Mitochondrial Quality Control in the Heart: The Balance between Physiological and Pathological Stress

Fajardo, Giovanni; Coronado, Michael; Matthews, Melia; Bernstein, Daniel

doi:10.3390/biomedicines10061375

Cited by 11 publications

(6 citation statements)

References 101 publications

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“…Mitochondria are highly dynamic organelles. Appropriate management of mitochondrial biogenesis, fission/fusion, and mitophagy is essential for preserving mitochondrial integrity and function ( Fajardo et al, 2022 ). In our current work, we detected the expression of critical proteins in mitochondrial quality control using western blot analysis.…”

Section: Resultsmentioning

confidence: 99%

Gypenosides exert cardioprotective effects by promoting mitophagy and activating PI3K/Akt/GSK-3β/Mcl-1 signaling

Zheng,

Wei,

Wang

et al. 2024

PeerJ

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Background Gynostemma pentaphyllum (Thunb.) Makino, a well-known edible and medicinal plant, has anti-aging properties and is used to treataging-associated conditions such as diabetes, metabolic syndrome, and cardiovascular diseases. Gypenosides (GYPs) are the primary constituents of G. pentaphyllum. Increasing evidence indicates that GYPs are effective at preserving mitochondrial homeostasis and preventing heart failure (HF). This study aimed to uncover the cardioprotective mechanisms of GYPs related to mitochondrial regulation. Methods The bioactive components in GYPs and the potential targets in treating HF were obtained and screened using the network pharmacology approach, followed by drug-disease target prediction and enrichment analyses. The pharmacological effects of GYPs in cardioprotection, mitochondrial function, mitochondrial quality control, and underlying mechanisms were further investigated in Doxorubicin (Dox)-stimulated H9c2 cardiomyocytes. Results A total of 88 bioactive compounds of GYPs and their respective 71 drug-disease targets were identified. The hub targets covered MAPK, EGFR, PI3KCA, and Mcl-1. Enrichment analysis revealed that the pathways primarily contained PI3K/Akt, MAPK, and FoxO signalings, as well as calcium regulation, protein phosphorylation, apoptosis, and mitophagy process. In Dox-stimulated H9c2 rat cardiomyocytes, pretreatment with GYPs increased cell viability, enhanced cellular ATP content, restored basal oxygen consumption rate (OCR), and improved mitochondrial membrane potential (MMP). Furthermore, GYPs improved PINK1/parkin-mediated mitophagy without influencing mitochondrial fission/fusion proteins and the autophagic LC3 levels. Mechanistically, the phosphorylation of PI3K, Akt, GSK-3β, and the protein level of Mcl-1 was upregulated by GYP treatment. Conclusion Our findings reveal that GYPs exert cardioprotective effects by rescuing the defective mitophagy, and PI3K/Akt/GSK-3β/Mcl-1 signaling is potentially involved in this process.

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Section: Resultsmentioning

confidence: 99%

Gypenosides exert cardioprotective effects by promoting mitophagy and activating PI3K/Akt/GSK-3β/Mcl-1 signaling

Zheng,

Wei,

Wang

et al. 2024

PeerJ

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“…Our data showed that at least the defective mitochondrial fusion and mitophagy partially mediated the impairment of mitochondria in cardiac muscles from patients with PD. The mitochondrial morphology, quality and abundance are recognized as being determined by the mitochondrial dynamics comprising mitochondrial fusion, fission, biogenesis and mitophagy 28 . Imbalanced or damaged mitochondrial dynamics have been implicated in the development and progression of cardiovascular pathologies 24,29 .…”

Section: Discussionmentioning

confidence: 99%

“…The mitochondrial morphology, quality and abundance are recognized as being determined by the mitochondrial dynamics comprising mitochondrial fusion, fission, biogenesis and mitophagy. 28 Imbalanced or damaged mitochondrial dynamics have been implicated in the development and progression of cardiovascular pathologies. 24 , 29 Mitochondrial fusion connects neighbouring depolarized mitochondria and mixes their contents to maintain membrane potential.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial dysfunction is associated with hypertrophic cardiomyopathy in Pompe disease‐specific induced pluripotent stem cell‐derived cardiomyocytes

Huang,

Zhou,

Jiang

et al. 2023

Cell Proliferation

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Pompe disease (PD) is a rare autosomal recessive disorder that presents with progressive hypertrophic cardiomyopathy. However, the detailed mechanism remains clarified. Herein, PD patient‐specific induced pluripotent stem cells were differentiated into cardiomyocytes (PD‐iCMs) that exhibited cardiomyopathic features of PD, including decreased acid alpha‐glucosidase activity, lysosomal glycogen accumulation and hypertrophy. The defective mitochondria were involved in the cardiac pathology as shown by the significantly decreased number of mitochondria and impaired respiratory function and ATP production in PD‐iCMs, which was partially due to elevated levels of intracellular reactive oxygen species produced from depolarized mitochondria. Further analysis showed that impaired fusion and autophagy of mitochondria and declined expression of mitochondrial complexes underlies the mechanism of dysfunctional mitochondria. This was alleviated by supplementation with recombinant human acid alpha‐glucosidase that improved the mitochondrial function and concomitantly mitigated the cardiac pathology. Therefore, this study suggests that defective mitochondria underlie the pathogenesis of cardiomyopathy in patients with PD.

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“…The expression analysis of genes involved in the regulation of mitochondria biogenesis and cell energetics, such as PGC1β (peroxisome-proliferator-activated receptor-γ-coactivator 1 β), TFAM (transcription factor A were greater in TgRRB hearts suggesting that there is greater OXPHOS gene expression [43,44] (Fig. S10).…”

Section: Tgrrb-cms Have Enhanced Mitochondrial Function Compared To W...mentioning

confidence: 99%

dATP Elevation Induces Myocardial Metabolic Remodeling to Support Improved Cardiac Function

Mhatre

Murray

Flint

et al. 2022

Preprint

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Hallmark features of systolic heart failure are reduced contractility and impaired metabolic flexibility of the myocardium. Cardiomyocytes (CMs) with elevated deoxy ATP (dATP) via overexpression of ribonucleotide reductase (RNR) enzyme robustly improve contractility. However, the effect of dATP elevation on cardiac metabolism is unknown. Here, we developed proteolysis-resistant versions of RNR and demonstrate that elevation of dATP/ATP to ~1% in CMs in a transgenic mouse (TgRRB) resulted in robust improvement of cardiac function. Pharmacological approaches showed that CMs with elevated dATP have greater basal respiratory rates by shifting myosin states to more active forms, independent of its isoform, in relaxed CMs. Targeted metabolomic profiling revealed a significant reprogramming towards oxidative phosphorylation in TgRRB CMs. Higher cristae density and activity in the mitochondria of TgRRB-CMs improved respiratory capacity. Our results revealed a critical property of dATP to modulate myosin states to enhance contractility and induce metabolic flexibility to support improved function in CMs.

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Mitochondrial Quality Control in the Heart: The Balance between Physiological and Pathological Stress

Cited by 11 publications

References 101 publications

Gypenosides exert cardioprotective effects by promoting mitophagy and activating PI3K/Akt/GSK-3β/Mcl-1 signaling

Gypenosides exert cardioprotective effects by promoting mitophagy and activating PI3K/Akt/GSK-3β/Mcl-1 signaling

Mitochondrial dysfunction is associated with hypertrophic cardiomyopathy in Pompe disease‐specific induced pluripotent stem cell‐derived cardiomyocytes

dATP Elevation Induces Myocardial Metabolic Remodeling to Support Improved Cardiac Function

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