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Normal Oxidative Phosphorylation in Mitochondria from the Failing Heart
- BURTON E. SOBEL,
- JAMES F. SPANN,
- PETER E. POOL,
- EDMUND H. SONNENBLICK and
- EUGENE BRAUNWALD
Circulation Research Volume 21, Issue 31 September 1967

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Oxidative phosphorylation was measured polarographically in mitochondria isolated from normal ventricles and from the ventricles of guinea pigs and cats with experimental heart failure produced by constriction of the aorta or pulmonary artery. The presence of heart failure was proved by the study of myocardial mechanics in vitro, by cardiac catheterization, and by postmortem examination. Mitochondria from failing ventricles had normal oxidative phosphorylation, and P-O ratios, respiratory control, oxygen consumption and ATPase activity did not differ from those of mitochondria from normal hearts. Results were the same whether incubations were performed at 25° or 37°C and whether glutamate or pyruvate and malate were used as the substrate. Mitochondria showed functional deterioration, probably due to fatty acid accumulation, when incubated for more than 10 min at 37°C or when isolated from hearts made hypoxic in vivo for as little as 3 min. The results of this study suggest that decreased myocardial contractility in experimental heart failure is not due to an intrinsic defect in mitochondrial function.
Oxidative Phosphorylation in Mitochondria Isolated from Chronically Stressed Dog Hearts
- CLINTON D. STONER,
- MEHDI M. RESSALLAT and
- HOWARD D. SIRAK
Circulation Research Volume 23, Issue 11 July 1968

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Oxidative and phosphorylative activities were measured polarographically in mitochondria isolated from the right and left ventricles of normal and chronically stressed dog hearts. Chronic myocardial stress was produced experimentally by surgical procedures (combined tricuspid insufficiency and pulmonary stenosis, pulmonary insufficiency, aortic stenosis, aortic insufficiency, Potts's anastomosis) and by inducing thyrotoxicosis. Experimental stress periods ranged from 332 to 608 days. Some of the dogs had overt symptoms of congestive heart failure at the time they were killed.Mitochondria isolated from the stressed hearts had abnormally high values for oxidative activity and respiratory control ratios when incubated in the presence of malate-pyruvate. In the presence of succinate, they had either normal or slightly elevated values for oxidative activity and respiratory control ratios. No differences were found between mitochondria from normal and stressed hearts with regard to the efficiency (ADP/O) of oxidative phosphorylation. Estimates of mitochondrial protein per gram of myocardial tissue indicated that the stressed hearts contained normal amounts of mitochondria. The results of this study suggest that the mitochondrial oxidative and phosphorylative capabilities of the chronically stressed myocardium are not impaired.
Making the Case for Skeletal Muscle Myopathy and Its Contribution to Exercise Intolerance in Heart Failure With Preserved Ejection Fraction
- Dalane W. Kitzman,
- Mark J. Haykowsky and
- Corey R. Tomczak
Circulation: Heart Failure Volume 10, Issue 71 July 2017

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p300 Plays a Critical Role in Maintaining Cardiac Mitochondrial Function and Cell Survival in Postnatal Hearts
- Yasuaki Nakagawa,
- Koichiro Kuwahara,
- Genzo Takemura,
- Masaharu Akao,
- Masashi Kato,
- Yuji Arai,
- Makoto Takano,
- Masaki Harada,
- Masao Murakami,
- Michio Nakanishi,
- Satoru Usami,
- Shinji Yasuno,
- Hideyuki Kinoshita,
- Masataka Fujiwara,
- Kenji Ueshima and
- Kazuwa Nakao
Circulation Research Volume 105, Issue 89 October 2009

