Patients with multiple myeloma develop resistance to thalidomide during therapy, and the mechanisms to counteract thalidomide resistance remain elusive. Here, we explored the interaction between cereblon and mitochondrial function to mitigate thalidomide resistance in multiple myeloma. Measurements of cell viability, ATP production, mitochondrial membrane potential, mitochondrial ROS, and protein expression via western blotting were conducted in vitro using KSM20 and KMS26 cells to assess the impact of thalidomide on multiple myeloma. An in vivo analysis using xenografted multiple myeloma cells in BALB/c nude mice revealed that KMS20 cells were resistant to thalidomide, whereas KMS26 cells were sensitive. Overexpression of CRBN in a KMS20 xenograft model reversed its resistance to thalidomide, reduced tumor growth, and significantly extended the survival rate of the mice. Overexpression of CRBN in thalidomide-resistant KMS20 cells during thalidomide treatment led to effective cell death through the modulation of mitochondrial function and protein expression, mediated by AMPKα1 signaling. Conversely, both genetic and pharmacological knockdowns of CRBN rendered KMS26 cells resistant to thalidomide, indicating that CRBN level modulation directly influences mitochondrial functions. These findings propose that targeting cereblon offers a promising strategy in overcoming thalidomide resistance in multiple myeloma through mitochondrial reprogramming. [BMB Reports 2026; 59(3): 193-200].

Diabetic cardiomyopathy (DCM) is a major complication of type 2 diabetes mellitus and a leading contributor to heart failure. A central feature of DCM is the disruption of mitochondrial bioenergetics and calcium homeostasis, processes that are tightly regulated through mitochondria-associated endoplasmic reticulum membranes (MAMs). These endoplasmic reticulum (ER)-mitochondria contact sites coordinate mitochondrial ion transport systems, including the mitochondrial calcium uniporter, Na+/Ca2+ exchanger, and potassium channels, which collectively govern mitochondrial metabolism, redox balance, and cell survival. Sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially developed as glucose-lowering agents, have recently demonstrated robust cardioprotective effects independent of glycemic control. Emerging evidence suggests that these benefits are partly mediated through the regulation of mitochondrial function and ER stress signaling. In this review, we discuss how SGLT2 inhibitors-particularly empagliflozin, canagliflozin, and dapagliflozin-modulate mitochondrial ion homeostasis, mitochondrial dynamics, and mitophagy in diabetic hearts. We further highlight their potential role in stabilizing ER-mitochondria communication by attenuating unfolded protein response signaling and restoring calcium balance at MAM interfaces. Finally, we explore the emerging concept that combining SGLT2 inhibitors with exercise may synergistically improve mitochondrial quality control and ER-mitochondria coupling, representing a promising pharmaco-lifestyle strategy for diabetic cardiomyopathy. Understanding how mitochondrial ion transport and organelle cross talk are modulated by SGLT2 inhibitors may provide new mechanistic insights and therapeutic opportunities for cardiometabolic diseases.

Ischemic cardiomyopathy (ICM) is characterized by impaired myocardial function resulting from reduced coronary blood flow, resulting in heart failure. Emerging evidence from proteomic studies indicates that ischemic preconditioning confers cardioprotection against ICM through the regulation of mitochondrial proteins. Proteomic analyses have identified phosphorylation in mitochondrial proteins, including malate dehydrogenase 2 (MDH2), as mediators of cardioprotective mechanisms. However, the mechanism by which MDH2 phosphorylation contributes to cardioprotection in cardiovascular diseases remains poorly understood. This study investigates the role of MDH2 phosphorylation, particularly at S246, in regulating cardiac function. Analysis of patients with dilated cardiomyopathy indicated no significant change in MDH2 expression, similar to a trend observed in ischemic patient data. Considering that a previous proteomic analysis of ischemic preconditioned rat hearts indicated phosphorylation at S246, we analyzed the functional role of this phosphorylation by introducing S246A phosphomutation. S246A phosphomutation significantly decreased MDH2 activity, accompanied by an increased accumulation of acetate and lactate as demonstrated by metabolomics. S246A phosphomutation also lowers mitochondrial membrane potential and ATP production. Under hypoxia/reoxygenation (H/R) conditions, S246A phosphomutation downregulates mitochondrial biogenesis and fusion proteins such as PGC1α and OPA1. Overall, these findings suggest that MDH2 phosphorylation at S246 is important in protecting against H/R injury through mitochondrial function regulation and activation of metabolic pathways. This discovery establishes a potential therapeutic strategy and a clear direction for drug development to specifically address conditions such as ICM.

