bims-mimcad 2024-07-14 papers

bims-mimcad

Biomed News

on Mitochondrial metabolism and cardiometabolic diseases

Issue of 2024–07–14
nine papers selected by
Henver Brunetta, University of Guelph

Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress.
The iAAA-mitochondrial protease YME1L1 regulates the degradation of the short-lived mitochondrial transporter SLC25A38.
Adjunctive therapy with an oral H2S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction.
Long-term Changes in Body Composition and Exercise Capacity Following Calorie Restriction and Exercise Training in Older Patients with Obesity and Heart Failure with Preserved Ejection Fraction.
Inhibition of dynamin-related protein 1-filamin interaction improves systemic glucose metabolism.
Downregulation of adipose LPL by PAR2 contributes to the development of hypertriglyceridemia.
Muscle mitochondrial function is impaired in adults with type 1 diabetes.
Mitochondrial dysfunction and metabolic reprogramming induce macrophage pro-inflammatory phenotype switch and atherosclerosis progression in aging.
GLP-1 receptor agonist treatment improved fasting and postprandial lipidomic profile independently of diabetes and weight loss.

Mol Cell. 2024 Jun 28. pii: S1097-2765(24)00512-4. [Epub ahead of print]

Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress.

Johannes Pilic, Benjamin Gottschalk, Benjamin Bourgeois, Hansjörg Habisch, Zhanat Koshenov, Furkan E Oflaz, Yusuf C Erdogan, Seyed M Miri, Esra N Yiğit, Mehmet Ş Aydın, Gürkan Öztürk, Emrah Eroglu, Varda Shoshan-Barmatz, Tobias Madl, Wolfgang F Graier, Roland Malli.

  Metabolic enzymes can adapt during energy stress, but the consequences of these adaptations remain understudied. Here, we discovered that hexokinase 1 (HK1), a key glycolytic enzyme, forms rings around mitochondria during energy stress. These HK1-rings constrict mitochondria at contact sites with the endoplasmic reticulum (ER) and mitochondrial dynamics protein (MiD51). HK1-rings prevent mitochondrial fission by displacing the dynamin-related protein 1 (Drp1) from mitochondrial fission factor (Mff) and mitochondrial fission 1 protein (Fis1). The disassembly of HK1-rings during energy restoration correlated with mitochondrial fission. Mechanistically, we identified that the lack of ATP and glucose-6-phosphate (G6P) promotes the formation of HK1-rings. Mutations that affect the formation of HK1-rings showed that HK1-rings rewire cellular metabolism toward increased TCA cycle activity. Our findings highlight that HK1 is an energy stress sensor that regulates the shape, connectivity, and metabolic activity of mitochondria. Thus, the formation of HK1-rings may affect mitochondrial function in energy-stress-related pathologies.

Keywords:  ER-mitochondria contact sites; energy stress; glucose starvation; glycolysis; hexokinase; live-cell imaging; mitochondrial constriction; mitochondrial fission; non-catalytic functions; protein cluster

DOI:  https://doi.org/10.1016/j.molcel.2024.06.009
bioRxiv. 2024 Jun 24. pii: 2024.05.12.593764. [Epub ahead of print]

The iAAA-mitochondrial protease YME1L1 regulates the degradation of the short-lived mitochondrial transporter SLC25A38.

Sijie Tan, Alisa Susan Dengler, Rami Zahi Darawsheh, Nora Kory.

Mitochondrial transporters facilitate the exchange of diverse metabolic intermediates across the inner mitochondrial membrane, ensuring an adequate supply of substrates and cofactors to support redox and biosynthetic reactions within the mitochondrial matrix. However, the regulatory mechanisms governing the abundance of these transporters, crucial for maintaining metabolic compartmentalization and mitochondrial functions, remain poorly defined. Through analysis of protein half-life data and mRNA-protein correlations, we identified SLC25A38, a mitochondrial glycine transporter, as a short- lived protein with a half-life of 4 hours under steady-state conditions. Pharmacological inhibition and genetic depletion of various cellular proteolytic systems revealed that SLC25A38 is rapidly degraded by the iAAA-mitochondrial protease YME1L1. Depolarization of the mitochondrial membrane potential induced by the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrozone prevented the degradation of SLC25A38. This dual regulation of SLC25A38 abundance by YME1L1 and mitochondrial membrane potential suggests a link between SLC25A38 turnover, the integrity of the inner mitochondrial membrane, and electron transport chain function. These findings open avenues for investigating whether mitochondrial glycine import coordinates with mitochondrial bioenergetics.

