 2023

Abstract Mitochondrial quality control is critical for cardiac homeostasis as these organelles are responsible generating most of the energy needed to sustain contraction. Dysfunctional mitochondria normally degraded via intracellular degradation pathways that converge on lysosome. Here, we identified an alternative mechanism eliminate when lysosomal function compromised. We show inhibition leads increased secretion in large extracellular vesicles (EVs). The EVs produced multivesicular bodies, and their release independent autophagy. Deletion small GTPase Rab7 cells or adult mouse heart containing ubiquitinated cargos, including intact mitochondria. secreted captured by macrophages without activating inflammation. Hearts from aged mice Danon disease patients have levels indicating activation vesicular during pathophysiology. Overall, findings establish eliminated through endosomal pathway inhibited.

Language: Английский

Citations

117
Quercetin inhibits necroptosis in cardiomyocytes after ischemia–reperfusion via DNA‐PKcs‐SIRT5‐orchestrated mitochondrial quality control DOI
Xing Chang, Qin Zhang, Yu Huang

et al.

Phytotherapy Research, Journal Year: 2024, Volume and Issue: 38(5), P. 2496 - 2517

Published: March 6, 2024

Abstract We investigated the mechanism by which quercetin preserves mitochondrial quality control (MQC) in cardiomyocytes subjected to ischemia–reperfusion stress. An enzyme‐linked immunosorbent assay was employed vivo experiments assess myocardial injury markers, measure transcript levels of SIRT5/DNAPK‐cs/MLKL during various time intervals ischemia–reperfusion, and observe structural changes using transmission electron microscopy. In vitro investigations, adenovirus transfection establish a gene‐modified model DNA‐PKcs, primary were obtained from mouse with modified SIRT5 gene. Reverse transcription polymerase chain reaction, laser confocal microscopy, immunofluorescence localization, JC‐1 fluorescence assay, Seahorse energy analysis, other assays applied corroborate regulatory influence on MQC network after ischemia–reperfusion. demonstrated that caused structure myocardium. It seen had beneficial effect tissue, providing protection. As process continued, DNA‐PKcs/SIRT5/MLKL transcripts also found change. investigations revealed mitigated cardiomyocyte oxidative stress through regulated mitophagy kinetics sustain optimal metabolism levels. Quercetin, desuccinylation, modulated stability together they “mitophagy‐unfolded protein response.” This preserved integrity membrane genome, dynamics, metabolism. Quercetin may operate synergistically oversee regulation unfolded response DNA‐PKcs‐SIRT5 interaction.

Language: Английский

Citations

58
Mitochondrial quality control in human health and disease DOI Creative Commons
Bohao Liu,

Chen-Zhen Xu,

Yi Liu

et al.

Military Medical Research, Journal Year: 2024, Volume and Issue: 11(1)

Published: May 29, 2024

Abstract Mitochondria, the most crucial energy-generating organelles in eukaryotic cells, play a pivotal role regulating energy metabolism. However, their significance extends beyond this, as they are also indispensable vital life processes such cell proliferation, differentiation, immune responses, and redox balance. In response to various physiological signals or external stimuli, sophisticated mitochondrial quality control (MQC) mechanism has evolved, encompassing key like biogenesis, dynamics, mitophagy, which have garnered increasing attention from researchers unveil specific molecular mechanisms. this review, we present comprehensive summary of primary mechanisms functions regulators involved major components MQC. Furthermore, critical regulated by MQC its diverse roles progression systemic diseases been described detail. We discuss agonists antagonists targeting MQC, aiming explore potential therapeutic research prospects enhancing stabilize function.

Language: Английский

Citations

36
Notoginsenoside R1 protects against myocardial ischemia/reperfusion injury in mice via suppressing TAK1-JNK/p38 signaling DOI
Jingjing Zeng,

Hanqing Shi,

Fangfang Ren

et al.

Acta Pharmacologica Sinica, Journal Year: 2023, Volume and Issue: 44(7), P. 1366 - 1379

Published: Jan. 31, 2023

Language: Английский

Citations

43
Mitochondrial dysfunction at the crossroad of cardiovascular diseases and cancer DOI Creative Commons
Carmine Rocca, Teresa Soda, Ernestina Marianna De Francesco

et al.

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Sept. 19, 2023

A large body of evidence indicates the existence a complex pathophysiological relationship between cardiovascular diseases and cancer. Mitochondria are crucial organelles whose optimal activity is determined by quality control systems, which regulate critical cellular events, ranging from intermediary metabolism calcium signaling to mitochondrial dynamics, cell death mitophagy. Emerging data indicate that impaired drives myocardial dysfunction occurring in several heart diseases, including cardiac hypertrophy, infarction, ischaemia/reperfusion damage metabolic cardiomyopathies. On other hand, diverse human cancers also dysregulate promote their initiation progression, suggesting modulating homeostasis may represent promising therapeutic strategy both cardiology oncology. In this review, first we briefly introduce physiological mechanisms underlying system, then summarize current understanding about impact dysregulated functions We discuss key increased risk complications secondary main anticancer strategies, highlighting potential strategies aimed at alleviating impairment-related tumorigenesis. It hoped summary can provide novel insights into precision medicine approaches reduce cancer morbidities mortalities.

