bims-mimcad 2024-06-23 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024‒06‒23
eleven papers selected by
Henver Brunetta, University of Guelph

Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension.
Intramuscular diacylglycerol accumulates with acute hyperinsulinemia in insulin-resistant phenotypes.
Loss of mitochondrial pyruvate transport initiates cardiac glycogen accumulation and heart failure.
Cardiomyocyte-specific Tbk1 Deletion Aggravated Chronic Doxorubicin Cardiotoxicity via Inhibition of Mitophagy.
Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor.
DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring.
Fueling the heartbeat: Dynamic regulation of intracellular ATP during excitation-contraction coupling in ventricular myocytes.
Complexities of treating co-morbidities in heart failure with preserved ejection fraction.
Hypertriglyceridemia Results From an Impaired Catabolism of Triglyceride-Rich Lipoproteins in PLIN1-Related Lipodystrophy.
Mitochondrial calcium in cardiac ischemia/reperfusion injury and cardioprotection.
Chronic mitochondrial dynamic-targeted therapy alleviates left ventricular dysfunction by reducing multiple programmed cell death in post-myocardial infarction rats.

bioRxiv. 2024 Jun 09. pii: 2024.06.06.597821. [Epub ahead of print]

Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension.

Justin H Berger, Yuji Shi, Timothy R Matsuura, Kirill Batmanov, Xian Chen, Kelly Tam, Mackenzie Marshall, Richard Kue, Jiten Patel, Renee Taing, Russell Callaway, Joanna Griffin, Attila Kovacs, Dinesh Hirenallur Shanthappa, Russell Miller, Bei B Zhang, Rachel J Roth Flach, Daniel P Kelly.

Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We have developed a novel "2-hit" model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57BL6/NJ mice fed a high fat diet for >10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse Renin1d . Control mice, HFD only, Renin only and HFD-Renin (aka "HFpEF") littermates underwent a battery of cardiac and extracardiac phenotyping. HFD-Renin mice demonstrated obesity and insulin resistance, a 2-3-fold increase in circulating renin levels that resulted in 30-40% increase in left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by altered E/e', IVRT, and strain measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to findings in human HFpEF. Treatment of these mice with the sodium-glucose cotransporter 2 inhibitor empagliflozin, an effective but incompletely understood HFpEF therapy, improved exercise tolerance, left heart enlargement, and insulin homeostasis. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Addition of HFD-Renin mice to the preclinical HFpEF model platform allows for orthogonal studies to increase validity in assessment of interventions.NEW & NOTEWORTHY: Heart failure with preserved ejection fraction (HFpEF) is a complex disease to study due to limited preclinical models. We rigorously characterize a new two-hit HFpEF mouse model, which allows for dissecting individual contributions and synergy of major pathogenic drivers, hypertension and diet-induced obesity. The results are consistent and reproducible in two independent laboratories. This high-fidelity pre-clinical model increases the available, orthogonal models needed to improve our understanding of the causes and assessment treatments for HFpEF.

DOI: https://doi.org/10.1101/2024.06.06.597821
Am J Physiol Endocrinol Metab. 2024 Jun 19.

Intramuscular diacylglycerol accumulates with acute hyperinsulinemia in insulin-resistant phenotypes.

Colleen F McKenna, Harrison D Stierwalt, Karin A Zemski Berry, Sarah E Ehrlicher, Matthew M Robinson, Simona Zarini, Darcy E Kahn, Janet K Snell-Bergeon, Leigh Perreault, Bryan C Bergman, Sean A Newsom.

