FUNDC1: An Emerging Mitochondrial and MAMs Protein for Mitochondrial Quality Control in Heart Diseases

Bai, Xizhe; Zhang, Zhe; Li, Xi; Yang, Yangjun; Ding, Shuzhe

doi:10.3390/ijms24119151

Cited by 6 publications

(3 citation statements)

References 87 publications

(122 reference statements)

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“…Fundc1-triggered mitophagy has been shown to offer protection against ischemia-reperfusion (I/R) injury and Dox-induced cardiac dysfunction. 55–57 Our data suggest that Fundc1-mediated mitophagy may be a potential mechanism through which Cyp1a inhibition mitigates Dox-induced cardiomyopathy. Wu et al previously reported that deficiency of Fundc1 in mice impairs heart function.…”

Section: Discussionmentioning

confidence: 81%

Inhibition of Cyp1a Protects Mice against Anthracycline Cardiomyopathy

Liu,

Curtin,

Lall

et al. 2024

Preprint

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Background: Anthracyclines such as doxorubicin (Dox) are highly effective anti-tumor agents, but their use is limited by dose-dependent cardiomyopathy and heart failure. Our laboratory previously reported that induction of cytochrome P450 family 1 (Cyp1) enzymes contributes to acute Dox cardiotoxicity in zebrafish and in mice, and that potent Cyp1 inhibitors prevent cardiotoxicity. However, the role of Cyp1 enzymes in chronic Dox cardiomyopathy, as well as the mechanisms underlying cardioprotection associated with Cyp1 inhibition, have not been fully elucidated. Methods: The Cyp1 pathway was evaluated using a small molecule Cyp1 inhibitor in wild-type (WT) mice, or Cyp1-null mice (Cyp1a1/1a2-/-, Cyp1b1-/-, and Cyp1a1/1a2/1b1-/-). Low-dose Dox was administered by serial intraperitoneal or intravenous injections, respectively. Expression of Cyp1 isoforms was measured by RT-qPCR, and myocardial tissue was isolated from the left ventricle for RNA sequencing. Cardiac function was evaluated by transthoracic echocardiography. Results: In WT mice, Dox treatment was associated with a decrease in Cyp1a2 and increase in Cyp1b1 expression in the heart and in the liver. Co-treatment of WT mice with Dox and the novel Cyp1 inhibitor YW-130 protected against cardiac dysfunction compared to Dox treatment alone. Cyp1a1/1a2-/- and Cyp1a1/1a2/1b1-/- mice were protected from Dox cardiomyopathy compared to WT mice. Male, but not female, Cyp1b1-/- mice had increased cardiac dysfunction following Dox treatment compared to WT mice. RNA sequencing of myocardial tissue showed upregulation of Fundc1 and downregulation of Ccl21c in Cyp1a1/1a2-/- mice treated with Dox, implicating changes in mitophagy and chemokine-mediated inflammation as possible mechanisms of Cyp1a-mediated cardioprotection. Conclusions: Taken together, this study highlights the potential therapeutic value of Cyp1a inhibition in mitigating anthracycline cardiomyopathy.

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Section: Discussionmentioning

confidence: 81%

Inhibition of Cyp1a Protects Mice against Anthracycline Cardiomyopathy

Liu,

Curtin,

Lall

et al. 2024

Preprint

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“…The subsequent degradation of mitofusin stimulates mitochondrial fission and induces mitophagy [242]. PINK1/Parkin-independent pathways to induce mitophagy are reviewed in detail elsewhere [240,243,244].…”

