The loss of cardiac SIRT3 decreases metabolic flexibility and proteostasis in an age-dependent manner

Li, Ping; Newhardt, Maria F.; Matsuzaki, Satoshi; Eyster, Craig A.; Pranay, Atul; Peelor, Frederick F.; Batushansky, Albert; Kinter, Caroline S.; Subramani, Kumar; Subrahmanian, Sandeep; Ahamed, Jasimuddin; Yu, Pengchun; Kinter, Michael; Miller, Benjamin F.; Humphries, Kenneth M.

doi:10.1007/s11357-022-00695-0

Cited by 8 publications

(7 citation statements)

References 54 publications

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“…Western blot analysis was performed for whole heart tissue homogenates and isolated mitochondria as previously described [23]. Briefly, samples were prepared using LDS sample buffer (Thermo Fisher Scientific) with addition of a protease and phosphatase inhibitor cocktail (Halt TM , Thermo Fisher Scientific), after which they were run on 4-12% Bis-Tris gels (Thermo Fisher Scientific) at 200 V for 45 minutes.…”

Section: Methodsmentioning

confidence: 99%

Loss of cardiac PFKFB2 drives Metabolic, Functional, and Electrophysiological Remodeling in the Heart

Harold,

Matsuzaki,

Pranay

et al. 2023

Preprint

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BackgroundPhosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK-2) is a critical glycolytic regulator responsible for upregulation of glycolysis in response to insulin and adrenergic signaling. PFKFB2, the cardiac isoform of PFK-2, is degraded in the heart in the absence of insulin signaling, contributing to diabetes-induced cardiac metabolic inflexibility. However, previous studies have not examined how the loss of PFKFB2 affects global cardiac metabolism and function.MethodsTo address this, we have generated a mouse model with a cardiomyocyte-specific knockout of PFKFB2 (cKO). Using 9-month-old cKO and control (CON) mice, we characterized impacts of PFKFB2 on cardiac metabolism, function, and electrophysiology.ResultscKO mice have a shortened lifespan of 9 months. Metabolically, cKO mice are characterized by increased glycolytic enzyme abundance and pyruvate dehydrogenase (PDH) activity, as well as decreased mitochondrial abundance and beta oxidation, suggesting a shift toward glucose metabolism. This was supported by a decrease in the ratio of palmitoyl carnitine to pyruvate-dependent mitochondrial respiration in cKO relative to CON animals. Metabolomic, proteomic, and western blot data support the activation of ancillary glucose metabolism, including pentose phosphate and hexosamine biosynthesis pathways. Physiologically, cKO animals exhibited impaired systolic function and left ventricular (LV) dilation, represented by reduced fractional shortening and increased LV internal diameter, respectively. This was accompanied by electrophysiological alterations including increased QT interval and other metrics of delayed ventricular conduction.ConclusionsLoss of PFKFB2 results in metabolic remodeling marked by cardiac ancillary pathway activation. This could delineate an underpinning of pathologic changes to mechanical and electrical function in the heart.Clinical PerspectiveWhat is New?We have generated a novel cardiomyocyte-specific knockout model of PFKFB2, the cardiac isoform of the primary glycolytic regulator Phosphofructokinase-2 (cKO).The cKO model demonstrates that loss of cardiac PFKFB2 drives metabolic reprogramming and shunting of glucose metabolites to ancillary metabolic pathways.The loss of cardiac PFKFB2 promotes electrophysiological and functional remodeling in the cKO heart.What are the Clinical Implications?PFKFB2 is degraded in the absence of insulin signaling, making its loss particularly relevant to diabetes and the pathophysiology of diabetic cardiomyopathy.Changes which we observe in the cKO model are consistent with those often observed in diabetes and heart failure of other etiologies.Defining PFKFB2 loss as a driver of cardiac pathogenesis identifies it as a target for future investigation and potential therapeutic intervention.

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Section: Methodsmentioning

confidence: 99%

Loss of cardiac PFKFB2 drives Metabolic, Functional, and Electrophysiological Remodeling in the Heart

Harold,

Matsuzaki,

Pranay

et al. 2023

Preprint

Self Cite

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“…With aging, the ability of cells to maintain protein homeostasis diminishes [106], leading to the accumulation of misfolded proteins [107]. Impaired protein homeostasis has been linked to the pathogenesis of a wide range of age-related diseases and conditions [108].…”

Section: Figurementioning

confidence: 99%

Geroscience and pathology: a new frontier in understanding age-related diseases

Fekete,

Major,

Feher

et al. 2024

Pathol. Oncol. Res.