DOI: https://doi.org/10.1101/2024.05.12.593764
Br J Pharmacol. 2024 Jul 09.

Adjunctive therapy with an oral H2S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction.

Jake E Doiron, Huijing Xia, Xiaoman Yu, Alexandra R Nevins, Kyle B LaPenna, Thomas E Sharp, Traci T Goodchild, Timothy D Allerton, Mona Elgazzaz, Eric Lazartigues, Sanjiv J Shah, Zhen Li, David J Lefer.

   BACKGROUND AND PURPOSE: Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a potent therapy for heart failure with preserved ejection fraction (HFpEF). Hydrogen sulphide (H2S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H2S donor in two preclinical models of cardiometabolic HFpEF was investigated.
EXPERIMENTAL APPROACH: Nine-week-old C57BL/6N mice received L-NAME and a 60% high fat diet for five weeks. Mice were then randomized to either control, SGLT2i monotherapy or SGLT2i and H2S donor, SG1002, for five additional weeks. Ten-week-old ZSF1 obese rats were randomized to control, SGLT2i or SGLT2i and SG1002 for 8 weeks. SG1002 monotherapy was investigated in additional animals. Cardiac function (echocardiography and haemodynamics), exercise capacity, glucose handling and multiorgan pathology were monitored during experimental protocols.
KEY RESULTS: SGLT2i treatment improved E/e' ratio and treadmill exercise in both models. Combination therapy afforded increases in cardiovascular sulphur bioavailability that coincided with improved left end-diastolic function (E/e' ratio), exercise capacity, metabolic state, cardiorenal fibrosis, and hepatic steatosis. Follow-up studies with SG1002 monotherapy revealed improvements in diastolic function, exercise capacity and multiorgan histopathology.
CONCLUSIONS AND IMPLICATIONS: SGLT2i monotherapy remediated pathological complications exhibited by two well-established HFpEF models. Adjunctive H2S therapy resulted in further improvements of cardiometabolic perturbations beyond SGLT2i monotherapy. Follow-up SG1002 monotherapy studies inferred an improved phenotype with combination therapy beyond either monotherapy. These data demonstrate the differing effects of SGLT2i and H2S therapy while also revealing the superior efficacy of the combination therapy in cardiometabolic HFpEF.

Keywords:  HFpEF; SGLT2 inhibitor; heart failure; hydrogen sulphide; sodium glucose cotransporter 2 inhibitors

DOI:  https://doi.org/10.1111/bph.16493
J Card Fail. 2024 Jul 04. pii: S1071-9164(24)00226-4. [Epub ahead of print]

Long-term Changes in Body Composition and Exercise Capacity Following Calorie Restriction and Exercise Training in Older Patients with Obesity and Heart Failure with Preserved Ejection Fraction.

Bharathi Upadhya, Peter H Brubaker, Barbara J Nicklas, Denise K Houston, Mark J Haykowsky, Dalane W Kitzman.

   BACKGROUND: Obesity with heart failure with preserved ejection fraction (HFpEF) is the dominant form of HF among older persons. In a randomized trial, we previously showed that a 5-month calorie restriction (CR) program, with or without aerobic exercise training (AT), resulted in significant weight and fat loss and improved exercise capacity. However, little is known regarding the long-term effects of these outcomes after a short-term (5-month) intervention of CR with or without AT in older patients with obesity and HFpEF.
METHODS: Sixteen participants from either the CR or CR+AT who experienced significant weight loss ≥2 kg were reexamined after a long-term follow-up endpoint (28.0±10.8 months) without intervention. The follow-up assessment included body weight and composition via dual-energy X-ray absorptiometry and exhaustive cardiopulmonary treadmill exercise testing.
RESULTS: Compared to the 5-month time point intervention endpoint, at the long-term follow-up endpoint, mean body weight increased +5.2±4.0 kg (90.7±11.2kg versus 95.9±11.9, p<0.001) due to increased fat mass (38.9± 9.3 versus 43.8 ± 9.8, p<0.001) with no change in lean mass (49.6±7.1 versus 49.9±7.6, p=0.67), resulting in worse body composition (decreased lean-to-fat mass). Change in total mass was strongly and significantly correlated with change in fat mass (r=0.75, p<0.001), whereas there appeared to be a weaker correlation with change in lean mass (r=0.50, p=0.051). Additionally, from the end of the 5-month time point intervention endpoint to the long-term follow-up endpoint, there were large, significant decreases in VO2peak (-2.2± 2.1ml/kg/min, p=0.003) and exercise time (-2.4±2.6min, p=0.006). There appeared to be an inverse correlation between the change in VO2peak and the change in fat mass (r=-0.52, p=0.062).
CONCLUSION: Although CR and CR+AT in older patients with obesity and HFpEF can significantly improve body composition and exercise capacity, these positive changes diminish considerably during long-term follow-up endpoint, and regained weight is predominantly adipose, resulting in worsened overall body composition compared to baseline. This suggests a need for long-term adherence strategies to prevent weight regain and maintain improvements in body composition and exercise capacity following CR in older patients with obesity and HFpEF.