center dot This study investigated how cereblon (CRBN), a substrate receptor of the E3 ubiquitin ligase complex that selectively degrades ion channels, targets cardiac transient receptor potential channel 1 (TRPC1). center dot Physiologically, CRBN ablation upregulated TRPC1 expression. center dot Mechanistically, the CRBN Lon domain directly interacts with the C- and N-terminals of TRPC1. center dot Increasing CRBN levels enhanced TRPC1 ubiquitination and proteasomal degradation. center dot TRPC1 overexpression in HEK293-CRBN KO cells enhanced TRPC1 current density and Ca2+ transients. center dot Pathologically, cardiac TRPC1 expression in CRBN-deficient mice was increased during ex vivo ischemic/reperfusion. center dot Targeting the CRBN-TRPC1 axis may serve as a novel therapeutic approach to address cardiac disease.

AIMS Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that was reported to target ion channel proteins. L-type voltage-dependent Ca2+ channel (LTCC) density and dysfunction is a critical player in heart failure with reduced ejection fraction (HFrEF). However, the underlying cellular mechanisms by which CRBN regulates LTCC subtype Cav1.2α during cardiac dysfunction remain unclear. Here, we explored the role of CRBN in HFrEF by investigating the direct regulatory role of CRBN in Cav1.2α activity and examining how it can serve as a target to address myocardial dysfunction. METHODS AND RESULTS Cardiac tissues from HFrEF patients exhibited increased levels of CRBN compared with controls. In vivo and ex vivo studies demonstrated that whole-body CRBN knockout (CRBN-/-) and cardiac-specific knockout mice (Crbnfl/fl/Myh6Cre+) exhibited enhanced cardiac contractility with increased LTCC current (ICaL) compared with their respective controls, which was modulated by the direct interaction of CRBN with Cav1.2α. Mechanistically, the Lon domain of CRBN directly interacted with the N-terminal of Cav1.2α. Increasing CRBN levels enhanced the ubiquitination and proteasomal degradation of Cav1.2α and decreased ICaL. In contrast, genetic or pharmacological depletion of CRBN via TD-165, a novel PROTAC-based CRBN degrader, increased surface expression of Cav1.2α and enhanced ICaL. Low CRBN levels protected the heart against cardiomyopathy in vivo. CONCLUSION Cereblon selectively degrades Cav1.2α, which in turn facilitates cardiac dysfunction. A targeted approach or an efficient method of reducing CRBN levels could serve as a promising strategy for HFrEF therapeutics. KEY QUESTION KEY FINDING TAKE-HOME MESSAGE Cereblon modulates cardiac function by altering Cav1.2α current density and CRBN-targeting therapy could serve as a novel strategy for future HFrEF therapeutics.

Recent trends suggest novel natural compounds as promising treatments for cardiovascular disease. The authors examined how neopetroside A, a natural pyridine nucleoside containing an α-glycoside bond, regulates mitochondrial metabolism and heart function and investigated its cardioprotective role against ischemia/reperfusion injury. Neopetroside A treatment maintained cardiac hemodynamic status and mitochondrial respiration capacity and significantly prevented cardiac fibrosis in murine models. These effects can be attributed to preserved cellular and mitochondrial function caused by the inhibition of glycogen synthase kinase-3 beta, which regulates the ratio of nicotinamide adenine dinucleotide to nicotinamide adenine dinucleotide, reduced, through activation of the nuclear factor erythroid 2-related factor 2/NAD(P)H quinone oxidoreductase 1 axis in a phosphorylation-independent manner.