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Geroscience, a burgeoning discipline at the intersection of aging and disease, aims to unravel the intricate relationship between the aging process and pathogenesis of age-related diseases. This paper explores the pivotal role played by geroscience in reshaping our understanding of pathology, with a particular focus on age-related diseases. These diseases, spanning cardiovascular and cerebrovascular disorders, malignancies, and neurodegenerative conditions, significantly contribute to the morbidity and mortality of older individuals. We delve into the fundamental cellular and molecular mechanisms underpinning aging, including mitochondrial dysfunction and cellular senescence, and elucidate their profound implications for the pathogenesis of various age-related diseases. Emphasis is placed on the importance of assessing key biomarkers of aging and biological age within the realm of pathology. We also scrutinize the interplay between cellular senescence and cancer biology as a central area of focus, underscoring its paramount significance in contemporary pathological research. Moreover, we shed light on the integration of anti-aging interventions that target fundamental aging processes, such as senolytics, mitochondria-targeted treatments, and interventions that influence epigenetic regulation within the domain of pathology research. In conclusion, the integration of geroscience concepts into pathological research heralds a transformative paradigm shift in our understanding of disease pathogenesis and promises breakthroughs in disease prevention and treatment.

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“…An NAD + -dependent deacetylase of nicotinamide adenine dinucleotides found in the mitochondrial matrix is sirtuin 3 (SIRT3) [15,16]. SIRT3 modulates mitochondrial respiration and intracellular metabolism [17].…”

Section: Introductionmentioning

confidence: 99%

MiR-29a-5p engages in the mechanism of diabetic retinopathy by specifically targeting SIRT3

He,

Wei,

Liang

et al. 2024

Preprint

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Whether miR-29a-5p is associated with diabetic retinopathy (DR) is still a subject of ongoing discussion. The current research examines the involvement of miR-29a-5p in regulating apoptosis, oxidative stress, and inflammation of retinal ganglion cells (RGCs) generated by high glucose (HG). Additionally, we are interested in analyzing the contribution of miR-29a-5p in developing DR. We obtained peripheral blood samples from 7 people with DR and 14 individuals without DR. Subsequently, we conducted biochemical indices analyses and qRT-PCR. We randomly divided RGCs into low glucose groups, HG groups, HG + inhibitor negative control groups, and HG + miR-29a-5p inhibitor groups. SIRT3 siRNA was transfected into RGCs through lipofectamine 3000 reagent. Cell vitality was detected by MTT; qRT-PCR was applied to identify miR-29a-5p expression; Detection of ROS, SOD, and MDA levels was quantified using the DCFH-DA, WST-1, and colorimetric methods, respectively; IL-6 and TNF-α contents were analyzed utilizing ELISA; Dual-luciferase gene reporter experiment was used to examine if SIRT3 is the specific target gene of miR-29a-5p; Flow cytometry evaluated apoptosis in RGCs; The technique of Western blotting identified the expression of Caspase-3, Bax and Bcl-2 proteins. The expression of miR-29a-5p was markedly elevated in individuals with DR, and it had positive correlations with levels of total cholesterol (TC) and fasting blood glucose (FBG). The combination of miR-29a-5p, total cholesterol, and triglycerides (TG) exhibits significant diagnostic value for DR, demonstrating both high sensitivity and specificity. High glucose stimulated the expression of miR-29a-5p in RGCs and worsened cellular oxidative stress, inflammatory response, and apoptotic levels. Transfection of miR-29a-5p inhibitor protected RGCs against HG-induced oxidative injury, inflammation, and apoptosis. Furthermore, the dual-luciferase reporter experiment provided confirmation that SIRT3 was a target gene of miR-29a-5p, as it negatively regulated SIRT3 expression. Notably, SIRT3 knockdown abolished the protection of miR-29a-5p inhibition on RGCs. Suppression of the miR-29a-5p gene safeguards RGCs against injury caused by high glucose via boosting SIRT3 signaling, which might provide a new prevention and treatment strategy for DR.

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The loss of cardiac SIRT3 decreases metabolic flexibility and proteostasis in an age-dependent manner

Cited by 8 publications

References 54 publications

Loss of cardiac PFKFB2 drives Metabolic, Functional, and Electrophysiological Remodeling in the Heart

Loss of cardiac PFKFB2 drives Metabolic, Functional, and Electrophysiological Remodeling in the Heart

Geroscience and pathology: a new frontier in understanding age-related diseases

MiR-29a-5p engages in the mechanism of diabetic retinopathy by specifically targeting SIRT3

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