Novel insights into the involvement of mitochondrial fission/fusion in heart failure: From molecular mechanisms to targeted therapies

Liu, Xinxin; Guo, Chenchen; Zhang, Qiming

doi:10.1007/s12192-023-01321-4

Cited by 12 publications

(8 citation statements)

References 133 publications

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“…Besides the action in the fission process, Mid51 can competitively decrease the interaction of Fis1 with Mfn1 and Mfn2 ( Yu et al, 2021 ). It was previously suggested that Fis1/Mid51 PPI regulation could provide a therapeutic target for CVD ( Vásquez-Trincado and Schinkel, 2016 ; Liu et al, 2023 ). Furthermore, peptides corresponding to specific regions of interacting proteins have been shown to be effective PPI inhibitors ( Disatnik et al, 2013 ; Qi et al, 2013 ).…”

Section: Resultsmentioning

confidence: 99%

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Selective inhibitors targeting Fis1/Mid51 protein-protein interactions protect against hypoxia-induced damage in cardiomyocytes

Zerihun,

Qvit

2023

Front. Pharmacol.

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Cardiovascular diseases (CVDs) are the most common non-communicable diseases globally. An estimated 17.9 million people died from CVDs in 2019, representing 32% of all global deaths. Mitochondria play critical roles in cellular metabolic homeostasis, cell survival, and cell death, as well as producing most of the cell’s energy. Protein–protein interactions (PPIs) have a significant role in physiological and pathological processes, and aberrant PPIs are associated with various diseases, therefore they are potential drug targets for a broad range of therapeutic areas. Due to their ability to mimic natural interaction motifs and cover relatively larger interaction region, peptides are very promising as PPI inhibitors. To expedite drug discovery, computational approaches are widely used for screening potential lead compounds. Here, we developed peptides that inhibit mitochondrial fission 1 (Fis1)/mitochondrial dynamics 51 kDa (Mid51) PPI to reduce the cellular damage that can lead to various human pathologies, such as CVDs. Based on a rational design approach we developed peptide inhibitors of the Fis1/Mid51 PPI. In silico and in vitro studies were done to evaluate the biological activity and molecular interactions of the peptides. Two peptides, CVP-241 and CVP-242 were identified based on low binding energy and molecular dynamics simulations. These peptides inhibit Fis1/Mid51 PPI (-1324.9 kcal mol−1) in docking calculations (CVP-241, -741.3 kcal mol−1, and CVP-242, -747.4 kcal mol−1), as well as in vitro experimental studies Fis1/Mid51 PPI (KD 0.054 µM) Fis1/Mid51 PPI + CVP-241 (KD 3.43 µM), and Fis1/Mid51 PPI + CVP-242 (KD 44.58 µM). Finally, these peptides have no toxicity to H9c2 cells, and they increase cell viability in cardiomyocytes (H9c2 cells). Consequently, the identified inhibitor peptides could serve as potent molecules in basic research and as leads for therapeutic development.

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Section: Resultsmentioning

confidence: 99%

“…It was suggested that Fis1/Mid51 PPI results in increased mitochondrial pathological fission ( Zhao et al, 2011 ; Vásquez-Trincado and Schinkel, 2016 ; Liu et al, 2023 ). Moreover, imbalanced mitochondrial dynamics were demonstrated to lead to a number of human pathologies, such as CVDs ( Zerihun et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Selective inhibitors targeting Fis1/Mid51 protein-protein interactions protect against hypoxia-induced damage in cardiomyocytes

Zerihun,

Qvit

2023

Front. Pharmacol.

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“…According to preliminary experimental findings on mitochondrial dynamics in the context of myocardial I/R injury, inhibiting Drp1-mediated mitochondrial fission triggered by myocardial ischemia may be a therapeutic strategy for shielding the heart against acute I/R injury ( Figure 8 ). The interplay between Drp1-mediated or other mitochondrial fission proteins (Fis1, Mff, Mid49, or Mid51) mediated disturbances in mitochondrial homeostasis which may lead to a series of complex CVDs, such as myocardial I/R injury, heart failure, and endothelial dysfunction [ 62 , 157 ]. The most-investigated proteins involved in mitochondrial fission are Drp1 and Fis1 [ 158 ].…”

Section: Mitochondrial Fission Proteins and Cardiovascular Diseasesmentioning

confidence: 99%

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

Zerihun

Sukumaran

Qvit

2023

IJMS

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

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“…Despite having a ȥ-potential of −31.4 ± 1.54 mV [227], the electrical biosensor potency has not been studied. As a result, PDT, CDT, and pH are being studied for mitochondrial membrane targeted therapy in cancer, with less off-target toxicity and more desirable therapeutic effects [229]. Nonetheless, the challenges of CuZn in overcoming MBD and PBD chemoresistance should be investigated further because a contrary study found that zinc (II) complexes have lower cytotoxicity than copper (II) complexes [162].…”

Section: Challenges and Futurementioning

confidence: 99%

Combining Copper and Zinc into a Biosensor for Anti-Chemoresistance and Achieving Osteosarcoma Therapeutic Efficacy

Zaidi¹,

Miskon²

2023

Preprint

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Due to its built-up chemoresistance after prolonged usage, the demand for replacing platinum in metal-based drugs (MBD) is rising. The first MBD approved by the FDA for cancer therapy was cisplatin in 1978. Even after nearly four and a half decades of trials, there has been no significant improvement in osteosarcoma (OS) therapy. In fact, many MBD have been developed, but the chemoresistance problem raised by platinum remains unresolved. This motivates us to elucidate the possibilities of the copper and zinc (CuZn) combination to replace platinum in MBD. Thus, the anti-chemoresistance properties of CuZn and their physiological functions for OS therapy are highlighted. Herein, we summarise their chelators, main organic solvents, and ligand functions in their structures that are involved in anti-chemoresistance properties. Through this review, it is rational to discuss their ligands’ roles as biosensors in drug delivery systems. Hereafter, an in-depth understanding of their redox and photoactive function relationships is provided. The disadvantage is that the other functions of biosensors cannot be elaborated on here. As a result, this review is being developed, which is expected to intensify OS drugs with higher cure rates. Nonetheless, this advancement intends to solve the major chemoresistance obstacle towards clinical efficacy.

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Novel insights into the involvement of mitochondrial fission/fusion in heart failure: From molecular mechanisms to targeted therapies

Cited by 12 publications

References 133 publications

Selective inhibitors targeting Fis1/Mid51 protein-protein interactions protect against hypoxia-induced damage in cardiomyocytes

Selective inhibitors targeting Fis1/Mid51 protein-protein interactions protect against hypoxia-induced damage in cardiomyocytes

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

Combining Copper and Zinc into a Biosensor for Anti-Chemoresistance and Achieving Osteosarcoma Therapeutic Efficacy

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