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Rationale: It is known that the transcriptional coactivator p300 is crucially involved in the differentiation and growth of cardiac myocytes during development. However, the physiological function of p300 in the postnatal hearts remains to be characterized.Objective: We have now investigated the physiological function of p300 in adult hearts.Methods and Results: We analyzed transgenic mice exhibiting cardiac-specific overexpression of a dominant-negative p300 mutant lacking the C/H3 domain (p300ΔC/H3 transgenic [TG] mice). p300ΔC/H3 significantly inhibited p300-induced activation of GATA- and myocyte enhancer factor 2-dependent promoters in cultured ventricular myocytes, and p300ΔC/H3-TG mice showed cardiac dysfunction that was lethal by 20 weeks of age. The numbers of mitochondria in p300ΔC/H3-TG myocytes were markedly increased, but the mitochondria were diminished in size. Moreover, cardiac mitochondrial gene expression, mitochondrial membrane potential and ATP contents were all significantly disrupted in p300ΔC/H3-TG hearts, suggesting that mitochondrial dysfunction contributes to the progression of the observed cardiomyopathy. Transcription of peroxisome proliferator-activated receptor γ coactivator (PGC)-1α, a master regulator of mitochondrial gene expression, and its target genes was significantly downregulated in p300ΔC/H3-TG mice, and p300ΔC/H3 directly repressed myocyte enhancer factor 2C-dependent PGC-1α promoter activity and disrupted the transcriptional activity of PGC-1α in cultured ventricular myocytes. In addition, myocytes showing features of autophagy were observed in p300ΔC/H3-TG hearts.Conclusions: Collectively, our findings suggest that p300 is essential for the maintenance of mitochondrial integrity and for myocyte survival in the postnatal left ventricular myocardium.
LTBP4 Protects Against Renal Fibrosis via Mitochondrial and Vascular Impacts
- Chi-Ting Su,
- Daniel H.W. See,
- Yue-Jhu Huang,
- Tzu-Ming Jao,
- Shin-Yun Liu,
- Chih-Yi Chou,
- Chun-Fu Lai,
- Wei-Chou Lin,
- Chih-Yuan Wang,
- Jenq-Wen Huang and
- Kuan-Yu Hung
Circulation Research Volume 133, Issue 123 June 2023

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Background:As a part of natural disease progression, acute kidney injury (AKI) can develop into chronic kidney disease via renal fibrosis and inflammation. LTBP4 (latent transforming growth factor beta binding protein 4) regulates transforming growth factor beta, which plays a role in renal fibrosis pathogenesis. We previously investigated the role of LTBP4 in chronic kidney disease. Here, we examined the role of LTBP4 in AKI.Methods:LTBP4 expression was evaluated in human renal tissues, obtained from healthy individuals and patients with AKI, using immunohistochemistry. LTBP4 was knocked down in both C57BL/6 mice and human renal proximal tubular cell line HK-2. AKI was induced in mice and HK-2 cells using ischemia-reperfusion injury and hypoxia, respectively. Mitochondrial division inhibitor 1, an inhibitor of DRP1 (dynamin-related protein 1), was used to reduce mitochondrial fragmentation. Gene and protein expression were then examined to assess inflammation and fibrosis. The results of bioenergetic studies for mitochondrial function, oxidative stress, and angiogenesis were assessed.Results:LTBP4 expression was upregulated in the renal tissues of patients with AKI. Ltbp4-knockdown mice showed increased renal tissue injury and mitochondrial fragmentation after ischemia-reperfusion injury, as well as increased inflammation, oxidative stress, and fibrosis, and decreased angiogenesis. in vitro studies using HK-2 cells revealed similar results. The energy profiles of Ltbp4-deficient mice and LTBP4-deficient HK-2 cells indicated decreased ATP production. LTBP4-deficient HK-2 cells exhibited decreased mitochondrial respiration and glycolysis. Human aortic endothelial cells and human umbilical vein endothelial cells exhibited decreased angiogenesis when treated with LTBP4-knockdown conditioned media. Mitochondrial division inhibitor 1 treatment ameliorated inflammation, oxidative stress, and fibrosis in mice and decreased inflammation and oxidative stress in HK-2 cells.Conclusions:Our study is the first to demonstrate that LTBP4 deficiency increases AKI severity, consequently leading to chronic kidney disease. Potential therapies focusing on LTBP4-associated angiogenesis and LTBP4-regulated DRP1-dependent mitochondrial division are relevant to renal injury.Graphical Abstract
Mitochondrial Dysfunction in Heart Failure With Preserved Ejection Fraction
- Anupam A. Kumar,
- Daniel P. Kelly and
- Julio A. Chirinos
Circulation Volume 139, Issue 1112 March 2019

