Mitochondrial Hyperacetylation in the Failing Hearts of Obese Patients Mediated Partly by a Reduction in SIRT3: The Involvement of the Mitochondrial Permeability Transition Pore

Ec, Castillo; Ja, Morales; Chapoy‐Villanueva, Héctor; Silva-Platas, Christian; Treviño‐Saldaña, Niria; Guerrero-Beltrán, Carlos Enrique; Bernal‐Ramírez, Judith; Torres‐Quintanilla, Alejandro; Garcı́a, Noemı́; Youker, Keith A.; Torre‐Amione, Guillermo; García‐Rivas, Gerardo

doi:10.33594/000000151

Cited by 46 publications

(13 citation statements)

References 47 publications

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“…Epigenetic modifications, including histone acetylation, have been shown to affect cellular metabolism [72,73]. In fact, obese patients with ventricular cardiac dysfunction displayed mitochondrial hyperacetylation [74]. Our study suggests that such variations may underline the observed differences in outcomes of spinal fusion between patients.…”

Section: Plos Onementioning

confidence: 67%

Role of oxidative metabolism in osseointegration during spinal fusion

et al. 2020

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Spinal fusion is a commonly performed orthopedic surgery. Autologous bone graft obtained from the iliac crest is frequently employed to perform spinal fusion. Osteogenic bone marrow stromal (a.k.a. mesenchymal stem) cells (BMSCs) are believed to be responsible for new bone formation and development of the bridging bone during spinal fusion, as these cells are located in both the graft and at the site of fusion. Our previous work revealed the importance of mitochondrial oxidative metabolism in osteogenic differentiation of BMSCs. Our objective here was to determine the impact of BMSC oxidative metabolism on osseointegration of the graft during spinal fusion. The first part of the study was focused on correlating oxidative metabolism in bone graft BMSCs to radiographic outcomes of spinal fusion in human patients. The second part of the study was focused on mechanistically proving the role of BMSC oxidative metabolism in osseointegration during spinal fusion using a genetic mouse model. Patients’ iliac crest-derived graft BMSCs were identified by surface markers. Mitochondrial oxidative function was detected in BMSCs with the potentiometric probe, CMXRos. Spinal fusion radiographic outcomes, determined by the Lenke grade, were correlated to CMXRos signal in BMSCs. A genetic model of high oxidative metabolism, cyclophilin D knockout (CypD KO), was used to perform spinal fusion in mice. Graft osseointegration in mice was assessed with micro-computed tomography. Our study revealed that higher CMXRos signal in patients’ BMSCs correlated with a higher Lenke grade. Mice with higher oxidative metabolism (CypD KO) had greater mineralization of the spinal fusion bridge, as compared to the control mice. We therefore conclude that higher oxidative metabolism in BMSCs correlates with better spinal fusion outcomes in both human patients and in a mouse model. Altogether, our study suggests that promoting oxidative metabolism in osteogenic cells could improve spinal fusion outcomes for patients.

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Section: Plos Onementioning

confidence: 67%

Role of oxidative metabolism in osseointegration during spinal fusion

et al. 2020

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“…qPCR reaction was performed using the SensiFAST SYBR Lo-ROX Kit (BIO-94020, Bioline, London, UK) in a Quant-Studio 3 RT PCR System (Thermo Fisher Scientific, Waltham, TX, USA). Data was analyzed by 2− ΔΔ Ct method to estimate mRNA expression from each gene [ 15 , 34 ]. T4 Oligo (Mexico) synthesized primers.…”

Section: Methodsmentioning

confidence: 99%

“…As described before [ 15 ], isolated mitochondria from right ventricles (1 mg) were solubilized in buffer containing (in mM) the following: 150 NaCl, 1 EGTA, Igepal 1%, 20 Tris-HCl, pH 7.2, and protease inhibitor cocktail (Roche). Afterwards, they were clarified of endogenous IgG and incubated with 2 μ g of mouse anti-CypD (ab110324, Abcam, UK), or the isotype IgG as control, 1 hour at 4°C in a rotator.…”