OBJECTIVE:Ischemic cardiomyopathy (ICM) is the leading cause of heart failure. Proteomic and genomic studies have demonstrated ischemic preconditioning (IPC) can assert cardioprotection against ICM through mitochondrial function regulation. Considering IPC is conducted in a relatively brief period, regulation of protein expression also occurs very rapidly, highlighting the importance of protein function modulation by post-translational modifications. This study aimed to identify and analyze novel phosphorylated mitochondrial proteins that can be harnessed for therapeutic strategies for preventing ischemia/reperfusion (I/R) injury.METHODS:Sprague-Dawley rat hearts were used in an ex vivo Langendorff system to simulate normal perfusion, I/R, and IPC condition, after which the samples were prepared for phosphoproteomic analysis. Employing human cardiomyocyte AC16 cells, we investigated the cardioprotective role of CKMT2 through overexpression and how site-directed mutagenesis of putative CKMT2 phosphorylation sites (Y159A, Y255A, and Y368A) can affect cardioprotection by measuring CKMT2 protein activity, mitochondrial function and protein expression changes.RESULTS:The phosphoproteomic analysis revealed dephosphorylation of mitochondrial creatine kinase (CKMT2) during ischemia and I/R, while preserving its phosphorylated state during IPC. CKMT2 overexpression conferred cardioprotection against hypoxia/reoxygenation (H/R) by increasing cell viability and mitochondrial adenosine triphosphate level, preserving mitochondrial membrane potential, and reduced reactive oxygen species (ROS) generation, while phosphomutations, especially in Y368, nullified cardioprotection by significantly reducing cell viability and increasing ROS production during H/R. CKMT2 overexpression increased mitochondrial function by mediating the proliferator-activated receptor γ coactivator-1α/estrogen-related receptor-α pathway, and these effects were mostly inhibited by Y368A mutation.CONCLUSION:These results suggest that regulation of quantitative expression and phosphorylation site Y368 of CKMT2 offers a unique mechanism in future ICM therapeutics.

Exercise has health benefits and prevents a range of chronic diseases caused by physiological and biological changes in the whole body. Generally, the metabolic regulation of skeletal muscle through exercise is known to have a protective effect on the pathogenesis of metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), and cardiovascular disease (CVD). Besides this, the importance of the liver as an endocrine organ is a hot research topic. Hepatocytes also secrete many hepatokines in response to nutritional conditions and/or physical activity. In particular, certain hepatokines play a major role in the regulation of whole-body metabolic homeostasis. In this review, we summarize the recent research findings on the exercise-mediated regulation of hepatokines, including fibroblast growth factor 21, fetuin-A, angiopoietin-like protein 4, and follistatin. These hepatokines serve as molecular transducers of the metabolic benefits of physical activity in chronic metabolic diseases, including NAFLD, T2D, and CVDs, in various tissues.

HS1793, a novel analogue of resveratrol, was previously determined to be more potent at lower dosages by improving mitochondrial function and increased mitochondrial biogenesis-related proteins. In this study, we focused on targeting the mitochondria to address muscle wasting with HS-1793. Dosage screening was performed by evaluating for cytotoxicity and cell proliferation. Mitochondrial mass, mitochondrial membrane potential (Δψm), reactive oxygen species (ROS) level, and mitochondria biogenesis-regulated genes and proteins were analyzed to determine the effects on mitochondrial biogenesis. HS-1793 reduced ROS generation, but treatment did not interfere with cellular viability at low dosages. HS-1793 also regulated mitochondrial function by increasing cellular and mitochondrial ATP synthesis function, stabilizing Δψm and decreasing ROS. More importantly, these dysfunction in these parameters were ameliorated by HS-1793 in a simulated oxidative stress model with tBHP. We also observed increase in mitochondrial mass and upregulation in vital mitochondrial biogenesis-related gene PGC1-α as a response to HS-1793 treatment. Moreover, phosphorylation of AKT and mTOR proteins, which are considered as regulators of skeletal muscle function were also increased during the treatment. Finally, HS-1793 also demonstrated protective effects against cisplatin-induced skeletal muscle cell injury by increasing expression of mitochondrial biogenesis-relate markers. Taken altogether, it shows the viability of HS-1793 as a compound that can restore mitochondrial function and render protection in skeletal muscle cells, especially during high oxidative stress levels.