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Heart failure with preserved ejection fraction (HFpEF) is a complex syndrome with an increasingly recognized heterogeneity in pathophysiology. Exercise intolerance is the hallmark of HFpEF and appears to be caused by both cardiac and peripheral abnormalities in the arterial tree and skeletal muscle. Mitochondrial abnormalities can significantly contribute to impaired oxygen utilization and the resulting exercise intolerance in HFpEF. We review key aspects of the complex biology of this organelle, the clinical relevance of mitochondrial function, the methods that are currently available to assess mitochondrial function in humans, and the evidence supporting a role for mitochondrial dysfunction in the pathophysiology of HFpEF. We also discuss the role of mitochondrial function as a therapeutic target, some key considerations for the design of early-phase clinical trials using agents that specifically target mitochondrial function to improve symptoms in patients with HFpEF, and ongoing trials with mitochondrial agents in HFpEF.
Ischemic and Pharmacological Preconditioning in Girardi Cells and C2C12 Myotubes Induce Mitochondrial Uncoupling
- Jan Minners,
- Lydia Lacerda,
- Joy McCarthy,
- James J. Meiring,
- Derek M. Yellon and
- Michael N. Sack
Circulation Research Volume 89, Issue 926 October 2001

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Pharmacological uncoupling of mitochondrial oxidation from phosphorylation promotes preconditioning-like cardioprotection in the isolated rat heart. We hypothesized that modest mitochondrial uncoupling may be a critical cellular event in orchestrating preconditioning. Human-derived Girardi cells and murine C2C12 skeletal myotubes were preconditioned using simulated ischemia, adenosine, and diazoxide. Cell viability after 6 hours of simulated ischemia was measured using lactate dehydrogenase release and propidium iodide uptake. Mitochondrial inner membrane potential (ΔΨm) was investigated by flow cytometry, cellular ATP by recombinant firefly-luciferase bioluminescence, and cellular oxygen consumption using oximetry. Preconditioning enhanced cell viability with attenuation of lactate dehydrogenase release (≥30%, P<0.05 versus ischemic controls) and a reduction in propidium iodide uptake by ≥26% versus ischemic controls after simulated ischemia in both cell lines. In Girardi cells, preconditioning induced the following phenotype immediately before index ischemia: (1) decreased ΔΨm (JC-1: simulated ischemia 90±3%, adenosine 82±7%, diazoxide 87±4%, versus control 100%, P<0.05); (2) attenuation in cellular ATP levels (CTL 0.21±0.03 nmol/L ATP/μg protein, simulated ischemia 0.12±0.02, adenosine 0.15±0.02, diazoxide 0.11±0.02, P<0.05); and (3) enhanced cellular oxygen consumption (control 2.3±0.1 nmol/L oxygen/min/1×10⁶ cells, simulated ischemia 3.1±0.1, adenosine 3.1±0.3, diazoxide 2.6±0.2, P<0.05). Cytoprotection, mitochondrial depolarization, and enhanced oxygen consumption were attenuated by the putative mitochondrial K_ATP-channel antagonist 5-hydroxydecanoate. The uncoupled phenotype in response to preconditioning was similarly observed in C2C12 myotubes. The present study suggests that modest mitochondrial uncoupling represents a unifying cellular response which may be important in directing preconditioning-mediated cytoprotection.
Overcoming Challenges With Statin Therapy
- J. David Spence and
- George K. Dresser
Journal of the American Heart Association Volume 5, Issue 1