Section: Methodsmentioning

confidence: 99%

“…More precisely, RES activates sirtuins, a relevant group of deacetylases that participate in the regulation of numerous cellular processes [ 12 ]. In the heart, sirtuin activation has been linked to the prevention of hypertrophy [ 13 ] and energetic dysfunction [ 14 , 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Thus, protecting mitochondrial function with cyclosporine A (CsA), which blocks mPTP opening by interacting with cyclophilin D (CypD), prevents mitochondrial disruption in PAH and preserves RV function [ 22 ]. CypD hyperacetylation is an essential trigger of mPTP opening [ 23 ], and its contribution to mitochondrial dysfunction and heart failure has been established in animal models [ 24 ] and humans [ 15 ]. Notably, CypD acetylation is regulated by SIRT3 [ 23 , 24 ], a sirtuin stimulated by RES [ 12 ], which is associated with the loss-of-function polymorphism found in PAH patients [ 25 ].…”

Section: Introductionmentioning

confidence: 99%

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Resveratrol Prevents Right Ventricle Dysfunction, Calcium Mishandling, and Energetic Failure via SIRT3 Stimulation in Pulmonary Arterial Hypertension

Bernal‐Ramírez

Silva-Platas

Jerjes‐Sánchez

et al. 2021

Oxidative Medicine and Cellular Longevity

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Pulmonary arterial hypertension (PAH) is characterized by pulmonary vessel remodeling; however, its severity and impact on survival depend on right ventricular (RV) failure. Resveratrol (RES), a polyphenol found in red wine, exhibits cardioprotective effects on RV dysfunction in PAH. However, most literature has focused on RES protective effect on lung vasculature; recent finding indicates that RES has a cardioprotective effect independent of pulmonary arterial pressure on RV dysfunction, although the underlying mechanism in RV has not been determined. Therefore, this study is aimed at evaluating sirtuin-3 (SIRT3) modulation by RES in RV using a monocrotaline- (MC-) induced PAH rat model. Myocyte function was evaluated by confocal microscopy as cell contractility, calcium signaling, and mitochondrial membrane potential ( Δ Ψ m ); cell energetics was assessed by high-resolution respirometry, and western blot and immunoprecipitation evaluated posttranslational modifications. PAH significantly affects mitochondrial function in RV; PAH is prone to mitochondrial permeability transition pore (mPTP) opening, thus decreasing the mitochondrial membrane potential. The compromised cellular energetics affects cardiomyocyte function by decreasing sarco-endoplasmic reticulum Ca2+-ATPase (SERCA) activity and delaying myofilament unbinding, disrupting cell relaxation. RES partially protects mitochondrial integrity by deacetylating cyclophilin-D, a critical component of the mPTP, increasing SIRT3 expression and activity and preventing mPTP opening. The preserved energetic capability rescues cell relaxation by maintaining SERCA activity. Avoiding Ca2+ transient and cell contractility mismatch by preserving mitochondrial function describes, for the first time, impairment in excitation-contraction-energetics coupling in RV failure. These results highlight the importance of mitochondrial energetics and mPTP in PAH.

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Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

Zhong

Xiao

Xie

et al. 2023

MedComm

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Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on the backbones or amino acid side chains of proteins and expand the diversity of proteins, which provides the basis for the emergence of organismal complexity. To date, more than 650 types of protein modifications, such as the most well‐known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short‐chain and long‐chain acylation modifications, redox modifications, and irreversible modifications, have been described, and the inventory is still increasing. By changing the protein conformation, localization, activity, stability, charges, and interactions with other biomolecules, PTMs ultimately alter the phenotypes and biological processes of cells. The homeostasis of protein modifications is important to human health. Abnormal PTMs may cause changes in protein properties and loss of protein functions, which are closely related to the occurrence and development of various diseases. In this review, we systematically introduce the characteristics, regulatory mechanisms, and functions of various PTMs in health and diseases. In addition, the therapeutic prospects in various diseases by targeting PTMs and associated regulatory enzymes are also summarized. This work will deepen the understanding of protein modifications in health and diseases and promote the discovery of diagnostic and prognostic markers and drug targets for diseases.

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Mitochondrial Hyperacetylation in the Failing Hearts of Obese Patients Mediated Partly by a Reduction in SIRT3: The Involvement of the Mitochondrial Permeability Transition Pore

Abstract: This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Cited by 46 publications

References 47 publications

Role of oxidative metabolism in osseointegration during spinal fusion

Role of oxidative metabolism in osseointegration during spinal fusion

Resveratrol Prevents Right Ventricle Dysfunction, Calcium Mishandling, and Energetic Failure via SIRT3 Stimulation in Pulmonary Arterial Hypertension

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

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