Section: Pten-induced Putative Kinase 1 (Pink1)mentioning

confidence: 99%

Mitochondrial Kinase Signaling for Cardioprotection

Boengler,

Eickelmann,

Kleinbongard

2024

IJMS

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Myocardial ischemia/reperfusion injury is reduced by cardioprotective adaptations such as local or remote ischemic conditioning. The cardioprotective stimuli activate signaling cascades, which converge on mitochondria and maintain the function of the organelles, which is critical for cell survival. The signaling cascades include not only extracellular molecules that activate sarcolemmal receptor-dependent or -independent protein kinases that signal at the plasma membrane or in the cytosol, but also involve kinases, which are located to or within mitochondria, phosphorylate mitochondrial target proteins, and thereby modify, e.g., respiration, the generation of reactive oxygen species, calcium handling, mitochondrial dynamics, mitophagy, or apoptosis. In the present review, we give a personal and opinionated overview of selected protein kinases, localized to/within myocardial mitochondria, and summarize the available data on their role in myocardial ischemia/reperfusion injury and protection from it. We highlight the regulation of mitochondrial function by these mitochondrial protein kinases.

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“…Since MQC, i.e., the regulation and maintenance of mitochondrial homeostasis, is essential not only for the fine-tuning of cell energy production [115] but also for overall cellular health, mitochondrial dysfunction and inadequate QC inevitably lead to metabolic disorders in many pathological conditions [116,117]. Defective MQC has been associated with diseases of the heart [118], lung [119,120], and kidneys [121], and in neuronal and muscular disorders [122]. Further, the metabolic switch from ATP production by oxidative phosphorylation to aerobic glycolysis (the Warburg effect) is one of the underlining mechanisms of cancer cell proliferation, allowing transformed cells to adjust and grow in a poorly oxygenated milieu [123].…”

Section: Mitochondrial Dysfunctionmentioning

confidence: 99%

Therapeutic Effects of Mesenchymal Stromal Cells Require Mitochondrial Transfer and Quality Control

Mukkala,

Jerkic,

Khan

et al. 2023

IJMS

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Due to their beneficial effects in an array of diseases, Mesenchymal Stromal Cells (MSCs) have been the focus of intense preclinical research and clinical implementation for decades. MSCs have multilineage differentiation capacity, support hematopoiesis, secrete pro-regenerative factors and exert immunoregulatory functions promoting homeostasis and the resolution of injury/inflammation. The main effects of MSCs include modulation of immune cells (macrophages, neutrophils, and lymphocytes), secretion of antimicrobial peptides, and transfer of mitochondria (Mt) to injured cells. These actions can be enhanced by priming (i.e., licensing) MSCs prior to exposure to deleterious microenvironments. Preclinical evidence suggests that MSCs can exert therapeutic effects in a variety of pathological states, including cardiac, respiratory, hepatic, renal, and neurological diseases. One of the key emerging beneficial actions of MSCs is the improvement of mitochondrial functions in the injured tissues by enhancing mitochondrial quality control (MQC). Recent advances in the understanding of cellular MQC, including mitochondrial biogenesis, mitophagy, fission, and fusion, helped uncover how MSCs enhance these processes. Specifically, MSCs have been suggested to regulate peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α)-dependent biogenesis, Parkin-dependent mitophagy, and Mitofusins (Mfn1/2) or Dynamin Related Protein-1 (Drp1)-mediated fission/fusion. In addition, previous studies also verified mitochondrial transfer from MSCs through tunneling nanotubes and via microvesicular transport. Combined, these effects improve mitochondrial functions, thereby contributing to the resolution of injury and inflammation. Thus, uncovering how MSCs affect MQC opens new therapeutic avenues for organ injury, and the transplantation of MSC-derived mitochondria to injured tissues might represent an attractive new therapeutic approach.

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FUNDC1: An Emerging Mitochondrial and MAMs Protein for Mitochondrial Quality Control in Heart Diseases

Cited by 6 publications

References 87 publications

Inhibition of Cyp1a Protects Mice against Anthracycline Cardiomyopathy

Inhibition of Cyp1a Protects Mice against Anthracycline Cardiomyopathy

Mitochondrial Kinase Signaling for Cardioprotection

Therapeutic Effects of Mesenchymal Stromal Cells Require Mitochondrial Transfer and Quality Control

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