  Elevated skeletal muscle diacylglycerols (DAG) and ceramides can impair insulin signaling, and acylcarnitines (acylCN) reflect impaired fatty acid oxidation, thus the intramuscular lipid profile is indicative of insulin resistance. Acute (i.e., postprandial) hyperinsulinemia has been shown to elevate lipids in healthy muscle and is an independent risk factor for type 2 diabetes (T2D). It is unclear how the relationship between acute hyperinsulinemia and the muscle lipidome interacts, thus contributing to or exacerbating insulin resistance. We investigated the impact of acute hyperinsulinemia on the muscle lipidome in order to help characterize the physiological basis in which hyperinsulinemia elevates T2D risk. Endurance athletes (n=12), sedentary lean adults (n=12), and individuals with obesity (n=13) and T2D (n=7) underwent a hyperinsulinemic-euglycemic clamp with muscle biopsies. While there were no significant differences in total 1,2-DAG fluctuations, there was a 2% decrease in athletes versus a 53% increase in T2D. C18 1,2-DAGs increased during the clamp with T2D only, which negatively correlated with insulin sensitivity. Basal muscle C18:0 ceramides were elevated with T2D, but not altered by clamp. Acylcarnitines were universally lowered during hyperinsulinemia, with more robust reductions of 80% in athletes compared to only 46% with T2D. Similar fluctuations with acute hyperinsulinemia increasing 1,2 DAGs in insulin-resistant phenotypes and universally lowering acylcarnitines were observed in male mice. In conclusion, acute hyperinsulinemia elevates muscle 1,2-DAG levels with insulin-resistant phenotypes. This suggests a possible dysregulation of intramuscular lipid metabolism in the fed state in individuals with low insulin sensitivity, which may exacerbate insulin resistance.

Keywords:  acylcarnitine; ceramides; diacylglycerol; insulin resistance; skeletal muscle

DOI:  https://doi.org/10.1152/ajpendo.00368.2023
bioRxiv. 2024 Jun 09. pii: 2024.06.06.597841. [Epub ahead of print]

Loss of mitochondrial pyruvate transport initiates cardiac glycogen accumulation and heart failure.

Rachel C Weiss, Kelly D Pyles, Kevin Cho, Michelle Brennan, Jonathan S Fisher, Gary J Patti, Kyle S McCommis.

Background: Heart failure involves metabolic alterations including increased glycolysis despite unchanged or decreased glucose oxidation. The mitochondrial pyruvate carrier (MPC) regulates pyruvate entry into the mitochondrial matrix, and cardiac deletion of the MPC in mice causes heart failure. How MPC deletion results in heart failure is unknown.Methods: We performed targeted metabolomics and isotope tracing in wildtype (fl/fl) and cardiac-specific Mpc2-/- (CS-Mpc2-/-) hearts after in vivo injection of U- 13 C-glucose. Cardiac glycogen was assessed biochemically and by transmission electron microscopy. Cardiac uptake of 2-deoxyglucose was measured and western blotting performed to analyze insulin signaling and enzymatic regulators of glycogen synthesis and degradation. Isotope tracing and glycogen analysis was also performed in hearts from mice fed either low-fat diet or a ketogenic diet previously shown to reverse the CS-Mpc2-/- heart failure. Cardiac glycogen was also assessed in mice infused with angiotensin-II that were fed low-fat or ketogenic diet.
Results: Failing CS-Mpc2-/- hearts contained normal levels of ATP and phosphocreatine, yet these hearts displayed increased enrichment from U- 13 C-glucose and increased glycolytic metabolite pool sizes. 13 C enrichment and pool size was also increased for the glycogen intermediate UDP-glucose, as well as increased enrichment of the glycogen pool. Glycogen levels were increased ∼6-fold in the failing CS-Mpc2-/- hearts, and glycogen granules were easily detected by electron microscopy. This increased glycogen synthesis occurred despite enhanced inhibitory phosphorylation of glycogen synthase and reduced expression of glycogenin-1. In young, non-failing CS-Mpc2-/- hearts, increased glycolytic 13 C enrichment occurred, but glycogen levels remained low and unchanged compared to fl/fl hearts. Feeding a ketogenic diet to CS-Mpc2-/- mice reversed the heart failure and normalized the cardiac glycogen and glycolytic metabolite accumulation. Cardiac glycogen levels were also elevated in mice infused with angiotensin-II, and both the cardiac hypertrophy and glycogen levels were improved by ketogenic diet.
Conclusions: Our results indicate that loss of MPC in the heart causes glycogen accumulation and heart failure, while a ketogenic diet can reverse both the glycogen accumulation and heart failure. We conclude that maintaining mitochondrial pyruvate import and metabolism is critical for the heart, unless cardiac pyruvate metabolism is reduced by consumption of a ketogenic diet.