Language: Английский

Citations

35
Galangin Attenuates Myocardial Ischemic Reperfusion-Induced Ferroptosis by Targeting Nrf2/Gpx4 Signaling Pathway DOI Creative Commons
Tao Yang,

Haiqiong Liu,

Chaobo Yang

et al.

Drug Design Development and Therapy, Journal Year: 2023, Volume and Issue: Volume 17, P. 2495 - 2511

Published: Aug. 1, 2023

Purpose: Myocardial ischemic reperfusion injury (MIRI) is a crucial clinical problem globally.The molecular mechanisms of MIRI need to be fully explored develop new therapeutic methods.Galangin (Gal), which natural flavonoid extracted from Alpinia Officinarum Hance and Propolis, possesses wide range pharmacological activities, but its effects on remain unclear.This study aimed determine the Gal MIRI.Methods: C57BL/6 mice underwent for 3 h after 45 min ischemia, neonatal rat cardiomyocytes (NRCs) subjected hypoxia reoxygenation (HR) were cultured as in vivo vitro models.Echocardiography TTC-Evans Blue staining performed evaluate myocardial injury.Transmission electron microscope JC-1 used validate mitochondrial function.Additionally, Western blot detected ferroptosis markers, including Gpx4, FTH, xCT.Results: treatment alleviated cardiac myofibril damage, reduced infarction size, improved function, prevented with MIRI.Gal significantly HR-induced cell death mitigated membrane potential reduction NRCs.Furthermore, inhibited by preventing iron overload lipid peroxidation, well regulating xCT expression levels.Moreover, up-regulated nuclear transcriptive factor Nrf2 HR-treated NRCs.Nrf2 inhibition Brusatol abolished protective effect against ferroptosis.Conclusion: This revealed that alleviates reperfusion-induced targeting Nrf2/Gpx4 signaling pathway.

Language: Английский

Citations

32
MGST1 overexpression ameliorates mitochondrial dysfunction and ferroptosis during myocardial ischemia/reperfusion injury after heart transplantation DOI
Yang Yang, Changying Zhao, Chenlu Li

et al.

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 299, P. 140135 - 140135

Published: Jan. 21, 2025

Language: Английский

Citations

2
SS-31@Fer-1 Alleviates ferroptosis in hypoxia/reoxygenation cardiomyocytes via mitochondrial targeting DOI Open Access
Hao Zheng,

Jinbo Ou,

Hui Han

et al.

Biomedicine & Pharmacotherapy, Journal Year: 2025, Volume and Issue: 183, P. 117832 - 117832

Published: Jan. 22, 2025

Language: Английский

Citations

2
Novel strategies targeting mitochondria-lysosome contact sites for the treatment of neurological diseases DOI Creative Commons
Yinyin Xie,

Wenlin Sun,

Aoya Han

et al.

Frontiers in Molecular Neuroscience, Journal Year: 2025, Volume and Issue: 17

Published: Jan. 14, 2025

Mitochondria and lysosomes are critical for neuronal homeostasis, as highlighted by their dysfunction in various neurological diseases. Recent studies have identified dynamic membrane contact sites between mitochondria lysosomes, independent of mitophagy the lysosomal degradation mitochondrial-derived vesicles (MDVs), allowing bidirectional crosstalk these cell compartments, regulation organelle networks, substance exchanges. Emerging evidence suggests that abnormalities mitochondria-lysosome (MLCSs) contribute to diseases, including Parkinson’s disease, Charcot–Marie-Tooth (CMT) storage epilepsy. This article reviews recent research advances regarding tethering processes, regulation, function MLCSs role

Language: Английский

Citations

1
Mitochondria–membranous organelle contacts at a glance DOI Creative Commons
Antigoni Diokmetzidou, Luca Scorrano

Journal of Cell Science, Journal Year: 2025, Volume and Issue: 138(9)

Published: May 1, 2025

ABSTRACT Mitochondrial contact sites are specialized interfaces where mitochondria physically interact with other organelles. Stabilized by molecular tethers and defined unique proteomic lipidomic profiles, these enable direct interorganellar communication functional coordination, playing crucial roles in cellular physiology homeostasis. Recent advances have expanded our knowledge of site-resident proteins, illuminated the dynamic adaptive nature interfaces, clarified their contribution to pathophysiology. In this Cell Science at a Glance article accompanying poster, we summarize mitochondrial contacts that been characterized mammals, mechanisms underlying formation, principal functions.

Language: Английский

Citations

1