Keywords:  Calorie restriction; Exercise training; HFpEF; Obesity; Sarcopenic obesity

DOI:  https://doi.org/10.1016/j.cardfail.2024.06.007
Br J Pharmacol. 2024 Jul 10.

Inhibition of dynamin-related protein 1-filamin interaction improves systemic glucose metabolism.

Yuri Kato, Kohei Ariyoshi, Yasunobu Nohara, Naoya Matsunaga, Tsukasa Shimauchi, Naoya Shindo, Akiyuki Nishimura, Xinya Mi, Sang Geon Kim, Tomomi Ide, Eiji Kawanishi, Akio Ojida, Naoki Nakashima, Yasuo Mori, Motohiro Nishida.

   BACKGROUND AND PURPOSE: Maintaining mitochondrial quality is attracting attention as a new strategy to treat diabetes and diabetic complications. We previously reported that mitochondrial hyperfission by forming a protein complex between dynamin-related protein (Drp) 1 and filamin, mediates chronic heart failure and cilnidipine, initially developed as an L/N-type Ca2+ channel blocker, improves heart failure by inhibiting Drp1-filamin protein complex. We investigated whether cilnidipine improves hyperglycaemia of various diabetic mice models.
EXPERIMENTAL APPROACH: Retrospective analysis focusing on haemoglobin A1c (HbA1c) was performed in hypertensive and hyperglycaemic patients taking cilnidipine and amlodipine. After developing diabetic mice by streptozotocin (STZ) treatment, an osmotic pump including drug was implanted intraperitoneally, followed by weekly measurements of blood glucose levels. Mitochondrial morphology was analysed by electron microscopy. A Ca2+ channel-insensitive cilnidipine derivative (1,4-dihydropyridine [DHP]) was synthesized and its pharmacological effect was evaluated using obese (ob/ob) mice fed with high-fat diet (HFD).
KEY RESULTS: In patients, cilnidipine was superior to amlodipine in HbA1c lowering effect. Cilnidipine treatment improved systemic hyperglycaemia and mitochondrial morphological abnormalities in STZ-exposed mice, without lowering blood pressure. Cilnidipine failed to improve hyperglycaemia of ob/ob mice, with suppressing insulin secretion. 1,4-DHP improved hyperglycaemia and mitochondria abnormality in ob/ob mice fed HFD. 1,4-DHP and cilnidipine improved basal oxygen consumption rate of HepG2 cells cultured under 25 mM glucose.
CONCLUSION AND IMPLICATIONS: Inhibition of Drp1-filamin protein complex formation becomes a new strategy for type 2 diabetes treatment.

Keywords:  Drp1; filamin; insulin; mitochondria quality control; type2 diabetes

DOI:  https://doi.org/10.1111/bph.16487
JCI Insight. 2024 Jul 08. pii: e173240. [Epub ahead of print]9(13):

Downregulation of adipose LPL by PAR2 contributes to the development of hypertriglyceridemia.

Yiheng Huang, Liujun Chen, Lisha Li, Yadan Qi, Haibin Tong, Hong Wu, Jinjie Xu, Lin Leng, Sukhinder Cheema, Guang Sun, Zhengyuan Xia, John McGuire, Brian Rodrigues, Lawrence H Young, Richard Bucala, Dake Qi.