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Alogliptin, a Dipeptidyl Peptidase‐4 Inhibitor, Alleviates Atrial Remodeling and Improves Mitochondrial Function and Biogenesis in Diabetic Rabbits
- Xiaowei Zhang,
- Zhiwei Zhang,
- Yungang Zhao,
- Ning Jiang,
- Jiuchun Qiu,
- Yajuan Yang,
- Jian Li,
- Xue Liang,
- Xinghua Wang,
- Gary Tse,
- Guangping Li and
- Tong Liu
Journal of the American Heart Association Volume 6, Issue 5

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BackgroundThere is increasing evidence implicating atrial mitochondrial dysfunction in the pathogenesis of atrial fibrillation. In this study, we explored whether alogliptin, a dipeptidyl peptidase‐4 inhibitor, can prevent mitochondrial dysfunction and atrial remodeling in a diabetic rabbit model.Methods and ResultsA total of 90 rabbits were randomized into 3 groups as follows: control group (n=30), alloxan‐induced diabetes mellitus group (n=30), and alogliptin‐treated (12.5 mg/kg per day for 8 weeks) diabetes mellitus group (n=30). Echocardiographic and hemodynamic assessments were performed in vivo. The serum concentrations of glucagon‐like peptide‐1, insulin, and inflammatory and oxidative stress markers were measured. Electrophysiological properties of Langendorff‐perfused rabbit hearts were assessed. Mitochondrial morphology, respiratory function, membrane potential, and reactive oxygen species generation rate were assessed. The protein expression of transforming growth factor β1, nuclear factor κB p65, and mitochondrial biogenesis–related proteins were measured by Western blot analysis. Diabetic rabbits exhibited left ventricular hypertrophy and left atrial dilation without obvious hemodynamic abnormalities, and all of these changes were attenuated by alogliptin. Compared with the control group, higher atrial fibrillation inducibility in the diabetes mellitus group was observed, and markedly reduced by alogliptin. Alogliptin decreased mitochondrial reactive oxygen species production rate, prevented mitochondrial membrane depolarization, and alleviated mitochondrial swelling in diabetic rabbits. It also improved mitochondrial biogenesis by peroxisome proliferator–activated receptor‐γ coactivator 1α/nuclear respiratory factor‐1/mitochondrial transcription factor A signaling regulated by adiponectin/AMP‐activated protein kinase.ConclusionsDipeptidyl peptidase‐4 inhibitors can prevent atrial fibrillation by reversing electrophysiological abnormalities, improving mitochondrial function, and promoting mitochondrial biogenesis.
Lower Mitochondrial Energy Production of the Thigh Muscles in Patients With Low‐Normal Ankle‐Brachial Index
- Majd AlGhatrif,
- Ariel Zane,
- Matt Oberdier,
- Marco Canepa,
- Stephanie Studenski,
- Eleanor Simonsick,
- Richard G. Spencer,
- Kenneth Fishbein,
- David Reiter,
- Edward G. Lakatta,
- Mary M. McDermott and
- Luigi Ferrucci
Journal of the American Heart Association Volume 6, Issue 9