DOI: https://doi.org/10.1101/2024.06.06.597841
Free Radic Biol Med. 2024 Jun 18. pii: S0891-5849(24)00526-4. [Epub ahead of print]

Cardiomyocyte-specific Tbk1 Deletion Aggravated Chronic Doxorubicin Cardiotoxicity via Inhibition of Mitophagy.

Wenjun Yu, Dawei Deng, Yang Li, Kehan Ding, Qiaofeng Qian, Hongjie Shi, Qiujie Luo, Jie Cai, Jinping Liu.

  Doxorubicin (Dox) use is limited by Dox-induced cardiotoxicity. TANK-blinding kinase 1 (TBK1) is an important kinase involved in the regulation of mitophagy, but the role of TBK1 in cardiomyocytes in chronic Dox-induced cardiomyopathy remains unclear. Cardiomyocyte-specific Tbk1 knockout (Tbk1CKO) mice received Dox (6 mg/kg, injected intraperitoneally) once a week for 4 times, and cardiac assessment was performed 4 weeks after the final Dox injection. Adenoviruses encoding Tbk1 or containing shRNA targeting Tbk1, or a TBK1 phosphorylation inhibitor were used for overexpression or knockdown of Tbk1, or inhibit phosphorylation of TBK1 in isolated primary cardiomyocytes. Our results revealed that moderate Dox challenge decreased TBK1 phosphorylation (with no effect on TBK1 protein levels), resulting in compromised myocardial function, obvious mortality and overt interstitial fibrosis, and the effects were accentuated by Tbk1 deletion. Dox provoked mitochondrial membrane potential collapse and oxidative stress, the effects of which were exacerbated and mitigated by Tbk1 knockdown， specific inhibition of phosphorylation and overexpression, respectively. However， Tbk1 （Ser172A） overexpression did not alleviate these effects. Further scrutiny revealed that TBK1 exerted protective effects on mitochondria via SQSTM1/P62-mediated mitophagy. Tbk1 overexpression mediated cardioprotective effects on Dox-induced cardiotoxicity were cancelled off by Sqstm1/P62 knockdown. Moreover, TBK1-mitophagy-mitochondria cascade was confirmed in heart tissues from dilated cardiomyopathy patients. Taken together, our findings denoted a pivotal role of TBK1 in Dox-induced mitochondrial injury and cardiotoxicity possibly through its phosphorylation and SQSTM1/P62-mediated mitophagy.

Keywords:  Doxorubicin cardiotoxicity; TBK1; mitochondria; mitophagy

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.06.009
Cell Metab. 2024 Jun 11. pii: S1550-4131(24)00186-4. [Epub ahead of print]

Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor.

Ajit Regmi, Eitaro Aihara, Michael E Christe, Gabor Varga, Thomas P Beyer, Xiaoping Ruan, Emily Beebe, Libbey S O'Farrell, Melissa A Bellinger, Aaron K Austin, Yanzhu Lin, Haitao Hu, Debra L Konkol, Samantha Wojnicki, Adrienne K Holland, Jessica L Friedrich, Robert A Brown, Amanda S Estelle, Hannah S Badger, Gabriel S Gaidosh, Sander Kooijman, Patrick C N Rensen, Tamer Coskun, Melissa K Thomas, William Roell.

  Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions in glucose, body weight, and triglyceride levels compared with selective GLP-1R agonists in people with type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte and mouse models, we investigated how long-acting GIPR agonists regulate fasted and fed adipocyte functions. In functional assays, GIPR agonism enhanced insulin signaling, augmented glucose uptake, and increased the conversion of glucose to glycerol in a cooperative manner with insulin; however, in the absence of insulin, GIPR agonists increased lipolysis. In diet-induced obese mice treated with a long-acting GIPR agonist, circulating triglyceride levels were reduced during oral lipid challenge, and lipoprotein-derived fatty acid uptake into adipose tissue was increased. Our findings support a model for long-acting GIPR agonists to modulate both fasted and fed adipose tissue function differentially by cooperating with insulin to augment glucose and lipid clearance in the fed state while enhancing lipid release when insulin levels are reduced in the fasted state.