  Lipoprotein lipase (LPL) hydrolyzes circulating triglycerides (TGs), releasing fatty acids (FA) and promoting lipid storage in white adipose tissue (WAT). However, the mechanisms regulating adipose LPL and its relationship with the development of hypertriglyceridemia are largely unknown. WAT from obese humans exhibited high PAR2 expression, which was inversely correlated with the LPL gene. Decreased LPL expression was also inversely correlated with elevated plasma TG levels, suggesting that adipose PAR2 might regulate hypertriglyceridemia by downregulating LPL. In mice, aging and high palmitic acid diet (PD) increased PAR2 expression in WAT, which was associated with a high level of macrophage migration inhibitory factor (MIF). MIF downregulated LPL expression and activity in adipocytes by binding with CXCR2/4 receptors and inhibiting Akt phosphorylation. In a MIF overexpression model, high-circulating MIF levels suppressed adipose LPL, and this suppression was associated with increased plasma TGs but not FA. Following PD feeding, adipose LPL expression and activity were significantly reduced, and this reduction was reversed in Par2-/- mice. Recombinant MIF infusion restored high plasma MIF levels in Par2-/- mice, and the levels decreased LPL and attenuated adipocyte lipid storage, leading to hypertriglyceridemia. These data collectively suggest that downregulation of adipose LPL by PAR2/MIF may contribute to the development of hypertriglyceridemia.

Keywords:  Adipose tissue; Cytokines; Metabolism; Signal transduction

DOI:  https://doi.org/10.1172/jci.insight.173240
J Diabetes Complications. 2024 Jun 13. pii: S1056-8727(24)00124-7. [Epub ahead of print]38(8): 108798

Muscle mitochondrial function is impaired in adults with type 1 diabetes.

Daniel Gottlieb, Layla A Abushamat, Kristen J Nadeau, Judith G Regensteiner, Jane E B Reusch, Kalie L Tommerdahl, John Rice, Leslie A Knaub, Cynthia M F Monaco, Thomas J Hawke, Christopher G R Perry, Melanie G Cree, Irene E Schauer.

   AIMS: Type 1 diabetes has been associated with mitochondrial dysfunction. However, the mechanism of this dysfunction in adults remains unclear.
METHODS: A secondary analysis was conducted using data from several clinical trials measuring in-vivo and ex-vivo mitochondrial function in adults with type 1 diabetes (n = 34, age 38.8 ± 14.6 years) and similarly aged controls (n = 59, age 44.6 ± 13.9 years). In-vivo mitochondrial function was assessed before, during, and after isometric exercise with 31phosphorous magnetic resonance spectroscopy. High resolution respirometry of vastus lateralis muscle tissue was used to assess ex-vivo measures.
RESULTS: In-vivo data showed higher rates of anaerobic glycolysis (p = 0.013), and a lower maximal mitochondrial oxidative capacity (p = 0.012) and mitochondrial efficiency (p = 0.024) in adults with type 1 diabetes. After adjustment for age and percent body fat maximal mitochondrial capacity (p = 0.014) continued to be lower and anaerobic glycolysis higher (p = 0.040) in adults with type 1 diabetes. Ex-vivo data did not demonstrate significant differences between the two groups.
CONCLUSIONS: The in-vivo analysis demonstrates that adults with type 1 diabetes have mitochondrial dysfunction. This builds on previous research showing in-vivo mitochondrial dysfunction in youths with type 1 diabetes and suggests that defects in substrate or oxygen delivery may play a role in in-vivo dysfunction.

Keywords:  (31)phosphorous magnetic resonance spectroscopy; High-resolution respirometry; Insulin resistance; Mitochondrial function; Muscle

DOI:  https://doi.org/10.1016/j.jdiacomp.2024.108798
Front Immunol. 2024 ;15 1410832

Mitochondrial dysfunction and metabolic reprogramming induce macrophage pro-inflammatory phenotype switch and atherosclerosis progression in aging.

Aleksandr E Vendrov, Andrey Lozhkin, Takayuki Hayami, Julia Levin, Jamille Silveira Fernandes Chamon, Ahmed Abdel-Latif, Marschall S Runge, Nageswara R Madamanchi.