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BackgroundLower muscle mitochondrial energy production may contribute to impaired walking endurance in patients with peripheral arterial disease. A borderline ankle‐brachial index (ABI) of 0.91 to 1.10 is associated with poorer walking endurance compared with higher ABI. We hypothesized that in the absence of peripheral arterial disease, lower ABI is associated with lower mitochondrial energy production.Methods and ResultsWe examined 363 men and women participating in the Baltimore Longitudinal Study of Aging with an ABI between 0.90 and 1.40. Muscle mitochondrial energy production was assessed by post‐exercise phosphocreatine recovery rate constant (kPCr) measured by phosphorus magnetic resonance spectroscopy of the left thigh. A lower post‐exercise phosphocreatine recovery rate constant reflects decreased mitochondria energy production.The mean age of the participants was 71±12 years. A total of 18.4% had diabetes mellitus and 4% were current and 40% were former smokers. Compared with participants with an ABI of 1.11 to 1.40, those with an ABI of 0.90 to 1.10 had significantly lower post‐exercise phosphocreatine recovery rate constant (19.3 versus 20.8 ms⁻¹, P=0.015). This difference remained significant after adjusting for age, sex, race, smoking status, diabetes mellitus, body mass index, and cholesterol levels (P=0.028). Similarly, post‐exercise phosphocreatine recovery rate constant was linearly associated with ABI as a continuous variable, both in the ABI ranges of 0.90 to 1.40 (standardized coefficient=0.15, P=0.003) and 1.1 to 1.4 (standardized coefficient=0.12, P=0.0405).ConclusionsAn ABI of 0.90 to 1.10 is associated with lower mitochondrial energy production compared with an ABI of 1.11 to 1.40. These data demonstrate adverse associations of lower ABI values with impaired mitochondrial activity even within the range of a clinically accepted definition of a normal ABI. Further study is needed to determine whether interventions in persons with ABIs of 0.90 to 1.10 can prevent subsequent functional decline.
Migraine‐Associated Mutation in the Na,K‐ATPase Leads to Disturbances in Cardiac Metabolism and Reduced Cardiac Function
Journal of the American Heart Association Volume 11, Issue 75 April 2022

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BackgroundMutations in ATP1A2 gene encoding the Na,K‐ATPase α₂ isoform are associated with familial hemiplegic migraine type 2. Migraine with aura is a known risk factor for heart disease. The Na,K‐ATPase is important for cardiac function, but its role for heart disease remains unknown. We hypothesized that ATP1A2 is a susceptibility gene for heart disease and aimed to assess the underlying disease mechanism.Methods and ResultsMice heterozygous for the familial hemiplegic migraine type 2–associated G301R mutation in the Atp1a2 gene (α₂^+/G301R mice) and matching wild‐type controls were compared. Reduced expression of the Na,K‐ATPase α₂ isoform and increased expression of the α₁ isoform were observed in hearts from α₂^+/G301R mice (Western blot). Left ventricular dilation and reduced ejection fraction were shown in hearts from 8‐month‐old α₂^+/G301R mice (cardiac magnetic resonance imaging), and this was associated with reduced nocturnal blood pressure (radiotelemetry). Cardiac function and blood pressure of 3‐month‐old α₂^+/G301R mice were similar to wild‐type mice. Amplified Na,K‐ATPase–dependent Src kinase/Ras/Erk1/2 (p44/42 mitogen‐activated protein kinase) signaling was observed in hearts from 8‐month‐old α₂^+/G301R mice, and this was associated with mitochondrial uncoupling (respirometry), increased oxidative stress (malondialdehyde measurements), and a heart failure–associated metabolic shift (hyperpolarized magnetic resonance). Mitochondrial membrane potential (5,5´,6,6´‐tetrachloro‐1,1´,3,3´‐tetraethylbenzimidazolocarbocyanine iodide dye assay) and mitochondrial ultrastructure (transmission electron microscopy) were similar between the groups. Proteomics of heart tissue further suggested amplified Src/Ras/Erk1/2 signaling and increased oxidative stress and provided the molecular basis for systolic dysfunction in 8‐month‐old α₂^+/G301R mice.ConclusionsOur findings suggest that ATP1A2 mutation leads to disturbed cardiac metabolism and reduced cardiac function mediated via Na,K‐ATPase–dependent reactive oxygen species signaling through the Src/Ras/Erk1/2 pathway.
Abstract 168: Drp1 Accumulates in Mitochondria and Plays a Protective Role in the Heart in Response to Pressure Overload
- Akihiro Shirakabe,
- Yoshiyuki Ikeda,
- Toshiro Saito,
- Peiyong Zhai and
- Junichi Sadoshima
Circulation Research Volume 117, Issue suppl_117 July 2015