Keywords:  GIP; GLP-1; adipocyte; adipose; carbohydrate metabolism; insulin; lipid metabolism; nutrient partitioning; tirzepatide

DOI:  https://doi.org/10.1016/j.cmet.2024.05.010
Nat Commun. 2024 Jun 20. 15(1): 5265

DYRK1A signalling synchronizes the mitochondrial import pathways for metabolic rewiring.

Adinarayana Marada, Corvin Walter, Tamara Suhm, Sahana Shankar, Arpita Nandy, Tilman Brummer, Ines Dhaouadi, F-Nora Vögtle, Chris Meisinger.

Mitochondria require an extensive proteome to maintain a variety of metabolic reactions, and changes in cellular demand depend on rapid adaptation of the mitochondrial protein composition. The TOM complex, the organellar entry gate for mitochondrial precursors in the outer membrane, is a target for cytosolic kinases to modulate protein influx. DYRK1A phosphorylation of the carrier import receptor TOM70 at Ser91 enables its efficient docking and thus transfer of precursor proteins to the TOM complex. Here, we probe TOM70 phosphorylation in molecular detail and find that TOM70 is not a CK2 target nor import receptor for MIC19 as previously suggested. Instead, we identify TOM20 as a MIC19 import receptor and show off-target inhibition of the DYRK1A-TOM70 axis with the clinically used CK2 inhibitor CX4945 which activates TOM20-dependent import pathways. Taken together, modulation of DYRK1A signalling adapts the central mitochondrial protein entry gate via synchronization of TOM70- and TOM20-dependent import pathways for metabolic rewiring. Thus, DYRK1A emerges as a cytosolic surveillance kinase to regulate and fine-tune mitochondrial protein biogenesis.

DOI: https://doi.org/10.1038/s41467-024-49611-4
Proc Natl Acad Sci U S A. 2024 Jun 18. 121(25): e2318535121

Fueling the heartbeat: Dynamic regulation of intracellular ATP during excitation-contraction coupling in ventricular myocytes.

Paula Rhana, Collin Matsumoto, Zhihui Fong, Alexandre D Costa, Silvia G Del Villar, Rose E Dixon, L Fernando Santana.

  The heart beats approximately 100,000 times per day in humans, imposing substantial energetic demands on cardiac muscle. Adenosine triphosphate (ATP) is an essential energy source for normal function of cardiac muscle during each beat, as it powers ion transport, intracellular Ca2+ handling, and actin-myosin cross-bridge cycling. Despite this, the impact of excitation-contraction coupling on the intracellular ATP concentration ([ATP]i) in myocytes is poorly understood. Here, we conducted real-time measurements of [ATP]i in ventricular myocytes using a genetically encoded ATP fluorescent reporter. Our data reveal rapid beat-to-beat variations in [ATP]i. Notably, diastolic [ATP]i was <1 mM, which is eightfold to 10-fold lower than previously estimated. Accordingly, ATP-sensitive K+ (KATP) channels were active at physiological [ATP]i. Cells exhibited two distinct types of ATP fluctuations during an action potential: net increases (Mode 1) or decreases (Mode 2) in [ATP]i. Mode 1 [ATP]i increases necessitated Ca2+ entry and release from the sarcoplasmic reticulum (SR) and were associated with increases in mitochondrial Ca2+. By contrast, decreases in mitochondrial Ca2+ accompanied Mode 2 [ATP]i decreases. Down-regulation of the protein mitofusin 2 reduced the magnitude of [ATP]i fluctuations, indicating that SR-mitochondrial coupling plays a crucial role in the dynamic control of ATP levels. Activation of β-adrenergic receptors decreased [ATP]i, underscoring the energetic impact of this signaling pathway. Finally, our work suggests that cross-bridge cycling is the largest consumer of ATP in a ventricular myocyte during an action potential. These findings provide insights into the energetic demands of EC coupling and highlight the dynamic nature of ATP concentrations in cardiac muscle.