   Introduction: Aging increases the risk of atherosclerotic vascular disease and its complications. Macrophages are pivotal in the pathogenesis of vascular aging, driving inflammation and atherosclerosis progression. NOX4 (NADPH oxidase 4) expression increases with age, correlating with mitochondrial dysfunction, inflammation, and atherosclerosis. We hypothesized that the NOX4-dependent mitochondrial oxidative stress promotes aging-associated atherosclerosis progression by causing metabolic dysfunction and inflammatory phenotype switch in macrophages.
Methods: We studied atherosclerotic lesion morphology and macrophage phenotype in young (5-month-old) and aged (16-month-old) Nox4 -/-/Apoe -/- and Apoe -/- mice fed Western diet.
Results: Young Nox4-/-/Apoe-/- and Apoe-/- mice had comparable aortic and brachiocephalic artery atherosclerotic lesion cross-sectional areas. Aged mice showed significantly increased lesion area compared with young mice. Aged Nox4-/-/Apoe-/- had significantly lower lesion areas than Apoe-/- mice. Compared with Apoe-/- mice, atherosclerotic lesions in aged Nox4-/-/Apoe-/- showed reduced cellular and mitochondrial ROS and oxidative DNA damage, lower necrotic core area, higher collagen content, and decreased inflammatory cytokine expression. Immunofluorescence and flow cytometry analysis revealed that aged Apoe-/- mice had a higher percentage of classically activated pro-inflammatory macrophages (CD38+CD80+) in the lesions. Aged Nox4-/-/Apoe-/- mice had a significantly higher proportion of alternatively activated pro-resolving macrophages (EGR2+/CD163+CD206+) in the lesions, with an increased CD38+/EGR2+ cell ratio compared with Apoe-/- mice. Mitochondrial respiration assessment revealed impaired oxidative phosphorylation and increased glycolytic ATP production in macrophages from aged Apoe-/- mice. In contrast, macrophages from Nox4-/-/Apoe-/- mice were less glycolytic and more aerobic, with preserved basal and maximal respiration and mitochondrial ATP production. Macrophages from Nox4-/-/Apoe-/- mice also had lower mitochondrial ROS levels and reduced IL1β secretion; flow cytometry analysis showed fewer CD38+ cells after IFNγ+LPS treatment and more EGR2+ cells after IL4 treatment than in Apoe-/- macrophages. In aged Apoe-/- mice, inhibition of NOX4 activity using GKT137831 significantly reduced macrophage mitochondrial ROS and improved mitochondrial function, resulting in decreased CD68+CD80+ and increased CD163+CD206+ lesion macrophage proportion and attenuated atherosclerosis.
Discussion: Our findings suggest that increased NOX4 in aging drives macrophage mitochondrial dysfunction, glycolytic metabolic switch, and pro-inflammatory phenotype, advancing atherosclerosis. Inhibiting NOX4 or mitochondrial dysfunction could alleviate vascular inflammation and atherosclerosis, preserving plaque integrity.

Keywords:  NOX4 NADPH oxidase; aging; atherosclerosis; macrophages; mitochondrial dysfunction

DOI:  https://doi.org/10.3389/fimmu.2024.1410832
Diabetes. 2024 Jul 08. pii: db230972. [Epub ahead of print]

GLP-1 receptor agonist treatment improved fasting and postprandial lipidomic profile independently of diabetes and weight loss.

Giuseppe Della Pepa, Bárbara G Patrício, Fabrizia Carli, Silvia Sabatini, Brenno Astiarraga, Ele Ferrannini, Stefania Camastra, Amalia Gastaldelli.

Treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduces liver steatosis and cardiometabolic risk (CMR). Only few data are available on lipid metabolism and no information on the postprandial lipidomic profile. Thus, we investigated how exenatide treatment changes lipid metabolism and composition during fasting and after a meal tolerance test (MTT) in adults with severe obesity without diabetes. Thirty individuals (26F/4M, 30-60 years old, BMI>40 kg/m2, HbA1c=5.76%) were assigned (1:1) to diet with exenatide treatment (EXE, n=15, 10 μg twice-daily) or without treatment as control (CT, n=15) for 3 months. Fasting and postprandial lipidomic profile (by LC/MS-QTOF) and fatty acid metabolism (following a 6-hour MTT/tracer study) and composition (by GC/MS) were evaluated before and after treatment. Both groups had slight weight loss (EXE: -5.5% vs CT: -1.9%, p=0.052). During fasting, exenatide, compared to CT, reduced some ceramides (CER) and lysophosphocholines (LPC) previously associated with CMR, while relatively increasing unsaturated phospholipid species (PC, LPC) with protective effects on CMR, although concentrations of total lipid species were unchanged. During MTT, both groups suppressed lipolysis equally to baseline, but EXE exenatide significantly lowered free fatty acid clearance and postprandial triacyclglycerols (TAG) concentrations, particularly saturated TAGs with 44-54 carbons. Exenatide also reduced some postprandial CERs, PCs, LPCs previously linked to cardiometabolic risk. These changes in lipidomic profile remained statistically significant after adjusting for weight loss. Exenatide improved fasting and postprandial lipidomic profile associated with CMR mainly by reducing saturated postprandial TAGs and CERs, independently of weight loss and diabetes.

DOI: https://doi.org/10.2337/db23-0972