Mitochondrion, a maternally hereditary, subcellular organelle, is the site of the tricarboxylic acid (TCA) cycle, electron transport chain (ETC), and oxidative phosphorylation (OXPHOS)—the basic processes of ATP production. Mitochondrial function plays a pivotal role in the development and pathology of different cancers. Disruption in its activity, like mutations in its TCA cycle enzymes, leads to physiological imbalances and metabolic shifts of the cell, which contributes to the progression of cancer. In this review, we explored the different significant mutations in the mitochondrial enzymes participating in the TCA cycle and the diseases, especially cancer types, that these malfunctions are closely associated with. In addition, this paper also discussed the different therapeutic approaches which are currently being developed to address these diseases caused by mitochondrial enzyme malfunction.

https://e-kcj.org Heart failure (HF) is a multi-factorial disease characterized by the inability of the heart to pump sufficient blood throughout the surrounding tissues. Scientific advances have recently aided in decreasing deaths attributed to HF; however, prevalence continues to increase as it threatens at least 26 million people globally.1) HF progression depends on several pre-existing conditions such as ischemic diseases like myocardial infarction (MI), eventually resulting in the death of cardiac cells. However, regeneration of cardiac cells in the adult heart is limited after injury and is instead replaced with a fibrotic scar. Therefore, researchers have resorted to stem cell therapy to restore these lost cells, and have demonstrated in numerous occasions the regenerative capabilities of cardiac progenitor cells (CPCs).2) CPCs can differentiate into various cell types including cardiomyocytes, and are capable of migration and tube formation, an important characteristic for developing therapies for ischemic myocardium.

Unlike stable and immobile cell line conditions, animal hearts contract and relax to pump blood throughout the body. Mitochondria play an essential role by producing biological energy molecules to maintain heart function. In this study, we assessed the effect of heart mimetic cyclic stretch on mitochondria in a cardiac cell line. To mimic the geometric and biomechanical conditions surrounding cells in vivo, cyclic stretching was performed on HL-1 murine cardiomyocytes seeded onto an elastic micropatterned substrate (10% elongation, 0.5 Hz, 4 h/day). Cell viability, semi-quantitative Q-PCR, and western blot analyses were performed in non-stimulated control and cyclic stretch stimulated HL-1 cell lines. Cyclic stretch significantly increased the expression of mitochondria biogenesis-related genes (TUFM, TFAM, ERRα, and PGC1-α) and mitochondria oxidative phosphorylation-related genes (PHB1 and CYTB). Western blot analysis confirmed that cyclic stretch increased protein levels of mitochondria biogenesis-related proteins (TFAM, and ERRα) and oxidative phosphorylation-related proteins (NDUFS1, UQCRC, and PHB1). Consequently, cyclic stretch increased mitochondrial mass and ATP production in treated cells. Our results suggest that cyclic stretch transcriptionally enhanced mitochondria biogenesis and oxidative phosphorylation without detrimental effects in a cultured cardiac cell line.

Decorin (DCN) is a proteoglycan constituent of the extracellular matrix (ECM) possessing powerful antifibrotic, anti-inflammation, antioxidant, and antiangiogenic properties. By attaching to receptors in the cell surface or to several ECM molecules, it regulates plenty of cellular functions, consequently influencing cell differentiation, proliferation, and apoptosis. These processes are dependent on cell types, biological contexts, and interfere with pathological processes such as cardiovascular diseases. In this review, we briefly discuss the potential of DCN targeting in addressing cardiovascular diseases (CVD). We dive into its interactome and discuss how its interaction with the proteins can affect disease progression, and how DCN can be a possible target for CVD therapeutics.