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Dynamin-related protein 1 (Drp1) plays an essential role in maintaining the quality control of mitochondria through mitochondrial (Mt) fission and mitophagy. We investigated how Mt function, autophagy and Drp1 are regulated in the heart during pressure overload (PO) and whether endogenous Drp1 plays an important role in regulating cardiac function. Mice were subjected to transverse aortic constriction (TAC) at multiple time points between 6 hours and 30 days. Left ventricular (LV) weight/tibial length (LVW/TL) was significantly elevated at Day 5 (TAC vs Baseline; 6.21 ± 0.28 vs 4.59 ± 0.36, p<0.05). Ejection fraction (EF) was maintained at Day 5 (79±5 vs 82±7%), but gradually decreased thereafter (30 days; 51±12%, p<0.05). LC3-II was decreased (-40.0%, p<0.05) while p62 accumulated (1.84 fold, p<0.05) significantly at Day 5. Both Mt ATP content (-65.6%, p<0.05) and production (-90.3%, p<0.05) were reduced significantly at Days 7 and 14, respectively, and thereafter. Mt mass, evaluated by electron microscopy, was also reduced (-19.9%, p<0.05) at Day 7. Drp1 accumulated in mitochondria at Day 7, and S616 phosphorylation of Drp1, associated with increased activity, was increased at Day 7. Thus, PO suppresses autophagy and induces Mt dysfunction by Day 7, at which time Drp1 accumulates in mitochondria and Mt mass is decreased. To examine the functional significance of endogenous Drp1 during PO, cardiac-specific heterozygous Drp1 knock out (Drp-hetCKO) mice were subjected to TAC. At Day 7, decreases in EF (57± 11 vs 80 ± 7%, p<0.05) and increases in LVW/TL (7.22 ± 0.26 vs 5.86 ± 0.65, p<0.05) and lung weight/TL (13.03 ± 1.09 vs 7.00 ± 1.31, p<0.05) were exacerbated in Drp-hetCKO compared to in control mice. LV end diastolic pressure was significantly higher (20.0 ± 5.7 vs 7.4 ± 3.1 mmHg, p<0.05) and myocardial fibrosis (14.1 ± 2.5 vs 6.2 ± 4.3 %, p<0.05) was greater, and Mt mass was also significantly greater in Drp-hetCKO than in control mice (relative Mt mass, 1.21 ± 0.46 vs 1.00 ± 0.02, p<0.05). These results suggest that PO inhibits autophagy and induces mitochondrial dysfunction by Day7, which coincides with Mt accumulation of Drp1. Drp1 plays an adaptive role in this condition, mediating decreases in Mt mass and protecting the heart from dysfunction.

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Normal Oxidative Phosphorylation in Mitochondria from the Failing Heart

Abstract

Oxidative Phosphorylation in Mitochondria Isolated from Chronically Stressed Dog Hearts

Abstract

Making the Case for Skeletal Muscle Myopathy and Its Contribution to Exercise Intolerance in Heart Failure With Preserved Ejection Fraction

Abstract

p300 Plays a Critical Role in Maintaining Cardiac Mitochondrial Function and Cell Survival in Postnatal Hearts

Abstract

LTBP4 Protects Against Renal Fibrosis via Mitochondrial and Vascular Impacts

Abstract

Mitochondrial Dysfunction in Heart Failure With Preserved Ejection Fraction

Abstract

Ischemic and Pharmacological Preconditioning in Girardi Cells and C2C12 Myotubes Induce Mitochondrial Uncoupling

Abstract

Overcoming Challenges With Statin Therapy

Abstract

Alogliptin, a Dipeptidyl Peptidase‐4 Inhibitor, Alleviates Atrial Remodeling and Improves Mitochondrial Function and Biogenesis in Diabetic Rabbits

Abstract

Lower Mitochondrial Energy Production of the Thigh Muscles in Patients With Low‐Normal Ankle‐Brachial Index

Abstract

Migraine‐Associated Mutation in the Na,K‐ATPase Leads to Disturbances in Cardiac Metabolism and Reduced Cardiac Function

Abstract

Abstract 168: Drp1 Accumulates in Mitochondria and Plays a Protective Role in the Heart in Response to Pressure Overload

Abstract