Keywords:  calcium; electrometabolic coupling; mitochondria; mitofusin 2

DOI:  https://doi.org/10.1073/pnas.2318535121
ESC Heart Fail. 2024 Jun 17.

Complexities of treating co-morbidities in heart failure with preserved ejection fraction.

Tadej Žlahtič, Miha Mrak, David Žižek.

  Atrial fibrillation and heart failure with preserved ejection fraction (HFpEF) are frequent concomitant diseases sharing several pathophysiological mechanisms leading to structural remodelling of both atria and ventricles. We present a case of an HFpEF patient with rapid atrial fibrillation who remained symptomatic even after successful cardioversion, initiation of antiarrhythmic therapy, and treatment of comorbidities. Due to asymmetric septal hypertrophy, the stress test was performed to exclude outflow tract obstruction and revealed a low basal heart rate with significant chronotropic insufficiency. In addition to SGLT2 initiation, the beta-blocker dose was reduced, and amiodarone was discontinued. This therapy modification led to a marked improvement in exercise capacity, significant reduction of palpitations, reduction of NT-proBNP, and signs of a decreased left ventricular filling pressure with reverse remodelling of LA. This case shows the importance of both individual tailoring of medical therapy and chronotropic insufficiency in HFpEF patients.

Keywords:  Atrial fibrillation; Heart failure; Heart rate; Sodium‐glucose transporter 2 inhibitors

DOI:  https://doi.org/10.1002/ehf2.14897
Arterioscler Thromb Vasc Biol. 2024 Jun 20.

Hypertriglyceridemia Results From an Impaired Catabolism of Triglyceride-Rich Lipoproteins in PLIN1-Related Lipodystrophy.

Bruno Vergès, Marie-Christine Vantyghem, Yves Reznik, Laurence Duvillard, Alexia Rouland, Emilie Capel, Corinne Vigouroux.

  BACKGROUND: Pathogenic variants in PLIN1-encoding PLIN1 (perilipin-1) are responsible for an autosomal dominant form of familial partial lipodystrophy (FPL) associated with severe insulin resistance, hepatic steatosis, and important hypertriglyceridemia. This study aims to decipher the mechanisms of hypertriglyceridemia associated with PLIN1-related FPL.METHODS: We performed an in vivo lipoprotein kinetic study in 6 affected patients compared with 13 healthy controls and 8 patients with type 2 diabetes. Glucose and lipid parameters, including plasma LPL (lipoprotein lipase) mass, were measured. LPL mRNA and protein expression were evaluated in abdominal subcutaneous adipose tissue from patients with 5 PLIN1-mutated FPL and 3 controls.
RESULTS: Patients with PLIN1-mutated FPL presented with decreased fat mass, insulin resistance, and diabetes (glycated hemoglobin A1c, 6.68±0.70% versus 7.48±1.63% in patients with type 2 diabetes; mean±SD; P=0.27). Their plasma triglycerides were higher (5.96±3.08 mmol/L) than in controls (0.76±0.27 mmol/L; P<0.0001) and patients with type 2 diabetes (2.94±1.46 mmol/L, P=0.006). Compared with controls, patients with PLIN1-related FPL had a significant reduction of the indirect fractional catabolic rate of VLDL (very-low-density lipoprotein)-apoB100 toward IDL (intermediate-density lipoprotein)/LDL (low-density lipoprotein; 1.79±1.38 versus 5.34±2.45 pool/d; P=0.003) and the indirect fractional catabolic rate of IDL-apoB100 toward LDL (2.14±1.44 versus 7.51±4.07 pool/d; P=0.005). VLDL-apoB100 production was not different between patients with PLIN1-related FPL and controls. Compared with patients with type 2 diabetes, patients with PLIN1-related FPL also showed a significant reduction of the catabolism of both VLDL-apoB100 (P=0.031) and IDL-apoB100 (P=0.031). Plasma LPL mass was significantly lower in patients with PLIN1-related FPL than in controls (21.03±10.08 versus 55.76±13.10 ng/mL; P<0.0001), although the LPL protein expression in adipose tissue was similar. VLDL-apoB100 and IDL-apoB100 indirect fractional catabolic rates were negatively correlated with plasma triglycerides and positively correlated with LPL mass.
CONCLUSIONS: We show that hypertriglyceridemia associated with PLIN1-related FPL results from a marked decrease in the catabolism of triglyceride-rich lipoproteins (VLDL and IDL). This could be due to a pronounced reduction in LPL availability, related to the decreased adipose tissue mass.