Metabolic disturbance and mitochondrial dysfunction are a hallmark of diabetic cardiomyopathy (DC). Resistance exercise (RE) not only enhances the condition of healthy individuals but could also improve the status of those with disease. However, the beneficial effects of RE in the prevention of DC and mitochondrial dysfunction are uncertain. Therefore, this study investigated whether RE attenuates DC by improving mitochondrial function using an in vivo rat model of diabetes. Fourteen Otsuka Long-Evans Tokushima Fatty rats were assigned to sedentary control (SC, n = 7) and RE ( n = 7) groups at 28 weeks of age. Long-Evans Tokushima Otsuka rats were used as the non-diabetic control. The RE rats were trained by 20 repetitions of climbing a ladder 5 days per week. RE rats exhibited higher glucose uptake and lower lipid profiles, indicating changes in energy metabolism. RE rats significantly increased the ejection fraction and fractional shortening compared with the SC rats. Isolated mitochondria in RE rats showed increase in mitochondrial numbers, which were accompanied by higher expression of mitochondrial biogenesis proteins such as proliferator-activated receptor-γ coactivator-1α and TFAM. Moreover, RE rats reduced proton leakage and reactive oxygen species production, with higher membrane potential. These results were accompanied by higher superoxide dismutase 2 and lower uncoupling protein 2 (UCP2) and UCP3 levels in RE rats. These data suggest that RE is effective at ameliorating DC by improving mitochondrial function, which may contribute to the maintenance of diabetic cardiac contractility.

Mitochondria are complex organelles essential for the production of energy. These dynamic, complex organelles found in every cell and tissues of the body have been well-studied in various physiological models, stressing that mitochondrial dysfunction is characteristic of pathological states, especially in cardiovascular diseases and heart failure. Since heart failure progresses due to energy deficits brought about by altered mitochondrial bioenergetics and functioning, novel ways of ameliorating mitochondrial dysfunction are being studied. Interestingly, various exercise modalities can serve as stimuli which can regulate the mitochondria in different ways, such as in the increase of mitochondrial mass and copy number, in the structural fusion and fission processes, and the removal of impaired mitochondria. Considering that there are numerous kinds and protocols for exercise, there are a number of ways exercise can affect the mitochondria as well. Nonetheless these processes affect each other to an extent, highlighting the pivotal role exercise plays in improving or enhancing the state of mitochondria during disease. This chapter will focus on how exercise of different can regulate mitochondrial processes, which could be used as therapeutic strategies in addressing heart failure.

Mast cells are primary mediators of allergic inflammation. Beta-1,3-glucan (BG) protects against infection and shock by activating immune cells. Activation of the BG receptor induces an increase in intracellular Ca2+, which may induce exocytosis. However, little is known about the precise mechanisms underlying BG activation of immune cells and the possible role of mitochondria in this process. The present study examined whether BG induced mast cell degranulation, and evaluated the role of calcium transients during mast cell activation. Our investigation focused on the role of the mitochondrial calcium uniporter (MCU) in BG-induced degranulation. Black mouse (C57) bone marrow-derived mast cells were stimulated with 0.5 µg/ml BG, 100 µg/ml peptidoglycan (PGN), or 10 µM A23187 (calcium ionophore), and dynamic changes in cytosolic and mitochondrial calcium and membrane potential were monitored. BG-induced mast cell degranulation occurred in a time-dependent manner, and was significantly reduced under calcium-free conditions. Ruthenium red, a mitochondrial Ca2+ uniporter blocker, significantly reduced mast cell degranulation induced by BG, PGN, and A23187. These results suggest that the mitochondrial Ca2+ uniporter has an important regulatory role in BG-induced mast cell degranulation.