Keywords:  kinetics; lipodystrophy; lipoprotein lipase; perilipin-1; triglycerides

DOI:  https://doi.org/10.1161/ATVBAHA.124.320774
Basic Res Cardiol. 2024 Jun 19.

Mitochondrial calcium in cardiac ischemia/reperfusion injury and cardioprotection.

Edoardo Bertero, Tudor-Alexandru Popoiu, Christoph Maack.

  Mitochondrial calcium (Ca2+) signals play a central role in cardiac homeostasis and disease. In the healthy heart, mitochondrial Ca2+ levels modulate the rate of oxidative metabolism to match the rate of adenosine triphosphate consumption in the cytosol. During ischemia/reperfusion (I/R) injury, pathologically high levels of Ca2+ in the mitochondrial matrix trigger the opening of the mitochondrial permeability transition pore, which releases solutes and small proteins from the matrix, causing mitochondrial swelling and ultimately leading to cell death. Pharmacological and genetic approaches to tune mitochondrial Ca2+ handling by regulating the activity of the main Ca2+ influx and efflux pathways, i.e., the mitochondrial Ca2+ uniporter and sodium/Ca2+ exchanger, represent promising therapeutic strategies to protect the heart from I/R injury.

Keywords:  Calcium handling; Cardiac myocytes; Ischemia/reperfusion injury; Mitochondria; Myocardial infarction; Reactive oxygen species

DOI:  https://doi.org/10.1007/s00395-024-01060-2
Eur J Pharmacol. 2024 Jun 13. pii: S0014-2999(24)00424-2. [Epub ahead of print]977 176736

Chronic mitochondrial dynamic-targeted therapy alleviates left ventricular dysfunction by reducing multiple programmed cell death in post-myocardial infarction rats.

Chanon Piamsiri, Chayodom Maneechote, Kewarin Jinawong, Busarin Arunsak, Titikorn Chunchai, Wichwara Nawara, Sasiwan Kerdphoo, Siriporn C Chattipakorn, Nipon Chattipakorn.

  Mitochondrial dysfunction and the activation of multiple programmed cell death (PCD) have been shown to aggravate the severity and mortality associated with the progression of myocardial infarction (MI). Although pharmacological modulation of mitochondrial dynamics, including treatment with the fusion promoter (M1) and the fission inhibitor (Mdivi-1), exerted cardioprotection against several cardiac complications, their roles in the post-MI model have never been investigated. Using a MI rat model instigated by permanent left-anterior descending (LAD) coronary artery occlusion, post-MI rats were randomly assigned to receive one of 4 treatments (n = 10/group): vehicle (DMSO 3%V/V), enalapril (10 mg/kg), Mdivi-1 (1.2 mg/kg) and M1 (2 mg/kg), while a control group of sham operated rats underwent surgery without LAD occlusion (n = 10). After 32-day treatment, cardiac and mitochondrial function, and histopathological morphology were investigated and molecular analysis was performed. Treatment with enalapril, Mdivi-1, and M1 significantly mitigated cardiac pathological remodeling, reduced myocardial injury, and improved left ventricular (LV) function in post-MI rats. Importantly, all interventions also attenuated mitochondrial dynamic imbalance and mitigated activation of apoptosis, necroptosis, and pyroptosis after MI. This investigation demonstrated for the first time that chronic mitochondrial dynamic-targeted therapy mitigated mitochondrial dysfunction and activation of PCD, leading to improved LV function in post-MI rats.

Keywords:  Heart failure; Mitochondrial dynamics; Mitochondrial fission; Mitochondrial fusion; Myocardial infarction; Programmed cell death

DOI:  https://doi.org/10.1016/j.ejphar.2024.176736