Heart failure (HF) is a multifactorial disease brought about by numerous, and oftentimes complex, etiological mechanisms. Although well studied, HF continues to affect millions of people worldwide and current treatments can only prevent further progression of HF. Mitochondria undoubtedly play an important role in the progression of HF, and numerous studies have highlighted mitochondrial components that contribute to HF. This review presents an overview of the role of mitochondrial biogenesis, mitochondrial oxidative stress, and mitochondrial permeability transition pore in HF, discusses ongoing studies that attempt to address the disease through mitochondrial targeting, and provides an insight on how these studies can affect future research on HF treatment.

Protein post-translational modifications (PTMs) are crucial in regulating cellular biology by playing key roles in processes such as the rapid on and off switching of signaling network and the regulation of enzymatic activities without affecting gene expressions.PTMs lead to conformational changes in the tertiary structure of protein and resultant regulation of protein function such as activation, inhibition, or signaling roles.PTMs such as phosphorylation, acetylation, and S-nitrosylation of specific sites in proteins have key roles in regulation of mitochondrial functions, thereby contributing to the progression to heart failure.Despite the extensive study of PTMs in mitochondrial proteins much remains unclear.Further research is yet to be undertaken to elucidate how changes in the proteins may lead to cardiovascular and metabolic disease progression in particular.We aimed to summarize the various types of PTMs that occur in mitochondrial proteins, which might be associated with heart failure.This study will increase the understanding of cardiovascular diseases through PTM. (

Although the antioxidant and cardioprotective effects of NecroX-5 on various in vitro and in vivo models have been demonstrated, the action of this compound on the mitochondrial oxidative phosphorylation system remains unclear. Here we verify the role of NecroX-5 in protecting mitochondrial oxidative phosphorylation capacity during hypoxia-reoxygenation (HR). Necrox-5 treatment (10 µM) and non-treatment were employed on isolated rat hearts during hypoxia/reoxygenation treatment using an ex vivo Langendorff system. Proteomic analysis was performed using liquid chromatography-mass spectrometry (LC-MS) and non-labeling peptide count protein quantification. Real-time PCR, western blot, citrate synthases and mitochondrial complex activity assays were then performed to assess heart function. Treatment with NecroX-5 during hypoxia significantly preserved electron transport chain proteins involved in oxidative phosphorylation and metabolic functions. NecroX-5 also improved mitochondrial complex I, II, and V function. Additionally, markedly higher peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC1α) expression levels were observed in NecroX-5-treated rat hearts. These novel results provide convincing evidence for the role of NecroX-5 in protecting mitochondrial oxidative phosphorylation capacity and in preserving PGC1α during cardiac HR injuries.

The physiological changes, including cardiac modification, that occur during starvation are not yet completely understood. The purpose of this study is to examine the effects of a 2-week starvation period on heart contractility, muscle mass, and irisin and corticosterone levels in rats. Rats in the starved group showed a significant reduction in the body, heart, kidney, and muscle weight (n = 23, p < 0.05). Blood glucose, total protein, and albumin showed a 44, 17.5, and 10.3 % reduction, respectively (p < 0.05). Lipid reserves, such as total lipid, triglyceride, and free fatty acid, were also comparably reduced (p < 0.05). However, the bilirubin, creatinine, blood urea nitrogen, and creatine kinase levels were higher than in the control group (p < 0.05). The blood irisin level was unchanged, but the stress-related corticosterone level was significantly higher in the starved group. The differences observed in M-mode echocardiography were further compared with the body-weight-matched control group. Starvation reduced the left ventricle mass; however, this difference was not significant compared with the body-weight-matched group (p > 0.05). In the starvation group, the impairment of cardiac output was dependent on the reduction in stroke volume and heart rate. Starvation induced a severe reduction in ejection fraction and fractional shortening when compared with the body-weight-matched control group (p < 0.05). In summary, prolonged starvation, which leads to a deficiency of available nutrition, increases the stress-related corticosterone level, impairs the cardiac output, and is associated with changes in cardiac morphogeometry.